A Single Arm, Open-label, Multi-centre, Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO3, a CAR T Cell Treatment Targeting CD19 and CD22 With Anti Programmed Cell Death Protein 1 (PD1) Antibody in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma
Phase: PHASE1
Conditions: Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Sponsor: Autolus Limited

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CLINICAL STUDY PROTOCOL 
A SINGLE-ARM, OPEN-LABEL, MULTI-CENTRE, PHASE I/II STUDY 
EVALUATING THE SAFETY AND CLINICAL ACTIVITY OF AUTO3, A CAR 
T CELL TREATMENT TARGETING CD19 AND CD22 WITH ANTI PD-1 
ANTIBODY IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE 
LARGE B CELL LYMPHOMA 
Short Study Title: 
Protocol Number: 
ALEXANDER 
AUTO3-DB1 
Study Products: 
AUTO3 for i.v. infusion; and pembrolizumab 
Development Phase: 
I/II 
Sponsor: 
Autolus Limited 
Forest House 
58 Wood Lane 
White City 
London, W12 7RZ 
United Kingdom (UK) 
Protocol Version: 
Version 10.0 
EudraCT Number: 
2016-004682-11 
Protocol Date: 
 06 May 2021 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
on Harmonisation), ethical principles that have their origin in 
the Declaration of Helsinki and all applicable national and local 
regulations.  
This protocol includes information and data that contain trade secrets and privileged or 
confidential information that is the property of the Sponsor (Autolus Limited). This information 
must not be made public without written permission from Autolus Limited. These restrictions 
on disclosure will apply equally to all future information supplied to you. This material may 
be disclosed to and used by your staff and associates as may be necessary to conduct the clinical 
study. 

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ADMINISTRATIVE AND CONTACT INFORMATION  
Sponsor: 
United Kingdom 
European Union 
Legal Representative 
United States of America 
Autolus Limited 
Autolus GmbH 
Autolus Inc 
Forest House 
58 Wood Lane 
White City 
London, W12 7RZ 
Arnulfpark 
Luise-Ullrich-Straße 20 
D-80636 Munich  
Germany 
805 King Farm Blvd.  
Suite 550  
Rockville, MD 20850 
 
Contact List 
The List of Service Providers for the study will be maintained separately by Autolus Limited 
and kept in the Trial Master File. 
Chief Investigator:  
 
 
 
 
 
Primary Medical Monitor 
 
 
 
  
 
 
Secondary Medical Monitor: 
     
 
     
 
     
 
     
 
  
     
  
  
  
Notification of SAEs: 
 
 
 
24-hour SAE Hotline: 
 
 
 
 
 
 

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SPONSOR SIGNATURE PAGE 
Study Title: A Single-arm, Open-label, Multi-centre, Phase I/II Study Evaluating the Safety 
and Clinical Activity of AUTO3, a CAR T Cell Treatment Targeting CD19 and CD22 with 
Anti PD-1 Antibody in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma. 
Short Study Title: 
ALEXANDER 
Protocol Number: 
AUTO3-DB1 
Version Number: 
10.0 
Version Date: 
06 May 2021 
I have read the protocol AUTO3-DB1 titled “A Single-arm, Open-label, Multi-centre, 
Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO3, a CAR T Cell 
Treatment Targeting CD19 and CD22 with Anti PD-1 Antibody in Patients with Relapsed or 
Refractory Diffuse Large B Cell Lymphoma” and confirm that, to the best of my knowledge, 
the protocol accurately describes the design and conduct of the study.  
 
 
 
This document has been electronically signed within the electronic data management system. 
Please refer to the last page of the document for the electronic signature. 
 
 
 
Signature  
 
 
 
Date 
(DD MMM YYYY) 

AUTOLUS LIMITED 
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Clinical Study Protocol  
 
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INVESTIGATOR SIGNATURE PAGE 
Study Title: A Single-arm, Open-label, Multi-centre, Phase I/II Study Evaluating the Safety 
and Clinical Activity of AUTO3, a CAR T Cell Treatment Targeting CD19 and CD22 with 
Anti PD-1 Antibody in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma. 
Short Study Title: 
ALEXANDER 
Protocol Number: 
AUTO3-DB1 
Version Number: 
10.0 
Version Date: 
06 May 2021 
I have read the protocol AUTO3-DB1 titled “A Single-arm, Open-label, Multi-centre, 
Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO3, a CAR T Cell 
Treatment Targeting CD19 and CD22 with Anti PD-1 Antibody in Patients with Relapsed or 
Refractory Diffuse Large B Cell Lymphoma”. By signing this protocol, I agree to conduct the 
clinical study, after approval by an Institutional Review Board or Independent Ethics 
Committee (as appropriate), in accordance with the protocol, the principles of the Declaration 
of Helsinki (2008), the standards of Good Clinical Practice (as defined by the International 
Council on Harmonisation) and applicable regulatory requirements.  
Changes to the protocol will only be implemented after written approval is received from 
Autolus Limited and the Institutional Review Board or Independent Ethics Committee (as 
appropriate), with the exception of medical emergencies. I will ensure that study staff fully 
understand and follow the protocol. 
 
 
 
Signature 
Name and address: 
 
Date  
(DD MMM YYYY) 

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PROTOCOL SYNOPSIS 
 
Title 
A Single-arm, Open-label, Multi-centre, Phase I/II Study Evaluating the Safety 
and Clinical Activity of AUTO3, a CAR T Cell Treatment Targeting CD19 and 
CD22 with Anti PD-1 Antibody in Patients with Relapsed or Refractory 
Diffuse Large B Cell Lymphoma. 
Short Title 
ALEXANDER 
Protocol 
Number 
AUTO3-DB1 
Sponsor 
Autolus Limited 
Phase 
I/II 
Study Product 
AUTO3, an advanced therapy investigational medicinal product (ATIMP), 
consisting of autologous enriched T cells retrovirally transduced to express 
two Chimeric Antigen Receptors (CARs), targeting cluster of differentiation 
(CD) 19 and/or CD22. 
Study 
Population 
Patients with confirmed diagnosis of diffuse large B cell lymphoma (DLBCL) 
and large B cell lymphoma subsets who have relapsed or refractory disease.  
Study Duration 
The study will take approximately 7 years from first patient enrolled until the 
end of the study. The end of the study is defined as the last patient last visit 
(LPLV) expected to be 36 months after the last patient has received AUTO3 
infusion or earlier, in the event of patient death or consent withdrawal. 
Overview 
A single-arm, open-label, multi-centre, Phase I/II dose escalation and 
expansion study to determine the safety and clinical activity of AUTO3 
administered intravenously (i.v.) with consolidation or pre-conditioning with 
anti-programmed cell death protein 1 (PD-1) antibody (pembrolizumab) in 
patients with relapsed or refractory DLBCL and large B cell lymphoma 
subsets. AUTO3 is an ATIMP consisting of autologous enriched T cells 
retrovirally transduced to express two CARs, targeting CD19 and/or CD22 on 
the same cell. AUTO3 cells express second generation CARs in which the 
CD19 CAR construct uses OX40-ζ endodomains and the CD22 CAR uses 
41BB-ζ endodomains. AUTO3 will be administered following 
lymphodepletion with fludarabine (FLU) and cyclophosphamide (CY). In 
addition, a limited duration of consolidation or pre-conditioning therapy with 
anti-PD-1 antibody (pembrolizumab) will be administered. 
This first in human study will assess the safety of AUTO3, determine the 
appropriate dose and dosing schedule for Phase II of the study, and evaluate the 
preliminary efficacy of the AUTO3 in patients with relapsed or refractory 
DLBCL and large B cell lymphoma subsets. 

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attend clinic visits for up to 36 months post-AUTO3 infusion (or less in case of 
withdrawal) for study-specific assessments including adverse event (AE) 
assessments, physical examination, and clinical laboratory and immunology 
tests. 
At the end of the study, or following early withdrawal from this study, all 
patients will be invited to enrol on a long-term follow-up study protocol 
(AUTO-LT1) and followed until death or withdrawal of consent for up to 15 
years following last treatment with AUTO3. 
 
 
  
Number of 
Patients 
Approximately to 171 patients in total are expected to be enrolled (consented) 
into Phase I and Phase II of the study and approximately 151 patients in total 
are anticipated to be treated with AUTO3 therapy. 
• 
Phase I: approximately 50 treated patients in total. Including 3 to 6 
patients per dose cohort following a rolling 6 dose escalation design, and 
approximately 12 patients at the RP2D/dose range, and 20 patients in the 
expansion cohort.  
• 
Phase II: up to 81 evaluable patients, using Simon’s 2-stage optimal 
design in Cohort 1; an additional 20 patients in Cohort 2 (a total of 
101 patients). 
Key Criteria for 
Eligibility 
Only patients whose leukapheresate sample has been successful in generating 
AUTO3 in adequate quantity and quality will be treated. The criteria for patient 
eligibility are summarised as follows:  
Inclusion Criteria:  
Patients must meet all the following criteria for study entry: 
1. Male or female, aged ≥18 years. 
2. Willing and able to give written, informed consent to the current study. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 
1. 
4. Histologically confirmed DLBCL and large B cell lymphoma) subsets, 
including: 
Phase I and Phase II Cohort 1: 
 

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a) DLBCL, not otherwise specified (NOS), per World Health 
Organisation classification and DLBCL with MYC and BCL2 and/or 
BCL6 rearrangements (double/triple hit).  
b) Transformed DLBCL from follicular lymphoma. 
c) High-grade B cell lymphoma with MYC expression (excluding 
Burkitt’s lymphoma). 
Phase I and Phase II Cohort 2: 
d) Transformed DLBCL from other indolent lymphomas (excluding 
Richter’s transformation). 
Primary mediastinal large B cell lymphoma. 
5. Chemotherapy-refractory disease, defined as one or more of the 
following: 
a) Stable disease (duration of stable disease must be ≤12 months) or 
progressive disease as best response to most recent chemotherapy 
containing regimen. Refractory disease after frontline 
chemo-immunotherapy is allowed. 
b) Disease progression or recurrence in ≤12 months of prior 
autologous haematopoietic stem cell transplantation (ASCT). 
OR 
6. Relapse after at least two lines of therapy or after ASCT. At a 
minimum: 
a) Patients must have received rituximab or another anti-CD20 
monoclonal antibody (unless Investigator determines that tumour is 
CD20-negative) and an anthracycline-containing chemotherapy 
regimen. 
b) Patients must have either failed ASCT, or be ineligible for or not 
consenting to ASCT. 
c) Patients with transformed DLBCL must have received at least one 
line of therapy after transformation to DLBCL. 
7. Positron emission tomography (PET)-positive disease per Lugano 
classification. 
8. For females of childbearing potential (defined as <24 months after last 
menstruation or not surgically sterile), a negative serum or urine 
pregnancy test must be documented at screening, prior to pre-
conditioning and confirmed before receiving the first dose of study 
treatment.  
For females who are not postmenopausal (<24 months of amenorrhea) or 
who are not surgically sterile (absence of ovaries and/or uterus), 
two methods of contraception comprising one highly effective method of 
contraception together with a barrier method must be used during the 
treatment period and for at least 12 months after the last dose of study 
treatment. They must agree not to donate eggs (ova, oocytes) for the 
purposes of assisted reproduction during the study and for 12 months after 
receiving the last dose of study drug (please refer to Appendix 3). 
9. For males, it must be agreed that two acceptable methods of 
contraception are used (one by the patient – usually a barrier method, 
and one highly effective method by the patient’s partner as defined in 
Appendix 3) during the treatment period and for at least 12 months 
after the last dose of study treatment and that sperm will not be donated 

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during the treatment period and for at least 12 months after the last 
dose of study treatment. 
10. Adequate renal, hepatic, pulmonary, and cardiac function defined as: 
a) Creatinine clearance ≥40 cc/min. 
b) Serum alanine aminotransferase/aspartate aminotransferase 
≤2.5 × upper limit of normal (ULN). 
c) Total bilirubin ≤1.5 × ULN, except in patients with Gilbert’s 
syndrome. 
d) Left ventricular ejection fraction (LVEF) ≥50% (by 
echocardiogram [ECHO] or multigated acquisition [MUGA]) 
unless the institutional lower limit of normal is lower.  
e) Baseline oxygen saturation >92% on room air and ≤Grade 1 
dyspnoea. 
11. Patient has adequate bone marrow function without requiring ongoing 
blood product or granulocyte-colony stimulating factor support and 
meets the following criteria: 
a) Absolute neutrophil count ≥1.0 × 109/L. 
b) Absolute lymphocyte count ≥0.3 × 109/L (at enrolment and prior to 
leukapheresis). 
c) Haemoglobin ≥80 g/L. 
d) Platelets ≥75 × 109/L. 
12. No contra-indications for leukapheresis. 
Exclusion Criteria:  
Patients meeting any of the following exclusion criteria must not be enrolled 
into the study: 
1. Prior allogeneic haematopoietic stem cell transplant. 
2. Females who are pregnant or lactating. 
3. History or presence of clinically relevant central nervous system (CNS) 
pathology such as epilepsy, paresis, aphasia, stroke within 3 months 
prior to enrolment, severe brain injuries, dementia, Parkinson’s disease, 
cerebellar disease, organic brain syndrome, uncontrolled mental illness, 
or psychosis. 
4. Patients with active CNS involvement by malignancy. Patients with 
history of CNS involvement with malignancy may be eligible if CNS 
disease has been effectively treated and provided treatment was at least 
4 weeks prior to enrolment (at least 8 weeks prior to AUTO3 infusion). 
5. Clinically significant, uncontrolled heart disease (New York Heart 
Association Class III or IV heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, sick-sinus syndrome, or 
electrocardiographic evidence of acute ischaemia or Grade 3 
conduction system abnormalities unless the patient has a pacemaker) or 
a recent (within 12 months) cardiac event. 
• 
Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial 
fibrillation are not excluded). 
• 
Evidence of pericardial effusion. 
6. Patients with a history (within 3 months) or evidence of pulmonary 
embolism requiring ongoing therapeutic anticoagulation at the time of 
pre-conditioning. 

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7. Patients with active gastrointestinal (GI) bleeding. 
8. Patients with any major surgical intervention in the last 3 months. 
9. Active bacterial, viral or fungal infection requiring systemic treatment. 
Active or latent hepatitis B infection or hepatitis C infection. Testing 
positive for human immunodeficiency virus, human T cell 
lymphotropic virus (HTLV1 and 2) or syphilis. 
10. History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, 
systemic lupus) resulting in end organ injury or requiring systemic 
immunosuppression/systemic disease modifying agents within the last 
24 months. 
11. Patients with a known history or prior diagnosis of optic neuritis or 
other immunologic or inflammatory disease affecting the CNS. 
12. Evidence of active pneumonitis on chest computed tomography (CT) 
scan at screening or history of drug-induced pneumonitis, idiopathic 
pulmonary fibrosis, organising pneumonia (e.g. bronchiolitis 
obliterans), or idiopathic pneumonitis. Prior radiation pneumonitis in 
the radiation field (fibrosis) is allowed (if >24 weeks since the event). 
13. History of other malignant neoplasms unless disease free for at least 
24 months (carcinoma in situ, non-melanoma skin cancer, breast or 
prostate cancer on hormonal therapy allowed). 
14. Prior treatment with PD-1, Programmed cell death ligand 1 (PD-L1), or 
cytotoxic T lymphocyte-associated protein 4 targeted therapy, or 
tumour necrosis factor (TNF) receptor superfamily agonists including 
CD134 (OX40), CD27, CD137 (41BB), and CD357 (glucocorticoid-
induced TNF receptor family-related protein) within 6 weeks prior to 
AUTO3 infusion (excluding study treatment with pembrolizumab on 
Day -1).  
15. Prior treatment with investigational or approved gene therapy or cell 
therapy products until a dose level has treated at least three patients and 
has been declared safe. 
16. Prior CD19 or CD22 targeted therapy.  
17. The following medications are excluded: 
• 
Steroids: Therapeutic doses of corticosteroids within 7 days of 
leukapheresis or 72 hours prior to AUTO3 administration. 
However, physiological replacement, topical, and inhaled steroids 
are permitted. 
• 
Immunosuppression: Immunosuppressive medication must be 
stopped ≥2 weeks prior to leukapheresis or AUTO3 infusion.  
• 
Cytotoxic chemotherapies within 2 weeks of AUTO3 infusion and 
1 week prior to leukapheresis (2 weeks for lymphodepleting 
chemotherapy). 
• 
Antibody therapy use including anti-CD20 therapy within 2 weeks 
prior to AUTO3 infusion, or 5 half-lives of the respective antibody, 
whichever is shorter. 
• 
Granulocyte-colony stimulating factor less than 10 days prior to 
leukapheresis. 
• 
Live vaccine ≤4 weeks prior to enrolment. 

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• 
Prophylactic intrathecal therapy: Methotrexate within 4 weeks and 
other intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to 
starting pre-conditioning chemotherapy. 
18. Prior limited radiation therapy (e.g. radiation to bone metastasis for 
pain control) within 4 weeks of AUTO3 infusion or chest/mediastinal 
radiation within 24 weeks of AUTO3 infusion. 
19. Research participants receiving any other investigational agents, or 
concurrent biological, chemotherapy, or radiation therapy. 
20. Known allergy to albumin, dimethyl sulphoxide, CY or FLU, 
pembrolizumab or tocilizumab. 
21. Any contraindications to receive anti-PD-1 antibody pembrolizumab 
will be excluded from cohorts requiring administration of 
pembrolizumab. 
22. Patients, who in the opinion of the Investigator, may not be able to 
understand or comply with the safety monitoring requirements of the 
study. 
23. Any other condition that in the Investigator’s opinion would make the 
patient unsuitable for the clinical trial. 
Phase I expansion cohort: 
24. Subjects who do not have caregiver support (in line with institutional 
outpatient transplant guidelines) for outpatient/ambulatory care setting. 
25. Subjects who are staying greater than 60 minutes (or whatever is 
permissible per institutional outpatient transplant guidelines) from the 
clinical trial site at the time of treatment. 
PATIENT ELIGIBILITY TO RECEIVE AUTO3: Patients meeting any of the 
following criteria must not initiate pre-conditioning or infusion with AUTO3 
(or pembrolizumab on Day 1) or- must have the AUTO3 infusion delayed until 
they no longer meet these criteria:  
1. Severe intercurrent infection.  
2. Requirement for supplementary oxygen or active pulmonary infiltrates. 
3. Clinical deterioration of organ function (renal and hepatic) exceeding 
the criteria set at study entry. 
 
Study Product 
Dose, Dosing 
Regimen, and 
Administration  
Eligible patients will receive a single dose i.v. infusion of AUTO3 following 
pre-conditioning treatment.  
The AUTO3 product contains both transduced (CD19/CD22 CAR-positive) 
and non-transduced T cells. The dose is expressed as the number of 
CD19/CD22 CAR-positive T cells.  
Starting dose will be 50 × 106 CD19/CD22 CAR-positive T cells administered 
as a single dose. The highest planned dose to be evaluated is 900 × 106 
CD19/CD22 CAR-positive T cells.  
All patients will be monitored for up to 10 days following AUTO3 
administration (inpatient or ambulatory care setting). 
Pre-
conditioning 
Treatment and 
Consolidation  
All patients will receive a pre-conditioning regimen using i.v. FLU followed by 
i.v. CY. FLU 30 mg/m2 will be given on Days -6, -5, -4, and -3 and CY 
500 mg/m2 will be given on Days -6 and -5. 
Regimen A will comprise 3 doses of pembrolizumab (200 mg i.v. on Days 14, 
35, and 56) as consolidation. 

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Regimen B will comprise 1 dose of pembrolizumab (200 mg i.v. on Day -1) 
during pre-conditioning. 
Safety Evaluation Safety will be assessed by physical examination, vital signs, clinical laboratory 
tests, electrocardiograms, AE and severe AE monitoring, performance status 
assessments and concomitant medication usage. The severity of AEs will be 
assessed using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (Version 5.0). Cytokine Release Syndrome (CRS) and 
neurological toxicity will be graded according to the American Society for 
Transplantation and Cellular Therapy/American Society for Blood and Marrow 
Transplantation (ASTCT/ASBMT) consensus grading (Lee et al. 2019). 
Efficacy 
Evaluation 
Efficacy will be evaluated as per Lugano Classification.  
Response evaluations will be assessed by PET scans, CT scans, magnetic 
resonance imaging (MRI) and physical examination. 
Efficacy assessments for Phase II will be performed by the Investigators and 
independent central radiology review. 
Biomarker 
Evaluation 
Biomarker evaluation will include the following: 
• 
Expansion and persistence of CD19/CD22 CAR-positive T cells as 
determined by polymerase chain reaction and/or flow cytometry. 
• 
Depletion of CD19 and/or CD22 cell compartment as determined by flow 
cytometry and/or immunohistochemistry on bone marrow. 
Special Study 
Procedures 
All patients will undergo an unstimulated leukapheresis for AUTO3 generation. 
Statistical 
Analysis 
Continuous data will be summarised using the mean, median, standard 
deviation, minimum and maximum, while frequency counts and percentages 
will be presented for discrete variables. Time-to-event endpoints will be 
summarised using the Kaplan-Meier method.  
Where appropriate, a 2-sided 95% confidence interval will be presented with 
the estimates. 
Data from all treated patients (Safety set) will be used for safety analyses and 
will be summarised by dose level. Efficacy analysis set (EAS) and other 
analysis sets will be defined for the efficacy analyses. 
Interim 
Analysis 
An end of Phase I analysis will be performed. The overall response rate will be 
calculated. If the upper limit of the 95% confidence interval is less than 30% 
for patients treated at the RP2D(s), the study will be stopped. If the upper limit 
of the 95% confidence interval is over 30%, the study will continue to the 
Phase II part of the study. 
In Phase II of the study, an interim analysis on response rates will be performed 
after 27 patients are treated in Cohort 1 and considered evaluable (12 weeks 
post-treatment of 27th evaluable patient). The study will be stopped in this first 
stage if no more than nine responses have been observed. If the response rate 
has exceeded interim analysis stopping criteria prior to 27 evaluable patients 
having been treated, then the study will continue to full recruitment without 
stopping. A formal interim analysis will still be performed based on the first 27 
evaluable patients. 
 
 

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6. 
Physical examination: Complete physical examination to be performed at screening including a complete neurological examination then focused examination as appropriate at following 
visits. 
7. 
Vital signs: Temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate and oxygen saturations will be performed. On Day 0 of any treatment phase, record vital signs 
immediately prior to AUTO3 infusion and every 30 minutes (±10 minutes) for 4 hours post-AUTO3 infusion, and thereafter monitored as per hospital policy but no less than once a day 
during hospital/ambulatory stay. During the Phase I expansion cohort, monitoring at a minimum every 2 to 3 days for 10 days. If clinically significant report as an AE as appropriate. Body 
surface area (BSA) to be recorded on Day -6.  
8. 
ECG: May be repeated when clinically indicated such as severe CRS. 
9. 
ECHO (preferred method) or MUGA: To be performed at screening and to be repeated if patient experiences CRS or if clinically indicated. Same method should be used throughout the 
study.  
10. 
Fresh (or archived) tumour tissue sample should be obtained where possible at screening (or at the most recent relapse), Day 14 (±7 days) and at disease progression. 
11. 
For those patients receiving a bridging chemotherapy regimen, the baseline PET/CT scans must be done after completion of bridging therapy and before pre-conditioning and AUTO3 
infusion. [18F]-FDG PET scan: If at 6 months the patient has a CMR on PET scan, CT scans alone may be used for future assessment time points, if clinically appropriate. If relapse occurs 
after CMR or disease progression is suspected (e.g. new or enlarging lesion(s) detected on CT scan), a PET scan is to be repeated to confirm relapse/progression. 
12. 
Bone marrow aspirate and biopsy: 6 mL (2 mL+ 4 mL) Bone marrow aspirate in ACD-A for evaluation of disease in marrow, biopsy is optional. Repeat aspirate/biopsy is required to 
confirm complete response if bone marrow involvement at baseline. Sample may also be used for biomarker evaluation. Samples will be sent to a central laboratory for analysis as detailed 
in the laboratory manual. 
13. 
Haematology: Full blood count: haemoglobin, red blood cell count, platelet count, white blood cell count with differential. During hospitalisation when this is performed daily as standard 
care, only results from the indicated time points will be recorded in the eCRF. Additional time points will be recorded if clinically appropriate or associated with AEs. Full blood count to 
be performed prior to chemotherapy on first day of pre-conditioning days and prior to AUTO3 infusion on Day 0 (or pembrolizumab on Day-1, whichever is first) of any treatment phase.  
14. 
Biochemistry: Sodium, phosphate, potassium, ALT, AST, urea, uric acid, creatinine, CPK, lactate dehydrogenase, total bilirubin, calcium, albumin, and results from the indicated time 
points will be recorded in the eCRF. Additional time points will be recorded if clinically appropriate or associated with AEs. All tests must be performed prior to AUTO3 infusion on 
Day 0. Glomerular filtration rate should be calculated at screening as per institutional preferred method. After Month 3 only clinically relevant assays will be performed.  
15. 
Coagulation: Prothrombin time, international normalised ratio, activated partial thromboplastin time, fibrinogen.  
16. 
Infectious disease screen: Human immunodeficiency virus, hepatitis B, hepatitis C, human T-lymphotropic virus-1, human T-lymphotropic virus-2, syphilis, (max 30 days before 
leukapheresis). Results must be available prior to leukapheresis. If required, an additional sample will be taken on the day of leukapheresis (or within 7 days of leukapheresis). 
17. 
Pregnancy test: Serum (β-Hcg) or urine pregnancy testing for women of childbearing potential.  
18. 
Blood for cytokines: Serum cytokine sample to be taken prior to pre-conditioning on Day -6. To be collected daily during cytokine release syndrome until it resolves or clinically indicated. 
During hospital stay, sample collection to be performed as per schedule of assessments (±2 days). Refer to laboratory manual for collection instructions. Additional optional samples may 
be collected between Day -3 and Day 0 if patient is hospitalised or in outpatient/ambulatory care. Based on emerging data, additional optional blood samples may be collected to assess 
the drug levels of FLU-CY prior to pre conditioning on Day-6 and approximately 1 hour or later after pre-conditioning on Day -6 and Day -3. 
19. 
AUTO3 persistence: 9 mL Lithium Heparin tube and 2.5 mL DNA PAXgene tube should be collected on visits as indicated, sent to central analysis as described in the lab manual. 
Additional samples may be collected if clinically appropriate. An optional sample will be collected at time of disease progression. Sample collection may be modified based on patient 
body weight. 
20. 
RCR: 5 mL blood in Lithium Heparin tubes will be taken on visits as indicated for cryopreservation of peripheral blood mononuclear cells and plasma in case RCR or integration site 
analysis is required and to central analysis as described in the lab manual. 
21. 
Blood for immunological and genomic profiling of CAR T cells: Blood collected in 2 × 10 mL Lithium Heparin tubes to be taken on visits as indicated for cryopreservation of peripheral 
blood mononuclear cells and plasma for immunological and genomic profiling of CAR T cells and other assays as developed. Samples may be collected at additional time points based on 
emerging data. 
22. 
Anti-PD-1 antibody (pembrolizumab) will be administered (according to the pembrolizumab dosing schedule the patient is assigned to) on Regimen A Day 14 (±3 days) and then every 3 
weeks for a total of 3 doses. However, administration may be delayed until any ongoing CRS or neurotoxicity has resolved in Regimen A. Patients will be monitored (inpatient or 
outpatient/ambulatory care setting) for 3 days following the first dose of Regimen A pembrolizumab on Day 14.  
23. 
Anti-PD-1 antibody (pembrolizumab) will be administered on Day -1 as part of the pre-conditioning treatment with FLU-CY (Regimen B) 

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Visits 
 
         Assessments 
EFFICACY & SAFETY FOLLOW-UP 
END OF 
STUDY*** 
 
M2 
±7d 
M3 
±7d 
M4 
±7d 
M6 
±7d 
M9 
±7d 
M12 
±7d 
M18 
±7d 
M24 
±7d 
q6 Months 
until EoS 
±4 weeks 
EoS / Early 
Withdrawal 
Cytokine Profile 
 
X 
 
 
 
 
 
 
 
 
AUTO3 persistence [15] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunogenicity [15]  
X 
 
Immunophenotyping of AUTO3 
[15] 
 
X 
 
X 
 
X 
X 
X 
 
 
Genomic profiling [16] 
 
X 
 
X 
 
X 
 
X 
 
 
RCR [17]  
 
X 
 
X 
 
X 
 
X 
Xq1y 
X 
Insertional Mutagenesis [18] 
 
X 
 
X 
 
X 
 
X 
Xq1y 
X 
Abbreviations: β-Hcg= β-human chorionic gonadotropin; ACD-A=anticoagulant citrate dextrose solution A; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; CAR=chimeric antigen receptor; CMR=complete metabolic response; CR=complete response; CSF=cerebrospinal fluid; CT=computed tomography; D=day; ECOG=Eastern 
Cooperative Oncology Group; ECHO=echocardiogram; eCRF=electronic case report form; EoS= End of Study; GFR=glomerular filtration rate; HTLV-1/-2=human T cell lymphotropic virus1/-
2; ICANS=immune effector cell-associated neurotoxicity syndrome; Ig=immunoglobulin; i.v.=intravenous; LDH=lactate dehydrogenase; M=month; MRI=magnetic resonance imaging; 
MUGA= multigated acquisition scan; NGS=next generation sequencing; PCR=polymerase chain reaction; PET=positron emission tomography; q1y=once per year; RCR=replication competent 
retrovirus. 
*** The end of the study (EoS) is defined as the LPLV expected to be 36 months after the last treated patient with AUTO3 or earlier in the event of patient death or consent withdrawal. 
1. 
Prior to Day -6 and after Month 6 only concomitant medications relevant to AUTO3 treatment or study related procedures will be collected. 
2. 
Survival Status: all enrolled patients will be followed up for survival. If a visit is skipped where survival status is required or if the timepoint does not align with a scheduled visit, the 
information can be obtained over the phone. 
3. 
Performance status: Performance status will be assessed by using ECOG. 
4. 
Physical examination: Complete physical examination to be performed at screening and Day -6 then focused examination as appropriate at following visits. 
5. 
Vital signs: Temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate and oxygen saturation will be performed. On dosing day, perform vital signs immediately prior 
to AUTO3 infusion and then hourly (±15 minutes) for 4 hours post infusion, and thereafter monitored no less than 2 to 3 days during hospital/ambulatory stay. Vital signs also to be 
performed if clinically indicated. Additional values considered as clinically significant abnormalities will be recorded as AEs. 
6. 
Haematology: Haemoglobin, platelet count, and white blood cell count with differential (neutrophils, monocytes and lymphocytes). This is performed daily during admission as standard 
care and results from the indicated time points will be recorded in the Electronic Case Report Form (eCRF). 

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7. 
Biochemistry: AST/ALT, alkaline phosphatase, LDH, total bilirubin, urea/blood urea nitrogen, creatinine, uric acid. GFR should be calculated at screening as per the institutional preferred 
method. The results from the indicated time points will be recorded in the eCRF. These tests are generally performed daily during admission as part of standard care. All tests must be 
performed prior to AUTO3 infusion on the dosing day. 
8. 
Coagulation: Prothrombin time, international normalised ratio, activated partial thromboplastin time, fibrinogen after baseline assessment may be repeated if patient experiences severe 
cytokine release syndrome. 
9. 
Pregnancy test: Serum (β-hCG) or urine pregnancy testing for women of childbearing potential. 
10. 
Adverse events: Adverse events will be collected on an ongoing basis throughout the study. After M6, all SAEs, AESI and ONLY non-serious AEs that are deemed related to AUTO3 
treatment or study related procedure will be collected. Please refer to Section 12.3 of the protocol for reporting requirements. 
11. 
Overall disease assessment: Once the patient has completed 24 months during the efficacy and safety follow-up, the overall disease assessment will be done by the Investigator reported 
outcome. 
12. 
Imaging: For those patients receiving a bridging chemotherapy regimen, the baseline PET/CT scans must be done after completion of bridging therapy and before pre-conditioning and 
AUTO3 infusion. [18F]-FDG PET scan: If at 6 months the patient has a CMR on PET scan, CT scans alone may be used for future assessment time points, if clinically appropriate. If 
relapse occurs after CMR or disease progression is suspected (e.g. new or enlarging lesion(s) detected on CT scan), a PET scan is to be repeated to confirm relapse/progression.   
13. 
Bone marrow aspirate: Bone marrow aspirate in ACD-A for evaluation of disease in marrow and biopsy are both optional at the time of screening.  If performed at screening and there is 
no evidence of disease, does not need to be repeated. If not performed at screening, then needs to be done to confirm CR.  Does not need to be performed if patients do not achieve CR. 
Assessment for disease involvement is done locally.  Sample with lymphoma involvement may also be used for biomarker evaluation.  
14. 
Tumour sample: Fresh (or archived) tumour tissue sample should be obtained where possible at screening (or at the most recent relapse), Day 15 (±7 days) and at disease progression. 
15. 
Biomarkers: Additional samples will be collected at relapse and may be collected in case of safety events or as clinically indicated. Please refer to the laboratory manual. The collection of 
AUTO3 persistence samples may stop when 2 consecutive samples are not detectable by PCR. In the event of neurotoxicity and CSF is obtained, CSF sample may also be used for AUTO3 
persistence.  Immunogenicity - assessment of anti-CAR antibodies or anti-CAR T-cell response from blood/serum samples will be done if clinically indicated. 
16. 
Genomic profiling: The collection of samples and the analysis performed are described in Section 9.3.3 of the protocol 
17. 
RCR Testing: If all results are negative during the first-year post first AUTO3 infusion, the subsequent samples will be collected and stored in case further follow-up analysis may be 
required.  After 24 months, the sample for RCR testing will be collected annually until the end of the study. 
18. 
Insertional Mutagenesis: Samples will be collected and stored for subsequent analysis as required. 
Note: If an assessment was performed as part of the patient’s routine clinical evaluation and not specifically for this study, it does not need to be repeated after signed informed consent has been 
obtained provided that the assessments fulfil the study requirements and are performed within the specified timeframe prior to the AUTO3 infusion. 
 
 

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4. 
Biomarkers: Additional samples will be collected at relapse and may be collected in case of safety events or as clinically indicated. Please refer to the laboratory manual. The collection of 
AUTO3 persistence samples may stop when 2 consecutive samples are not detectable by PCR. In the event of neurotoxicity and CSF is obtained, CSF sample may also be used for AUTO3 
persistence.  Assessment of Anti-CAR antibodies or anti-CAR T-cell response from blood/serum samples. 
5. 
RCR Testing: If all results are negative during the first-year post first AUTO3 infusion, the subsequent samples will be collected and stored in case further follow-up analysis may be 
required.  After 24 months, the sample for RCR testing will be collected annually until the end of the study. 
6. 
Insertional Mutagenesis: Samples will be collected and stored for subsequent analysis as required. 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................ 5 
SCHEDULE OF ASSESSMENTS: ...................................................................................... 13 
TABLE OF CONTENTS ...................................................................................................... 24 
LIST OF APPENDICES ....................................................................................................... 29 
LIST OF TABLES ................................................................................................................. 29 
LIST OF FIGURES ............................................................................................................... 30 
LIST OF ABBREVIATIONS ............................................................................................... 31 
1 
INTRODUCTION ......................................................................................................... 35 
1.1 
DIFFUSE LARGE B CELL LYMPHOMA INCLUDING SUB-TYPES ........... 35 
1.2 
CD19 AND CD22 AS TARGETS FOR THERAPY ............................................ 37 
1.3 
CLINICAL EXPERIENCE WITH CAR T THERAPIES IN DLBCL................. 37 
1.4 
PD-1/PD-L1 AXIS IN CAR T CELLS AND LYMPHOMA AND THE ROLE 
OF ANTI-PD-1 THERAPY .................................................................................. 39 
1.4.1 
CAR T Cell Exhaustion ..................................................................... 39 
1.4.2 
Role of PD-L1/PD-1 Axis on Cancer Immune Suppression .............. 39 
1.4.3 
Effect of PD-1/ PD-L1 Axis Blockade on CAR T Cell 
Immunotherapy in Lymphoma ........................................................... 40 
1.5 
DESCRIPTION OF AUTO3- CD19/CD22 CAR-POSITIVE T CELLS ............. 41 
1.6 
SUMMARY OF NONCLINICAL STUDIES ...................................................... 41 
1.6.1 
In Vitro and In Vivo Pharmacology ................................................... 41 
1.6.2 
Toxicology ......................................................................................... 43 
1.7 
SUMMARY OF CLINICAL STUDIES ............................................................... 43 
1.8 
OVERALL RATIONALE FOR THE STUDY .................................................... 45 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................... 46 
2.1 
PRIMARY OBJECTIVES AND ENDPOINTS ................................................... 46 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS ............................................. 46 
2.3 
EXPLORATORY OBJECTIVES ......................................................................... 47 
3 
STUDY DESIGN ........................................................................................................... 48 
3.1 
STUDY OVERVIEW ........................................................................................... 48 
3.2 
PHASE I - DOSE ESCALATION ........................................................................ 50 
3.3 
PLANNED DOSE LEVELS ................................................................................. 51 
3.4 
PHASE I – EXPANSION COHORT.................................................................... 53 
3.5 
PHASE II .............................................................................................................. 53 
3.6 
DOSE LIMITING TOXICITY ............................................................................. 53 
3.7 
SAFETY STOPPING CRITERIA FOR THE CLINICAL TRIAL ...................... 54 
3.8 
STUDY DURATION ........................................................................................... 55 
3.9 
EARLY STUDY TERMINATION ...................................................................... 55 
3.10 NUMBER OF PATIENTS.................................................................................... 55 

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4 
SCIENTIFIC RATIONALE FOR STUDY ................................................................ 57 
4.1 
DESIGN RATIONALE ........................................................................................ 57 
4.2 
POPULATION RATIONALE .............................................................................. 58 
4.3 
STARTING DOSE RATIONALE........................................................................ 59 
4.4 
RATIONALE FOR DOSING SCHEDULE ......................................................... 60 
4.5 
FLUDARABINE AND CYCLOPHOSPHAMIDE .............................................. 61 
4.6 
ANTI-PD-1 CONSOLIDATION / PRE-CONDITIONING RATIONALE ......... 62 
4.7 
BIOMARKER COLLECTION AND ASSESSMENT RATIONALE ................ 63 
5 
RISKS AND MITIGATION STRATEGY .................................................................. 65 
5.1 
LEUKAPHERESIS ............................................................................................... 65 
5.2 
FLU-CY PRE-CONDITIONING CHEMOTHERAPY ....................................... 65 
5.3 
AUTO3 INFUSION .............................................................................................. 66 
5.4 
ANTI-PD-1 (PEMBROLIZUMAB) (PRE-CONDITIONING OR 
CONSOLIDATION) THERAPY ......................................................................... 68 
5.5 
UNKNOWN LONG-TERM RISKS OF GENE THERAPY ............................... 70 
6 
PATIENT POPULATION ............................................................................................ 71 
6.1 
INCLUSION CRITERIA ...................................................................................... 71 
6.2 
EXCLUSION CRITERIA..................................................................................... 72 
7 
ATIMP: AUTO3 ............................................................................................................ 75 
7.1 
AUTO3 DESCRIPTION....................................................................................... 75 
7.2 
AUTO3 MANUFACTURING ............................................................................. 75 
7.3 
PACKAGING AND LABELLING ...................................................................... 75 
7.4 
SUPPLY AND STORAGE ................................................................................... 76 
7.5 
ACCOUNTABILITY AND DESTRUCTION ..................................................... 76 
8 
STUDY PROCEDURES AND TREATMENT .......................................................... 77 
8.1 
CONSENT, SCREENING AND REGISTRATION ............................................ 77 
8.2 
LEUKAPHERESIS ............................................................................................... 78 
8.3 
PRE-CONDITIONING CHEMOTHERAPY ....................................................... 79 
8.3.1 
Pre-conditioning Dose and Regimen ................................................. 79 
8.3.2 
Supply of Pembrolizumab .................................................................. 80 
8.3.3 
Supply of Fludarabine and Cyclophosphamide ................................. 80 
8.3.4 
Accountability of Fludarabine and Cyclophosphamide and 
Pembrolizumab .................................................................................. 81 
8.4 
AUTO3 TREATMENT AND PATIENT MONITORING .................................. 81 
8.4.1 
Assessment Prior to AUTO3 Infusion ............................................... 81 
8.4.2 
AUTO3 Administration ..................................................................... 81 
8.4.3 
Monitoring During and After Drug Administration........................... 82 
8.4.4 
Dose Delay ......................................................................................... 83 
8.4.5 
Interruption of Infusion ...................................................................... 83 
8.4.6 
Duration of Treatment ........................................................................ 84 

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8.4.7 
Re-treatment of Patients ..................................................................... 84 
8.5 
CONSOLIDATION THERAPY........................................................................... 85 
8.5.1 
Pembrolizumab Dose and Regimen ................................................... 85 
8.5.2 
Supply of Pembrolizumab .................................................................. 85 
8.5.3 
Accountability of Pembrolizumab ..................................................... 86 
8.6 
FOLLOW-UP PHASE .......................................................................................... 86 
8.6.1 
Efficacy and Safety Follow-up .......................................................... 86 
8.6.2 
Safety and Survival Follow-up .......................................................... 87 
8.7 
LONG-TERM FOLLOW-UP ............................................................................... 87 
9 
STUDY ASSESSMENTS .............................................................................................. 89 
9.1 
DEMOGRAPHIC AND BASELINE ASSESSMENTS....................................... 89 
9.1.2 
Demographic Data and Baseline Variables........................................ 89 
9.2 
SAFETY EVALUATIONS .................................................................................. 89 
9.2.1 
Adverse Events and Toxicity ............................................................. 89 
9.2.2 
Clinical Laboratory Tests ................................................................... 90 
9.2.3 
12-lead Electrocardiogram ................................................................. 90 
9.2.4 
Echocardiogram and Multigated Acquisition .................................... 91 
9.2.5 
Vital Signs .......................................................................................... 91 
9.2.6 
Physical Examination ......................................................................... 91 
9.2.7 
ECOG Performance Status ................................................................. 91 
9.3 
PHARMACODYNAMICS AND BIOMARKER EVALUATION ..................... 91 
9.3.1 
Evaluation of AUTO3 Persistence in Peripheral Blood and Bone 
Marrow ............................................................................................... 92 
9.3.2 
Evaluation of RCR in Peripheral Blood ............................................. 92 
9.3.3 
Insertional Mutagenesis ..................................................................... 92 
9.3.4 
B Cell Aplasia (Flow Cytometry) ...................................................... 92 
9.3.5 
Serum IgG Levels .............................................................................. 92 
9.3.6 
Immunogenicity Analysis .................................................................. 92 
9.3.7 
Exploratory Biomarker Assessments ................................................. 93 
9.4 
EFFICACY EVALUATION ................................................................................ 93 
9.4.1 
PET Scan ............................................................................................ 93 
9.4.2 
Bone Marrow Assessment ................................................................. 94 
9.4.3 
Physical Examination ......................................................................... 94 
9.4.4 
Efficacy Criteria ................................................................................. 95 
9.5 
BLOOD VOLUME COLLECTIONS .................................................................. 96 
10 
GUIDELINES FOR PREVENTION, MONITORING, AND MANAGEMENT 
OF ADVERSE EVENTS .............................................................................................. 97 
10.1 GENERAL SUPPORTIVE CARE GUIDELINES FOR PATIENTS 
RECEIVING CAR T CELL THERAPY .............................................................. 97 
10.2 PRE- AND POST-CAR T INFUSION SUPPORTIVE THERAPY .................... 99 
10.3 TREATMENT OF AUTO3 INFUSION-RELATED REACTIONS .................... 99 

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10.4 GRADING AND MANAGEMENT OF CYTOKINE RELEASE 
SYNDROME ...................................................................................................... 101 
10.5 MANAGEMENT MACROPHAGE ACTIVATION SYNDROME (MAS) ..... 106 
10.6 GRADING AND MANAGEMENT OF NEUROTOXICITY (ICANS) ........... 107 
10.7 MANAGEMENT OF TUMOUR LYSIS SYNDROME .................................... 112 
10.8 HYPOGAMMAGLOBULINEMIA AND B CELL APLASIA ......................... 113 
10.9 INFECTIOUS DISEASES .................................................................................. 113 
10.10 MANAGEMENT OF IMMUNE RELATED ADVERSE EVENTS DUE TO 
ON-TARGET BUT OFF-TUMOUR TOXICITY .............................................. 113 
10.11 MANAGEMENT OF PEMBROLIZUMAB RELATED IMMUNE 
TOXICITY .......................................................................................................... 114 
10.11.1 
Pneumonitis and Pulmonary AE ...................................................... 114 
10.11.2 
Diarrhoea/Colitis .............................................................................. 115 
10.11.3 
Type 1 diabetes mellitus................................................................... 115 
10.11.4 
Hypophysitis .................................................................................... 116 
10.11.5 
Hyperthyroidism or Hypothyroidism ............................................... 116 
10.11.6 
Hepatic Events ................................................................................. 116 
10.11.7 
Renal Failure or Nephritis ................................................................ 116 
10.11.8 
Rash and Pruritus ............................................................................. 117 
10.11.9 
Management of Infusion Reactions ................................................. 117 
11 
CONCOMITANT MEDICATIONS AND THERAPIES ........................................ 119 
11.1 BRIDGING THERAPY ...................................................................................... 119 
11.2 ALLOWED CONCOMITANT MEDICATIONS/THERAPIES ....................... 119 
11.3 PROHIBITED AND CAUTIONARY THERAPIES ......................................... 120 
11.4 OVER-DOSAGE ................................................................................................ 120 
11.5 DIETARY AND LIFESTYLE RESTRICTIONS .............................................. 120 
12 
SAFETY AND PHARMACOVIGILANCE ............................................................. 121 
12.1 DEFINITIONS .................................................................................................... 121 
12.1.1 
Definition of an Adverse Event........................................................ 121 
12.1.2 
Definition of an Adverse Reaction ................................................... 121 
12.1.3 
Definition of a Serious Adverse Event............................................. 121 
12.1.4 
Suspected Unexpected Serious Adverse Reactions ......................... 123 
12.1.5 
Adverse Events of Special Interest .................................................. 123 
12.1.6 
Disease Progression ......................................................................... 123 
12.2 ASSESSMENT OF ADVERSE EVENTS ......................................................... 123 
12.2.1 
Severity of Adverse Events .............................................................. 124 
12.2.2 
Relationship of AEs to Treatment .................................................... 124 
12.3 REPORTING PROCEDURES ........................................................................... 125 
12.3.1 
All Adverse Events .......................................................................... 125 
12.3.2 
Adverse Events Associated with Laboratory Values ....................... 127 
12.3.3 
Adverse Events Associated with Cytokine Release Syndrome ....... 127 

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12.3.4 
Adverse Events Associated with CAR T Neurotoxicity (ICANS) .. 127 
12.3.5 
Serious Adverse Events Reporting................................................... 128 
12.3.6 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Reporting .......................................................................................... 129 
12.3.7 
Adverse Events of Special Interests Reporting ................................ 129 
12.3.8 
Pregnancy Reporting and Management ........................................... 130 
12.3.9 
Overdose Reporting and Dosing Errors ........................................... 131 
13 
OVERSIGHT COMMITTEES .................................................................................. 132 
13.1 SAFETY EVALUATION COMMITTEE .......................................................... 132 
13.2 INDEPENDENT DATA MONITORING COMMITTEE ................................. 132 
14 
STATISTICS ............................................................................................................... 134 
14.1 SAMPLE SIZE ESTIMATION .......................................................................... 134 
14.2 DESCRIPTION OF ANALYSIS DATASETS .................................................. 134 
14.2.1 
Screened Set ..................................................................................... 134 
14.2.2 
Enrolled Set ...................................................................................... 134 
14.2.3 
Infused Set ........................................................................................ 135 
14.2.4 
Safety Set ......................................................................................... 135 
14.2.5 
Efficacy Analysis Set ....................................................................... 135 
14.3 STATISTICAL ANALYSES AND METHODS ............................................... 135 
14.3.1 
Primary Endpoints ............................................................................ 135 
14.3.2 
Secondary Endpoints ........................................................................ 136 
14.3.3 
Exploratory ....................................................................................... 138 
14.3.4 
Interim Analysis ............................................................................... 138 
15 
STUDY COMPLETION, DISCONTINUATION AND WITHDRAWAL OF 
PATIENTS ................................................................................................................... 140 
15.1 COMPLETION ................................................................................................... 140 
15.2 WITHDRAWAL FROM THE STUDY ............................................................. 140 
15.2.1 
Procedures for Handling Withdrawals ............................................. 140 
15.3 REPLACEMENT POLICY ................................................................................ 141 
16 
END OF TRIAL/TERMINATION ............................................................................ 142 
17 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 143 
17.1 ETHICS COMMITTEE REVIEW AND APPROVAL...................................... 143 
17.2 REGULATORY AUTHORITY REVIEW AND APPROVAL ......................... 143 
17.3 INVESTIGATOR RESPONSIBILITIES ........................................................... 143 
17.3.1 
Overall Responsibilities ................................................................... 143 
17.3.2 
Site Review ...................................................................................... 143 
17.3.3 
Informed Consent ............................................................................. 144 
17.3.4 
Delegation of Investigator Duties .................................................... 144 
17.3.5 
Communication with IEC/IRB ......................................................... 144 
17.3.6 
Confidentiality of Trial Documents and Patient Records ................ 145 

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17.4 LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE 
RESEARCH ........................................................................................................ 145 
18 
ADMINISTRATIVE REQUIREMENTS ................................................................. 146 
18.1 DATA QUALITY CONTROL AND ASSURANCE ........................................ 146 
18.1.1 
Compliance with the Protocol and Protocol Revisions .................... 146 
18.1.2 
Protocol Violations and Deviations ................................................. 146 
18.1.3 
Monitoring ....................................................................................... 147 
18.1.4 
Audits and Site Inspections .............................................................. 147 
18.2 DATA HANDLING AND RECORD KEEPING .............................................. 147 
18.2.1 
Data Management ............................................................................ 147 
18.2.2 
Study Documentation and Retention of Records ............................. 148 
18.3 CLINICAL TRIAL AGREEMENT, FINANCE, AND INSURANCE .............. 148 
19 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS.......... 150 
20 
REFERENCES ............................................................................................................ 151 
21 
APPENDICES ............................................................................................................. 163 
LIST OF APPENDICES 
Appendix 1:  Patient with NHL will be Evaluated using Response Criteria for Non-
Hodgkin Lymphoma for Documenting Disease Response ............................ 163 
Appendix 2: Eastern Cooperative Oncology Group Performance Status Score ................. 167 
Appendix 3:  Highly Effective Methods of Birth Control ................................................... 168 
LIST OF TABLES 
Table 1: 
Assessments from Screening to End of Treatment Phase ................................ 13 
Table 2: 
Efficacy and Safety Follow-up ......................................................................... 18 
Table 3: 
Safety and Survival Follow-up ......................................................................... 22 
Table 4: 
Primary Objectives and Endpoints for Phase I ................................................. 46 
Table 5: 
Primary Objectives and Endpoints for Phase II ............................................... 46 
Table 6: 
Secondary Objectives and Endpoints for Phase I and II .................................. 47 
Table 7: 
Rolling 6 Dose Escalation Decision Rules ....................................................... 51 
Table 8: 
Treatment Cohorts in Phase I Dose Escalation ................................................ 52 
Table 9: 
Leukapheresis – Risks and Mitigation Strategy ............................................... 65 
Table 10: 
Pre-conditioning Chemotherapy – Risks and Mitigation Strategy ................... 66 
Table 11: 
AUTO3 Infusion – Risks and Mitigation Strategy ........................................... 66 
Table 12: 
Anti-PD-1 AUTO3 Consolidation or Pre-conditioning Therapy – Risks and 
Mitigation Strategy (per SmPC) ....................................................................... 69 
Table 13: 
Infectious Disease Screening ........................................................................... 78 
Table 14: 
Clinical Laboratory Tests ................................................................................. 90 

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Table 15: 
General Supportive Care Guidelines for Patients Receiving CAR T Cell 
Therapy ............................................................................................................. 97 
Table 16: 
Pre- and Post-infusion Medications ................................................................. 99 
Table 17: 
Guidelines for the Management of Infusion-related Reactions ..................... 100 
Table 18: 
Severity Grading of Cytokine Release Syndrome (ASTCT/ASBMT CRS 
Consensus Grading and CTCAE Version 5.0) (Lee et al. 2019) ................... 102 
Table 19: 
Management of Cytokine Release Syndrome ................................................ 102 
Table 20: 
Pharmacologic Management of CRS ............................................................. 104 
Table 21:  
Assessment & Grading of ICANS ................................................................. 108 
Table 22:  
Immune Effector Cell-associated Encephalopathy (ICE) Scale .................... 109 
Table 23: 
Management of ICANS .................................................................................. 110 
Table 24:  
Recommendations for the Management of Status Epilepticus After CAR T 
Cell Therapy ................................................................................................... 111 
Table 25:  
Recommendation for Management of Raised Intracranial Pressure After 
CAR T Cell Therapy ...................................................................................... 112 
Table 26: 
Management and Follow-up of Pulmonary Adverse Events ......................... 114 
Table 27: 
Management and Follow-up of Immune-related GI AEs ............................... 115 
Table 28: 
Pembrolizumab Infusion Reaction Treatment Guidelines ............................. 117 
Table 29: 
Severity Grading of AEs Not Listed on the NCI CTCAE Grading System .. 124 
Table 30: 
Reporting Period for All AEs ......................................................................... 126 
LIST OF FIGURES 
Figure 1: 
Structure of the Proteins Expressed on the Surface of AUTO3 Cells .............. 41 
Figure 2: 
Study Design .................................................................................................... 48 
Figure 3: 
Overview of the Stages of the Study ................................................................ 49 
Figure 4: 
CRS Management Overview .......................................................................... 103 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event  
AESI 
Adverse events of special interest 
ALL 
Acute lymphoblastic leukaemia 
ASCT 
Autologous haematopoietic stem cell transplantation 
ASH 
American Society of Hematology 
ASTCT/ASBMT 
American Society for Transplantation and Cellular 
Therapy/American Society for Blood and Marrow Transplantation 
ATIMP 
Advanced therapy investigational medicinal product 
AUC 
Area under the curve 
BM 
Bone marrow 
BOR 
Best overall response 
CAR 
Chimeric antigen receptor 
CD3, -19, -20, -28, -134 
Cluster of differentiation 3, 19, 20, 28, 134 
CDISC 
Clinical Data Interchange Standards  
CI 
Confidence interval 
CMR 
Complete metabolic response 
CNS 
Central nervous system 
CR 
Complete response, complete remission 
CRS 
Cytokine release syndrome 
CSF 
Cerebrospinal fluid 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL019 
CD19 CAR with 41BB- endodomain 
CY 
Cyclophosphamide 
DFS 
Disease-free survival 
DLBCL 
Diffuse large B cell lymphoma 
DLT 
Dose limiting toxicity 
DMSO 
Dimethyl sulphoxide 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
EAS 
Efficacy analysis set 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 

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Abbreviation 
Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EU 
European Union 
EudraCT 
European Clinical Trials Database  
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FL 
Follicular lymphoma 
FLU 
Fludarabine 
FLU-CY 
Fludarabine and cyclophosphamide 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
G-CSF 
Granulocyte-colony stimulating factor 
HLH 
Haemophagocytic lymphohistiocytosis 
HTLV 
Human T cell lymphotropic virus 
HuCAR-19 
Human CD19 CAR 
IB 
Investigator’s Brochure 
ICANS 
Immune effector cell-associated neurotoxicity syndrome 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive care unit 
ID 
Identification  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee 
IFN 
Interferon 
Ig (A, M, G) 
Immunoglobulin (A, M, G) 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMPD 
Investigational Medicinal Product Dossier 
IND 
Investigational New Drug 
irAE 
Immune-related adverse event 
IRB 
Institutional review board 
i.v. 
Intravenous(ly) 

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Abbreviation 
Definition 
LPLV 
Last patient, last visit 
LVEF 
Left ventricular ejection fraction 
q1y 
Once per year 
MAD 
Maximum administered dose 
MAS 
Macrophage activation syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mesoCAR 
CAR T cells against mesothelin 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
NOS 
Not otherwise specified 
ORR 
Overall response rate 
OS 
Overall survival 
OX40 
Also known as tumour necrosis factor receptor superfamily 4 
(TNFRSF4) and cluster of differentiation 134 (CD134) 
PBMCs 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand 1 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PIS 
Patient information sheet 
PR 
Partial response 
PT 
Preferred term 
QP 
Qualified Person 
R-CHOP 
Rituximab cyclophosphamide, doxorubicin, vincristine, and 
prednisone  
RCR 
Replication competent retrovirus 
RP2D(s) 
Recommended Phase II dose(s) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SEC 
Safety Evaluation Committee 
scFv 
Single chain variable fragment 

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Abbreviation 
Definition 
SmPC 
Summary of Product Characteristics 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TLS 
Tumour lysis syndrome 
TNF 
Tumour necrosis factor 
UK 
United Kingdom 
ULN 
Upper limit of normal 
UPENN 
University of Pennsylvania 
USPI 
United States Prescribing Information 
 

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1 INTRODUCTION 
AUTO3 is an advanced therapy investigational medicinal product (ATIMP) consisting of 
autologous enriched T cells retrovirally transduced to express two Chimeric Antigen Receptors 
(CARs) targeting cluster of differentiation (CD) 19 and/or CD22 (herein referred to as 
CD19/CD22 CAR). AUTO3 cells express second generation CARs in which the CD19 CAR 
uses OX40-ζ endodomains and the CD22 CAR uses 41BB-ζ endodomains. Both CARs are 
delivered from a single retroviral vector during drug product manufacture. 
Since CD19 and CD22 both are pan B lymphocyte markers, AUTO3 can target B cell 
lymphoma such as diffuse large B cell lymphoma (DLBCL) and other lymphomas that express 
these antigens. In pre-clinical studies, AUTO3 efficiently lyses B cell lymphoma lines 
expressing both CD19 and CD22 or either antigen alone. The objectives of this Phase I/II 
first -in-human study (AUTO3-DB1) are to: (1) evaluate the safety profile, (2) establish (a) 
recommended Phase II dose(s) (RP2D[s]), and (3) in Phase II determine the preliminary 
anti-tumour activity of AUTO3 in patients with relapsed or refractory DLBCL and its defined 
subsets. AUTO3 will be administered following lymphodepletion with fludarabine (FLU) and 
cyclophosphamide (CY). A limited duration of consolidation or pre-conditioning with 
pembrolizumab, an antibody targeting the programmed cell death protein 1 (PD-1), will follow 
or precede AUTO3 infusion. 
A summary of the nonclinical characteristics of AUTO3 are described below in Section 1.5. 
For the most comprehensive nonclinical information, refer to the Investigator's Brochure (IB). 
Details regarding AUTO3 administration and laboratory procedures are provided in the Product 
Handling Manual and Lab Manual, respectively. 
1.1 
DIFFUSE LARGE B CELL LYMPHOMA INCLUDING SUB-TYPES 
Diffuse large B cell lymphoma is the most common aggressive lymphoid malignancy and 
accounts for 30% to 58% of newly diagnosed lymphoma cases. With standard 
chemoimmunotherapy, including rituximab and an anthracycline-containing regimen, 
approximately 67% of patients are alive without lymphoma with a median follow-up of 4 years. 
However, one-third of patients have disease that is either refractory to initial therapy or relapses 
after standard therapy. The 3-year progression-free survival (PFS) for patients who experience 
an early relapse after rituximab treatment is only 23% (Gisselbrecht et al. 2010). Standard of 
care for patients who relapse after, or are refractory to, first-line chemotherapy is salvage 
chemotherapy followed by high dose therapy and autologous haematopoietic stem cell 
transplantation (ASCT) (Philip et al. 1995) and has long-term disease-free survival (DFS) rates 
above 50% to 60% (Sauter et al. 2015). 
Prognosis for patients who relapse after ASCT or fail initial salvage is particularly poor. In 
patients with DLBCL that has progressed after ASCT, median overall survival (OS) is 
<10 months (Vose et al. 1992, Nagle et al. 2013). Among ASCT eligible patients, 50% cannot 
get ASCT due to inadequate response to high dose therapy. Prognosis of patients not eligible 
for high dose therapy and ASCT is poor. Among patients refractory to second-line 
chemotherapy, <50% of patients respond to third-line chemotherapy, and few experience 
long-term survival (Elstrom et al. 2010, Friedberg 2011, Moore et al. 2012). The median OS 
of patients requiring third-line treatment is 4.4 months (Van Den Neste et al. 2016). Patients 
with histologic transformation of follicular lymphoma (FL) or other indolent lymphomas 
to DLBCL have similar OS and PFS as de novo DLBCL when treated similarly with rituximab 
based chemoimmunotherapy (Guirguis et al. 2014), but those who are resistant to initial 

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therapy or who relapse following initial therapy, do poorly. When treated with salvage 
chemotherapy and ASCT, the responses and outcomes for transformed indolent lymphoma 
patients are poor and similar to those with de novo DLBCL (Kuruvilla et al. 2015, Sorigue et 
al. 2016). Interestingly, therapies inducing complete remission (CR) in aggressive 
non-Hodgkin’s lymphoma (NHL) such as DLBCL result in significantly improved OS (Van 
Den Neste et al. 2016). Therefore, more effective therapies that can induce CR in NHL subtypes 
are urgently required. 
CD19, a cell surface biomarker that is highly expressed on the surface of almost all B cell 
lymphomas, is an attractive target for therapeutic intervention. Successful results have been 
reported with blinatumomab, a bi-specific T cell engaging antibody targeting CD19, in NHL 
(Viardot et al. 2016). Immunotherapies with CAR T cells targeting CD19 antigen have also 
shown promising efficacy (Kochenderfer et al. 2015). A limitation of this single antigen 
therapeutic approach is tumour escape due to antigen downregulation, which has been well 
demonstrated in acute lymphoblastic leukaemia (ALL) (Lee et al. 2014, Maude et al. 2014, 
Topp et al. 2014, Shah et al. 2016, Turtle et al. 2016) and recently in lymphoma (Brudno and 
Kochenderfer 2016). Since CD22 is also selectively expressed on normal and malignant B cells 
(Polson et al. 2010), targeting both CD19 and CD22 simultaneously is likely to be more 
effective and prevent development of CD19 or CD22 negative tumour escape.  
Another observation with CD19 CAR therapy in DLBCL and other lymphomas is that partial 
responses (PR) are not durable and only 70% of CRs are durable, similar observation also noted 
with primary mediastinal B cell lymphoma and transformed FL (Neelapu et al. 2016). In 
addition, a quarter of DLBCL patients do not respond to CAR therapy. Therefore, approaches 
targeting reactive or de novo resistance to T cell therapy will likely improve CAR T cell therapy 
efficacy.  
Increase in programmed cell death ligand 1 (PD-L1) expression by tumour cells plays a crucial 
role in tumour’s adaptive resistance to the immune response and likely plays a role in de novo 
and acquired resistance to CAR immunotherapies. The PD-L1 mediates its anti-immune 
response through interaction with PD-1, which is typically expressed by T cells. The PD-L1 
protein is expressed on 10% to 30% of DLBCL tumours (Andorsky et al. 2011, Chen et al. 
2013, Rossille et al. 2014, Kiyasu et al. 2015, Dong et al. 2016) and the percentage of tumours 
expressing PD-L1 increases to ~50% in patients with refractory, treatment-resistant DLBCL 
(Vranic et al. 2016). Recently, a patient whose tumour was PD-L1 positive and had progressive 
disease after CD19 CAR T cell therapy was administered the anti-PD-1 antibody 
pembrolizumab on Day 26 following CAR T cell infusion which resulted in clinically 
significant anti-tumour response (Chong et al. 2016). Similar observations have been noted in 
ALL patients treated with blinatumomab (Kohnke et al. 2015, Feucht et al. 2016). Using an 
anti-PD-1 antibody, such as pembrolizumab, can reverse such immune inhibition and may also 
decrease PD-1-mediated CAR T cell exhaustion (Cherkassky et al. 2016). In addition to the 
baseline PD-L1 expression seen in patients with DLBCL, there is evidence that DLBCL can 
upregulate PD-L1 as a defence mechanism against CAR T cell attack (Neelapu et al. 2017) . 
Long-term follow-up from the ZUMA1 study of CD19 CAR in patients with NHL 
demonstrated that 62% (13/21) of available biopsies showed PD-L1 expression at progression.  
In this study, we will evaluate the safety of AUTO3 alone and with an anti-PD-1 antibody, 
pembrolizumab.  

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1.2 
CD19 AND CD22 AS TARGETS FOR THERAPY 
CD19 is a cell surface biomarker for lymphocytes that is present on most B cell malignancies, 
including B cell NHL and ALL. Its selective expression on the B cell lineage make it an 
excellent target for immunotherapy approaches avoiding toxicity to the non-lymphoid tissues. 
Clinical studies have shown that CAR T cells directed against CD19 are highly efficacious in 
treating relapsed/refractory B lineage ALL, with 70% to 90% of patients achieving CR (Davila 
et al. 2014, Lee et al. 2014, Maude et al. 2014, Turtle et al. 2016). However, not all patients 
respond and CD19-negative escape relapses have been observed (Lee et al. 2014, Maude et al. 
2014, Turtle et al. 2016), therefore, additional targets are needed. Like CD19, CD22 is a cell 
surface biomarker for B lymphocytes that is selectively expressed on normal B cells and most 
B cell malignancies, including >90% ALL (Shah et al. 2015), DLBCL, and various other NHL 
subtypes (Mason et al. 1987). 
Importantly, CD22 expression has been shown to be maintained in ALL that has lost CD19 
expression, making CD22 CAR T cells a potential combination or follow-on therapy after 
CD19 CAR T cell therapy. Recently CD19-negative tumour escape has also been reported in 
lymphoma (Brudno et al. 2016). Since CD19 and CD22 are cell surface markers for 
lymphocytes that are present on most B cell malignancies, a combination of two CARs 
targeting CD19 and CD22 is likely to be a promising therapeutic approach for B cell 
malignancies addressing the issue of antigen escape. 
1.3 
CLINICAL EXPERIENCE WITH CAR T THERAPIES IN DLBCL 
CD19 CAR T cell therapies for DLBCL have demonstrated efficacy in clinical trials (Brentjens 
et al. 2003, Cooper et al. 2003, Hoyos et al. 2010, Jensen et al. 2010, Kochenderfer et al. 2010, 
Porter et al. 2011, Savoldo et al. 2011, Kochenderfer et al. 2012). While the CD19 CAR 
construct used by each institution differs in several respects, including CAR design, T cell 
activation, transduction methods, and cell doses, the net observed effects remain consistent 
with regards to the safety and efficacy of CD19-targeted CAR T therapies. Data from some of 
the key CD19 CAR studies have been summarised in IB Section 2.4 and briefly below. 
National Cancer Institute (NCI) studies: One NCI study using a CD19 (CD28-ζ 
endodomain) 
CAR 
reported 
CR 
in 
four 
of 
seven 
evaluable 
patients 
with 
chemotherapy-refractory DLBCL; three of these four CRs were ongoing, with durations 
ranging from 9 to 22 months at the time of the report (Kochenderfer et al. 2015). In another 
study, with a fully human CD19 CAR (HuCAR-19) in lymphoma, 86% objective response rate 
was observed in the nine patients treated. Three patients experienced Grade 3 cytokine release 
syndrome (CRS) and one experienced significant neurological toxicity (encephalopathy); 
however, all toxicities resolved fully in all patients. Interestingly, the authors reported, for the 
first time in lymphoma, a patient with complete loss of CD19 expression by lymphoma cells 
after two HuCAR-19 T cell infusions, which was associated with lymphoma progression 
(Brudno et al. 2016). 
University of Pennsylvania (UPENN) studies: In a study in adults with relapsed/refractory 
NHL with a CD19 CAR with 41BB- endodomain (CTL019) following Investigators’ choice 
of lymphodepleting chemotherapy. Eighteen of 28 evaluable patients achieved objective 
response. Six of 14 patients with DLBCL and ten of 14 patients with FL achieved a CR 
(Schuster et al. 2017).  

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Another study with CTL019 in DLBCL reported at the American Society of Hematology 
(ASH) 2016 meeting, among the 13 patients that were evaluable for response at 3 months 
post-CTL019, overall response rate (ORR) was 52%. Complete response rate at 3 months was 
38%. To date, no patient achieving CR has relapsed. At median follow-up (23.3 months for 
responding patients), 85.7% (95% CI: range 33.7% to 97.9%) maintained response (Schuster 
et al. 2016). This study was updated and published in the New England Journal of Medicine in 
2019 and showed an ORR of 52% and CR of 40% in 93 patients who received infusion 
(Schuster et al. 2019). 
Juno Therapeutics studies: A study in NHL with a CD19 CAR with 41BB- endodomains 
(JCAR017) was reported at the ASH meeting in 2016. In the DLBCL subgroup, overall 
response rates were 82% (nine of 11 patients), CR rate was 73% (eight of 11 patients), and PR 
rate of 9% (one of 11 patients) and 18% (two of 11 patients) had progressive disease at the time 
of post-treatment assessment on Day 29. One DLBCL patient in CR had a parenchymal brain 
lesion in the right temporal lobe that also completely resolved. Of note, this patient had no CRS 
or neurotoxicity (NT) associated with JCAR017 treatment. Three patients had low grade CRS 
(21%, two Grade 1; one Grade 2) and none required treatment with tocilizumab. Two of the 
14 treated patients (14%) had NT: one Grade 4 encephalopathy and one Grade 4 seizure. Two 
deaths were seen in the DLBCL group which were due to disease progression (Abramson et al. 
2016). At a subsequent investor update at the 35th Annual J.P. Morgan Healthcare Conference 
on 10 January 2017, it was reported that at 1 month, the CR rate was 60% (12 of 20 patients) 
and decreased to 42% (eight of 20 patients) at 3 months. Overall, the study reported a durability 
rate of 66% for CRs at 3 months, similar to the durability rate reported with Kite’s axicabtagene 
ciloleucel in a similar patient population (Neelapu et al. 2016). 
Kite Pharma studies: The ZUMA-1 study in DLBCL with axicabtagene ciloleucel, was the 
basis of approval of this product by the Food and Drug Administration (FDA) in October 2017. 
Of the 101 patients treated, the ORR was 82% and median time to response was 0.9 months, 
with 54% of patients achieving a CR. Response durations were longer in patients who achieved 
CR. Forty percent of the patients continue to be in CR with a median follow-up of 15.4 months 
(Neelapu et al. 2017). 
Cytokine release syndrome was reported in 94% of the patients, most were mild, with 
13% being ≥Grade 3. Neurotoxicity occurred in 87% of patients, Grade 3 or higher in 31% of 
patients. Most NT (98%) occurred within the first 8 weeks of infusion (YESCARTA 
Prescribing Information 2017). 
Safety: The major toxicities observed after CD19 CAR-positive T cell transfusion are B cell 
depletion, CRS and NT. B cell aplasia arises because of the expression of CD19 or CD22 on 
all cells committed to the B lineage, therefore this population is eliminated in the presence of 
effective CD19- or CD22-reactive CAR T cells. The duration of B cell aplasia is a useful 
surrogate of persistence of CAR T cells and depends on the CAR construct employed. 
CD19/CD22 CARs employing both an OX40 and a 41BB domain may mediate B cell aplasia 
for durations similar to those seen with 41BB containing CD19 CARs i.e. up to 24 months or 
longer (Grupp et al. 2014), whereas durations of 1 to 3 months are more likely following 
therapy with CD28-containing CAR T cells (Davila et al. 2014, Lee et al. 2014). Persistent 
B cell aplasia could result in increased risk of infection; however, long-term immunoglobulin 
(Ig) replacement can mitigate infectious complications. Management of CRS has significantly 
improved with use of guidelines and early use of tocilizumab, but management of NT still 
needs further improvement. However, close monitoring, use of appropriate doses and use of 
steroids have improved the management of NT (Brudno and Kochenderfer 2016). 

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1.4 
PD-1/PD-L1 AXIS IN CAR T CELLS AND LYMPHOMA AND THE 
ROLE OF ANTI-PD-1 THERAPY 
1.4.1 
CAR T Cell Exhaustion 
It is well accepted that the anti-tumour efficacy of adoptively-transferred T cells requires 
efficient expansion and persistence in vivo (Kowolik et al. 2006). Cells expressing CARs can 
show limited expansion, persistence, and anti-tumour efficacy. T cell exhaustion is a major 
factor limiting anti-viral and anti-tumour responses in the setting of chronic antigen exposure 
(Ahmadzadeh et al. 2009, Kao et al. 2011). Exhausted T cells have low proliferative and 
cytokine producing capacities, high rates of apoptosis, and express high levels of inhibitory 
receptors such as PD-1, TIM-3, and LAG-3 (Virgin et al. 2009, Kao et al. 2011). The 
phenomenon of CAR T cell exhaustion, both functionally and in actual numbers, is well 
described in pre-clinical literature. 
In pre-clinical studies, overexpression of PD-1 in CAR T cells upon antigen stimulation is often 
observed and this can lead to an exhausted or hypofunctional phenotype (John et al. 2013, 
Moon et al. 2014, Gargett et al. 2016). In an anti-GD2 CAR T model, repeated antigen 
stimulations lead to PD-1 overexpression, reduced cytokine production by CAR T cells and 
activation induced cell death. Repeated antigen stimulation also reduced the number of viable 
GD2 CAR T cells. Administration of pembrolizumab, an anti-PD-1 antibody, restored cytokine 
production, viability of CAR T cells, and enhanced tumour killing (Gargett et al. 2016). In an 
anti-Her2 CAR T model, antigen stimulation led to overexpression of PD-1 on Her2 CAR T 
and administration of an anti-PD-1 antibody increased tumour killing by Her2 CAR T (John et 
al. 2013). The significance of PD-1 expression and CAR T cell hypofunction was further 
demonstrated in another pre-clinical model involving CAR T cells against mesothelin 
(mesoCAR). Stimulated mesoCAR T cells exhibited elevated PD-1 expression, reduced 
cytokine production, and reduced tumour killing. Administration of PD-L1 inhibitors restored 
cytokine production and tumour killing (Moon et al. 2014). 
Clinical examples of PD-1 upregulation have also been observed in CAR T cells isolated from 
patients. Kochenderfer et al showed that PD-1 expression on CD19 CD4+ CAR T cells 
increased in 8/11 DLBCL patients treated with CD19 directed CAR T cells (Kochenderfer et 
al. 2015). In patients with B lymphoblastic leukaemia treated with tisagenlecleucel, it has also 
been postulated that CD19-positive relapses are largely due to early CAR T cell loss (Li et al. 
2018). T cell exhaustion or activation-induced CAR T cell death has been suspected to 
contribute to poor persistence of CAR T cells, and inhibiting the PD-1/PD-L1 checkpoint axis 
may decrease T cell exhaustion, thereby improving CAR T cell function and persistence (Li et 
al. 2018).  
1.4.2 
Role of PD-L1/PD-1 Axis on Cancer Immune Suppression 
Programmed cell death ligands 1 and 2 (PD-L1 and PD-L2) are expressed on tumour cells in 
numerous cancers, including haematological malignancies such as myeloma, NHL and 
Hodgkin’s lymphoma (Okazaki and Honjo 2007, Andorsky et al. 2011, Chen et al. 2013, 
Atanackovic et al. 2014, Kiyasu et al. 2015). Increased PD-L1 expression by tumour cells is a 
crucial part of the tumour’s adaptive resistance to the immune response and likely plays a role 
in CAR immunotherapies as well. PD-L1 expression results in suppression of tumour immunity 
through a number of different mechanisms including induction of T cell apoptosis, T cell 
anergy and functional exhaustion, and interleukin (IL)-10 production (Chen and Han 2015). 

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Importantly, PD-L1 acts as a molecular shield on tumour cells, as binding of PD-1 on cytotoxic 
T cells to PD-L1 on tumour cells inhibits the T cells’ cytolytic activity (Chen and Han 2015)  
1.4.2.1 
PD-L1 Expression in DLBCL De Novo 
In DLBCL, 10% to 30% of tumours express PD-L1 (Andorsky et al. 2011, Chen et al. 2013, 
Rossille et al. 2014, Kiyasu et al. 2015, Dong et al. 2016, Menter et al.). PD-L1 is expressed 
on both select DLBCL tumour cells (11%) and on tumour-infiltrating non-malignant cells 
(15.3%) (Kiyasu et al. 2015). The percentage of tumours expressing PD-L1 increases to 
approximately 50% in patients with refractory, treatment-resistant DLBCL (Vranic et al. 2016). 
PD-L1 expression in DLBCL has been reported to have prognostic value (Kiyasu et al. 2015, 
Dong et al. 2016) and is an independent indicator of poor prognosis. Although PD-L1 is 
associated with a poor prognosis, blockade of the PD-1/PD-L1 axis in DLBCL has not 
translated into an effective therapy. In a large Phase II trial in patients with relapsed/refractory 
DLBCL, nivolumab only resulted in an ORR of 10% in transplant-eligible patients and 3% in 
transplant-ineligible patients (Ansell et al. 2019). Thus, it has been conclusively demonstrated 
that PD-1/PD-L1 inhibitors essentially have no activity in patients with relapsed/refractory 
DLBCL.  
1.4.2.2 
Impact of CAR T Cell Immunotherapy on PD-L1 Expression in DLBCL 
In addition to the baseline PD-L1 expression seen in a quarter of DLBCL patients, there is 
evidence that other tumour cells also use PD-L1 checkpoint upregulation as a defence 
mechanism against CAR T cell attack. This has also been reported in a CD19-CAR T cell 
(axicabtagene ciloleucel) trial in DLBCL (ZUMA-1 study; (NCT02348216 2015)). In the 
ZUMA-1 study, gene expression profile comparisons of pre- and post-axicabtagene ciloleucel 
treatment biopsies showed profound changes in gene expression within the tumour 
environment after infusion, including immune checkpoints PD-L1 and LAG3 upregulation 
(Galon et al. 2017). Post-progression biopsies were available in 21 patients of whom 62% had 
PD-L1 expression at progression (Neelapu et al. 2017). 
1.4.3 
Effect of PD-1/ PD-L1 Axis Blockade on CAR T Cell Immunotherapy in 
Lymphoma 
This expression of PD-L1 on DLBCL cells and activation-dependent expression of PD-1 on 
CAR T cells after infusion has led to the hypothesis that PD-1 pathway blockade may augment 
the activity of CAR T therapy and result in improved clinical outcomes in DLBCL. Combining 
CAR T cell therapy with immune checkpoint blockade therapy targeting the PD-1/PD-L1 
interaction could thus improve efficacy and overcome resistance following engineered T cell 
therapy for cancer patients in general and for DLBCL more specifically. Multiple clinical trials 
investigating the combination of CD19-specific CAR T cells and PD-1 or PD-L1 blockade are 
ongoing (Yoon et al. 2018). Notably, the most clinically advanced CD19 CAR T therapies, 
axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel (JCAR017) are now 
being investigated in combination with an anti-PD-1/PD-L1 antibody (refer to Section 4.6). 
The totality of data from these studies suggests that the combination of CD19 CAR T cells with 
PD-1/PD-L1 antibodies is well tolerated and safety is comparable to that of CD19 CAR T cells 
alone; specifically, no worsening of CRS or NT has been observed. With the administration of 
PD-1/PD-L1 antibodies the CAR T cells may have better expansion and persistence thus 
possibly leading to deeper and more durable responses. 

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1.5 
DESCRIPTION OF AUTO3- CD19/CD22 CAR-POSITIVE T CELLS 
AUTO3 is a novel cellular gene therapy, consisting of autologous patient T cells, genetically 
modified to express two CARs targeting CD19 and CD22 from a single construct. The active 
substance is the genetically modified T cells, named CD19/CD22 CAR-positive T cells. To 
generate AUTO3, autologous T cells are isolated, activated and transduced to express both 
CD19 and CD22 CARs on the same cell (Figure 1), expanded and frozen down. The 
CD19/CD22 CAR construct utilises humanised forms of the murine anti-CD19 antibody HD37 
and the murine anti-CD22 antibody LT22 converted into a single chain variable fragment 
(scFv) format. The protein structure of each of the CD19 and CD22 CARs consists of the 
binding domains (scFv) followed by a spacer derived from either the dimeric human CD8a for 
the CD19 CAR or a pentameric coiled-coil structure from human collagen oligomeric matrix 
protein for the CD22 CAR. Both CARs contain a human tyrosinase-related protein-1 (Tyrp-1) 
transmembrane domain. In a second-generation format, the CD19 CAR construct uses OX40-ζ 
endodomains and the CD22 CAR uses 41BB-ζ endodomains. 
Figure 1: 
Structure of the Proteins Expressed on the Surface of AUTO3 Cells 
 
The CD19 CAR and CD22 CAR are type I transmembrane proteins. The anti-CD19 CAR is shown on the left. Humanised 
HD37 derived scFv recognises CD19 at the extreme amino-terminus, and it is connected to the CD8 stalk, transmembrane 
and anchor. The intracellular endodomains are composed of co-stimulatory OX40 and CD3- (TCRz). The anti-CD22 CAR 
is shown on the right. Humanised LT22 derived scFv recognises CD22 at the extreme amino-terminus and is connected to 
the pentameric α-helical coiled-coil multimer-forming domain of cartilage oligomeric matrix protein (COMP) and 
transmembrane anchor. The intracellular endodomains are composed from 41BB-ζ and CD3- (TCRz). 
1.6 
SUMMARY OF NONCLINICAL STUDIES 
Further details regarding AUTO3 can be found in the IB. 
1.6.1 
In Vitro and In Vivo Pharmacology 
Surface plasmon resonance was used to evaluate binding kinetics between the humanised Fc 
binding domains of CD19-CAR (HD37) and CD22-CAR (LT22) and their respective ligands. 

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Binding affinities of 1.09 and 32 nM were measured between CD19 and CD22 respectively. 
The kinetic binding parameters were consistent with the parent mouse-derived binding domains 
and those of other scFv of CAR T cells currently being clinically tested. 
The functionality of the CD19/CD22 CAR construct was compared to that of individual CD19 
and CD22 CAR constructs. Target cells used were SupT1 cells (a human T lymphoblast cell 
line) naturally negative for CD19 and CD22 (negative control); SupT1 cells engineered to 
express either CD19 or CD22 or Raji cells (a human B cell line) naturally expressing both 
CD19 and CD22. The specificity of the CD19 CAR was confirmed by restricted cytotoxicity 
toward the CD19-positive SupT1 cells and Raji cells only. Likewise, co-cultures with CD22 
CAR showed restricted cytotoxicity to CD22+ SupT1 cells and Raji cells only. Similar levels 
of cytotoxicity were observed using the CD19/CD22 CAR construct and the CD19 and CD22 
single CAR constructs, demonstrating no loss of function of the CD19 and CD22 CARs when 
expressed on the same construct. Similar results were observed when measuring interferon 
(IFN)-γ, tumour necrosis factor (TNF)-α and IL-2 secretion and proliferative responses after 
co-culture of CD19-positive, CD22-positive and dual-positive target cells with CAR T cells 
confirming the functionality of the CD19 and CD22 CARs.  
The ability of CD19/CD22 CAR-positive T cells to kill CD19-escape variants was confirmed 
in co-cultures using mixtures of Raji cells and CD19-knockout Raji cells. Similar levels of 
cytotoxicity were detected against the mixed culture as with wild-type Raji cells only, 
demonstrating that T cells transduced with the CD19/CD22 CAR constructs can effectively 
destroy CD19-negative, CD22-positive targets. Likewise, CD19/CD22 CAR-positive T cells 
could secrete IFN-γ and IL-2 and proliferate in response to targets expressing either antigen. 
These data demonstrate that CD19/CD22 CAR-positive T cells specifically recognise target 
cells expressing both CD19 and CD22 antigens and should effectively delete CD19-negative 
escape variants. CD19/CD22 CAR-positive T cells were tested in an in vivo tumour xenograft 
mouse model using non-obese diabetic severe combined immunodeficiency gamma mice. 
Mice received wild-type Raji cells i.v. and 3 days later, mice were stratified between treatment 
groups to equalise tumour burden. Treated animals were given i.v. CD19/CD22 CAR-positive 
T cells or mock-transduced T cells. Assessment of disease burden 16 days after tumour cell 
injection demonstrated significant retardation of tumour growth in all mice receiving 
CD19/CD22 CAR T cells compared to the control group. Analysis of the bone marrow (BM) 
and spleens of mice treated with CD19/CD22 CAR-positive T cells reveal complete abrogation 
of tumour cells (P<0.01) and expansion of CAR T cells (P<0.01), compared to controls. 
To determine if treatment with an anti-PD-1 antibody may affect CAR T cell performance, the 
effect of addition of an anti-PD antibody to co-cultures of CD19/CD22 CAR T cell and Raji 
tumour cells was also assessed. No differences in CAR T cell cytotoxicity, proliferation, or 
cytokine production were observed in cultures containing the anti-PD-1 antibody compared to 
activity of CAR T cells alone. In a second study, an in vitro system was established to mimic 
the potential exhausted cellular phenotypes observed during tumour-mediated downregulation 
of T cell responses. To this end, CAR T cells were pre-activated in order to increase the surface 
expression of PD-1 and target cells were transduced to constitutively express PD-L1. Co-
culture of pre-stimulated CD19/CD22 CAR T cells with PD-L1-positive target cells showed 
decreased cytotoxicity and cytokine production compared to co-culture with wild-type target 
cells. However, addition of anti-PD-1 to these co-cultures restored cytotoxicity and cytokine 
production to levels observed for co-cultures with wild-type target cells. These data suggest 
that co-treatment with an anti-PD-1 antibody could potentially enhance CD19/CD22 CAR T 
cell functionality in the context of tumour-mediated immunosuppression. Anti-PD-1 antibodies 

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such as pembrolizumab can therefore overcome CAR T cell exhaustion, and this serves as a 
rationale for pembrolizumab to be incorporated into the pre-conditioning regimen of this 
current study. For further details, see the IB.  
1.6.2 
Toxicology 
A Good Laboratory Practice tissue cross-reactivity study was conducted to characterise the 
potential cross reactivity of humanised HD37 (CD19-CAR) and LT22 (CD22-CAR) binders 
by immunohistochemistry (IHC). A panel of 42 different frozen human tissues and blood 
smears (3 donors per tissue) was evaluated. The optimised IHC assay was validated in an initial 
study and two different concentrations of HD37 (0.1 and 0.5 µg/mL) and LT22 (0.2 and 
1 µg/mL) were investigated. 
LT22 and HD37 binders elicited prominent membrane (with variable cytoplasmic) staining in 
scattered mononuclear cells, within lymphoid aggregates/infiltrates and/or within 
inflammatory foci in several tissues, including adrenal gland, oesophagus, liver, lung, ovary, 
oviduct, pancreas, prostate, parathyroid gland, parotid salivary gland, ureter, urinary bladder, 
uterus cervix and endometrium.  
Cell morphology and distribution were generally consistent with lymphocytes. HD37 binders 
also produced minimal to marked membrane/cytoplasmic staining in numerous mononuclear 
cells within the lamina propria throughout the digestive tract, from stomach to rectum. This 
staining pattern was not seen with the LT22 binder. The labelled cells may represent 
lymphocytes but other cell types such as dendritic cells and/or macrophages cannot be ruled 
out. 
No positive staining was observed in the brain (cerebellum and cerebral cortex), spinal cord, 
eye, heart, blood vessel, kidney, nerve, pituitary gland, placenta, skeletal muscle, skin, testes, 
and thyroid gland. 
In summary, humanised LT22 and HD37 binders produced prominent membrane (with 
variable cytoplasmic) staining in follicular compartments of lymphoid organs and in scattered 
mononuclear cells, within lymphoid aggregates/infiltrates and/or within inflammatory foci in 
many other tissues. Based on morphology and distribution, the targeted cells were most 
consistent with lymphocytes. Importantly, binding of both antibodies was restricted to 
haemopoietic tissues and lymphoid organs with no binding to other tissues, limiting the 
likelihood of “on target, off tumour” toxicity. 
1.7 
SUMMARY OF CLINICAL STUDIES 
The current study is the first in human study of this ATIMP, AUTO3, in the DLBCL patient 
population and the study has been initiated in the UK and USA.  
As of 30 October 2020, 49 patients had been treated with AUTO3. The median (range) age was 
59 (27 to 83) years and median number of prior therapies was 3 (1 to 11). Overall, 69% of 
patients had DLBCL NOS, 22% had Transformed/Indolent Lymphoma, and 6% of patients had 
High Grade B Cell Lymphoma and 2% had Primary Mediastinal Large B Cell Lymphoma. No 
DLT was observed during dose escalation. Treatment emergent AEs that occurred in > 20% of 
patients were neutropenia (59%), anaemia (51%), thrombocytopenia (47%), CRS (35%), 
pyrexia (27%), and fatigue (25%). Treatment emergent AEs ≥Grade 3 that occurred in >20% 
of patients were neutropenia (57.1%), thrombocytopenia (37%), and anaemia (41%).  

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morphological and molecular remission was 87% (13/15 patients) in this patient population. 
Two patients did not respond to AUTO3 treatment. As of the cut-off date (29-Jul-2020), 
9 patients ultimately had morphological relapse. The majority of the relapses (6 of 9 patients) 
were CD19 positive/CD22 positive disease associated with a lack of long-term CAR T cell 
persistence. 
1.8 
OVERALL RATIONALE FOR THE STUDY 
Despite these major advances, most cases of relapsed/refractory DLBCL remain incurable with 
the currently established therapy modalities. A considerable number of DLBCL patients will 
ultimately experience a final tumour relapse without an additional, effective treatment option. 
Novel immunotherapies such as CAR T cell therapies hold promise for significant 
improvement in the overall outcome of patients with DLBCL. CD19 CAR-positive T cells in 
clinical development for the treatment of B lineage malignancies have demonstrated significant 
efficacy in clinical trials. The major causes of treatment failure after CD19 CAR T cell therapy 
include CD19-negative escape variants, non-persistence of CAR T cells and potentially 
reactive upregulation of PD-L1 checkpoint by tumour cells. In contrast to targeting a single 
antigen expressed on lymphoma cells, targeting two antigens (CD19 and/or CD22) with the 
same CAR T cell is likely to be more advantageous. We hypothesise this will prevent tumour 
cell escape by target antigen down-regulation and significantly enhance the overall efficacy. 
Further, AUTO3 has also been engineered to be more effective with the incorporation of both 
OX40 and 41BB-ζ co-stimulatory signals and utilises humanised antigen binding domains in 
both CARs, hence reducing the risk of immune-mediated rejection. Furthermore, consolidation 
therapy with a short course (3 doses) of anti-PD-1 antibody will help overcome any resistance 
due to de novo or reactive upregulation of PD-L1 checkpoint by the tumour cells. Lastly, pre-
conditioning with anti-PD-1 antibody on Day -1 prior to CAR T infusion may mitigate CAR T 
exhaustion and lead to improved CAR T cell expansion, persistence, and function.  
This Phase I/II study will assess the safety and preliminary activity of AUTO3 with anti-PD-1 
antibody (pembrolizumab) consolidation or pre-conditioning, in patients with relapsed or 
refractory DLBCL and large B cell lymphoma subtypes. 

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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVES AND ENDPOINTS 
Primary objectives and endpoints for Phase I and Phase II of the study are presented in Table 4 
and Table 5, respectively.  
Table 4: 
Primary Objectives and Endpoints for Phase I 
Objectives 
Endpoints 
Escalation  
To assess the safety and tolerability of AUTO3 
administration with pembrolizumab. 
Incidence of Grade 3 to 5 toxicity occurring within 
75 days of AUTO3 infusion. 
To identify the recommended Phase II dose 
(RP2D[s]) and maximum tolerated dose (MTD), if 
an MTD exists, of AUTO3. 
Frequency of dose limiting toxicity (DLT) of 
AUTO3. 
Expansion  
To assess the safety and tolerability of AUTO3 
administration with pembrolizumab in the 
outpatient/ambulatory care setting 
Incidence of Grade 3 to 5 toxicity occurring within 
75 days of AUTO3 infusion. 
DLT=dose limiting toxicity; MTD=maximum tolerated dose; RP2D=recommended Phase II dose 
Table 5: 
Primary Objectives and Endpoints for Phase II 
Objectives 
Endpoints 
To evaluate the clinical efficacy of AUTO3 at the 
RP2D(s) with pembrolizumab in Cohort 1. 
To assess the overall safety and tolerability of 
AUTO3 with pembrolizumab in Cohort 2 at the 
RP2D(s). 
Best overall response post-AUTO3 infusion.  
Incidence of Grade 3 to 5 toxicity occurring 
within 75 days of AUTO3 infusion. 
AE=adverse event; RP2D=recommended Phase II dose; SAE=severe adverse event 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS 
Secondary objectives and endpoints are presented in Table 6. 

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Table 6: 
Secondary Objectives and Endpoints for Phase I and II 
Objectives 
Endpoints 
To assess the overall safety and tolerability of 
AUTO3 with pembrolizumab.  
Frequency and severity of all AEs and SAEs.  
Incidence and duration of severe 
hypogammaglobulinaemia. 
To evaluate the feasibility of generating the 
ATIMP, AUTO3. 
Proportion of patients for whom an AUTO3 product can be 
generated (feasibility). 
To evaluate the overall clinical efficacy of 
AUTO3 with pembrolizumab. 
Determine the CR rate following treatment with AUTO3. 
To evaluate clinical outcomes including DOR, PFS and OS. 
To determine the expansion and persistence of 
AUTO3 following adoptive transfer in different 
lymphoma subtypes. 
PCR and/or flow cytometry at a range of time points in the 
peripheral blood.  
Duration of B cell aplasia. 
Depletion of circulating B cells assessed by flow cytometry 
at a range of time points in the peripheral blood. 
AE=adverse event; ATIMP=advanced therapy investigational medicinal product; CR=complete response; DOR=duration of 
response; OS=overall survival; PFS=progression free survival; PCR=quantitative polymerase chain reaction; 
SAE=serious adverse event 
2.3 
EXPLORATORY OBJECTIVES  
The exploratory objectives for this study are as follows: 
• 
To determine the time course and magnitude of cytokine release evaluated using an 
appropriate assay. 
• 
To evaluate the effect of anti-PD-1 antibody on the time course and magnitude of cytokine 
release using an appropriate assay. 
• 
To assess the duration of depletion of circulating B cells as determined by flow cytometry 
on the peripheral blood and correlate this with disease response. 
• 
To assess antibody and/or T cell mediated immune responses against AUTO3. 
• 
To characterise the relationship between the CAR T cell phenotype/genomics and 
persistence in vivo. 
• 
Seek any relationship between parameters of activity, level of CD19 or CD22 expression 
(flow cytometry), tumour PD-L1 expression, and CAR T cell phenotype. 
• 
Seek any relationship between incidence and severity of CRS, NT or other toxicity, and 
tumour burden, level of CD19 or CD22 expression (IHC or flow cytometry), CAR T cell 
phenotype, and PD-1 expression. 
• 
To evaluate cerebrospinal fluid (CSF) for potential markers associated with NT. 

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3 STUDY DESIGN 
3.1 
STUDY OVERVIEW 
This multi-centre, single-arm study will consist of two parts, a Phase I phase and a Phase II 
phase:  
• 
Phase I:  
o 
Dose escalation to identify the optimal dose of AUTO3 with pembrolizumab (doses 
from 50 × 106 to 900 × 106 CD19/CD22 CAR-positive T cells, administered as a 
single dose, will be evaluated). 
o 
Expansion cohort to assess the safety and tolerability of AUTO3 at the RP2Ds or 
dose range and pembrolizumab regimen identified in the dose escalation part. 
Approximately 20 patients with DLBCL will be treated in an outpatient/ambulatory 
care setting.  
• 
Phase II: To further assess safety and anti-tumour activity at the RP2D(s) or dose range. 
An overview of the study design is presented in Figure 2 below.  
Figure 2: 
Study Design 
  
CY=cyclophosphamide; FLU=fludarabine. 
Note: Cohort 1 may include 3 to 6 patients without consolidation therapy, and 3 to 6 patients with consolidation therapy. 
The study will consist of the following six stages: 
• 
Screening: After providing written informed consent for study participation, all patients 
will be screened for study eligibility. Eligible patients will proceed to leukapheresis. 
• 
Leukapheresis: Eligible patients will undergo leukapheresis to facilitate manufacture of 
the ATIMP, AUTO3. Once the leukapheresate is accepted for manufacturing, the patient 
will be enrolled on to the study. 
• 
Pre-conditioning: If sufficient AUTO3 is successfully manufactured and released, and the 
patients continue to meet eligibility requirements for the study, they will proceed to receive 

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a standard lymphodepleting pre-conditioning treatment with FLU for 4 days and CY for 
2 days, to end 3 days before AUTO3 infusion. For Regimen B, pre-conditioning will 
include in addition to FLU and CY a single dose of pembrolizumab, 200 mg given on 
Day -1. 
• 
Treatment: AUTO3 will be administered i.v. as a single infusion on Day 0. The treatment 
phase will extend from Day 0 (infusion day) until Day 28 post AUTO3 administration. 
Patients are expected to be monitored closely (in hospital or ambulatory care as clinically 
appropriate) for 10 days or longer if clinically necessary for monitoring and management. 
• 
Consolidation: Provided any acute toxicities have resolved, anti-PD1 antibody 
(pembrolizumab, 200 mg infused over 30 min) will be administered for Regimen A on 
Days 14, 35 and 56 (3 days). 
• 
Follow-up: The follow-up phase will begin 1 month post AUTO3 infusion and end at the 
end of the study; at death or withdrawal of consent, which ever happens first. 
An overview of the six study stages is presented in Figure 3. 
Figure 3: 
Overview of the Stages of the Study 
 
 
 
 
From signing of consent until the End of Study visit, information relating to AEs, laboratory 
abnormalities, disease response and biomarker changes will be collected according to the AE 
reporting period (Section 12.3). 
All patients who have received AUTO3 will be eligible for enrolment into a long-term follow-
up protocol (AUTO-LT1) at the end of the study. The patients will be followed for safety 

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evaluation and survival for up to 15 years from their last AUTO3 infusion or until death or 
withdrawal of consent, which ever happens first.  
3.2 
PHASE I - DOSE ESCALATION 
The dose escalation part of Phase I is designed to determine the RP2D(s) of AUTO3 with 
pembrolizumab (based on total CD19/CD22 CAR-positive T cells) in patients with DLBCL 
and its defined subsets. Each dose level may treat up to six patients (up to 12 patients in the 
dose level 1 cohort). Evaluation of a dose level with at least three patients treated at the planned 
dose level completing the DLT evaluation period is required prior to escalation to the next dose 
level. Dose escalation will follow a rolling 6 design (Skolnik et al. 2008). DLT criteria are 
described in Section 3.6. The dose escalation decision rules are outlined in Table 7. 
Patients in the dose level 1 will receive consolidation therapy (Regimen A) with 
pembrolizumab from the fourth patient onwards. However, if a DLT is observed in the first 
three patients treated without consolidation therapy, then up to three additional patients may 
be treated without consolidation therapy before initiating consolidation therapy, if considered 
clinically necessary. A total of up to 12 patients may be treated in this cohort. All subsequent 
dose levels will include 3 doses of pembrolizumab consolidation therapy for patients treated 
on Regimen A or 1 dose of pembrolizumab as part of pre-conditioning therapy for patients 
treated on Regimen B.  
The trial will consist of up to four dose levels (Figure 2); eligible patients will be assigned to 
treatment groups sequentially. The inter-patient dosing interval (inclusive of the time for 
pre-conditioning) for AUTO3 in Phase I will be at least 14 days, to allow for assessment of 
possible toxicity, until a dose level is declared safe. After the dose level is declared safe, there 
will be no minimum inter-patient dosing interval required for patients treated at the same dose. 
Patients treated on Regimen B will have an inter-patient dosing interval of 7 days (inclusive of 
pre-conditioning) as it will be opened after the dose has been declared safe on Regimen A. 
Patients will be monitored for a minimum of 10 days (inpatient or ambulatory care setting), or 
until all AUTO3-related non-haematological toxicities have returned to Grade ≤1 or baseline, 
or longer as clinically necessary. The DLT evaluation period will be 28 days after AUTO3 
administration or at least 14 days after the first dose of pembrolizumab in situations where the 
first dose of pembrolizumab is delayed beyond Day 14. 
The Safety Evaluation Committee (SEC) will meet after the first patient at every new dose 
level completes 14 days, to confirm continuation of enrolment to that dose level. The SEC will 
meet again after the third and or sixth patient in a cohort has completed the DLT assessment 
period. Only after a cohort is declared safe by the SEC can the next higher dose level be opened. 
Back filling of a cohort (maximum n=6 evaluable patients/cohort) declared safe may be 
undertaken in parallel to the ongoing enrolment of a higher dose level, to obtain additional 
biomarker and safety data. All patients will be evaluated for efficacy. 
The starting dose level will be 50 × 106 CD19/CD22 CAR-positive T cells (Table 8) and if it 
is declared safe then the second cohort will be opened at a dose of up to 150 × 106 CD19/CD22 
CAR-positive T cells and third cohort at 450 × 106 CD19/CD22 CAR-positive T cells. Once 
three patients have been treated at a dose of 450 × 106 CD19/CD22 CAR-positive T cells 
followed by pembrolizumab starting on Day 14, a new cohort will be opened at the same dose 
level but will receive pembrolizumab starting on Day -1 (Regimen B). Dose escalation will 
continue until the planned maximum administered dose (MAD) of 900 × 106 CD19/CD22 

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CAR positive T cells is reached. If the new consolidation schedule is not safe or well tolerated, 
then the earlier schedule may continue with dose escalation. A dose lower than pre-planned 
next higher dose may be evaluated if emerging safety data suggest that it may be more 
appropriate. Additionally, based on emerging data, more than one RP2D may be determined. 
For example, if 150 × 106 CD19/CD22 CAR-positive T cells is declared as RP2D then Phase II 
can be opened and in parallel further dose escalation may be continued to determine a second 
RP2D dose and schedule. If a higher dose (e.g. 450 × 106) is declared RP2D then based on 
emerging data a RP2D dose range can be declared that can extend to a lower dose (e.g. 450 to 
150 × 106). If patients are treated below the planned dose level due to AUTO3 manufacturing 
limitations or other reasons, then those patients will not be considered evaluable for making 
dose escalation decisions (additional patients will be treated to meet the minimum number 
needed to make the dose escalation decision). However, dose escalation decisions will consider 
all available data, including biomarker data and the safety profile of all patients treated. No 
patient will be treated below 15 × 106 CD19/CD22 CAR-positive T cells. 
Based on emerging data, the initiation of consolidation or pre-conditioning therapy can be 
delayed or withdrawn altogether. All dose escalation decisions will be made by the SEC, 
however the Independent Data Monitoring Committee (IDMC) may change any of these 
decisions. 
Table 7: 
Rolling 6 Dose Escalation Decision Rules 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Escalate to the next dose level (except in dose level 1). 
1 out of 3 
Treat three additional patients at the current dose level for a total of 
six patients. 
1 out of 6 
Escalate to the next dose level or an intermediate dose level. 
2 or more patients in a dosing cohort 
(up to 6 patients)  
The MTD has been exceeded. Either:  
• Evaluate a dose lower than the current dose.  
• Evaluate an alternative pembrolizumab dosing schedule 
• Expand a prior cohort up to six patients.  
DLT=dose limiting toxicity; MTD=maximum tolerated dose.  
Note: The Investigators may override these guidelines if there are particular safety issues, for which moving to a higher dose 
is not considered appropriate. 
The dose escalation decisions will be made by SEC (Section 13.1) and study could be stopped 
by SEC upon occurrence of any of the events described in Section 3.7. 
3.3 
PLANNED DOSE LEVELS 
The planned dose levels are presented in Table 8. These dose levels were selected as they 
provide an optimum range for assessing safety, CAR T cell persistence and anti-tumour 
activity. The overall study range is within the dose levels assessed in other CAR T studies. 
Based on emerging data, intermediate dose levels may also be explored with either 
consolidation or pre-conditioning therapy.  

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Table 8: 
Treatment Cohorts in Phase I Dose Escalation 
Dose 
Levels  
Treatment 
Cohorts 
Pre-conditioning 
(FLU-CY; 
Days -6, -5, -4, -3) 
Total CD19/CD22 
CAR-Positive 
T Cells  
(Day 0) 
Regimen A: 
Consolidation 
(pembrolizumab; 
Days 14, 35, 56) 
Regimen B:  
Pre-conditioning 
(pembrolizumab; 
Day -1) 
Dose 
Level 1 
Cohort 1 
Yes 
50 × 10
6 
None in first 
three patients, 
then Yes 
 
Dose 
Level 2 
Cohort 2A 
Yes 
150 × 10
6 
Yes 
 
Dose 
Level 3 
Cohort 3A 
Yes 
450 × 10
6 
Yes 
 
Cohort 3B 
Yes 
450 × 10
6 
 
Yes 
Dose 
Level 4 
Cohort 4A 
Yes 
900 × 106 
Yes 
 
Cohort 4B 
Yes 
900 × 10
6 
 
Yes 
RP2D 
RP2D or 
Dose Range 
Cohort 
Yes 
150 to 450 × 106 
 
Yes 
CAR=chimeric antigen receptor; FLU-CY=fludarabine and cyclophosphamide ; RP2D=recommended Phase II dose. 
• 
In dose level 1, the first three patients treated at 50 × 106 CD19/CD22 CAR-positive 
T cells will not receive consolidation with pembrolizumab. 
• 
Consolidation therapy with pembrolizumab (except dose on Day -1) will be administered 
only after any CRS has resolved to ≤Grade 1 or NT has resolved. Based on emerging data, 
either one or both pembrolizumab dosing regimens will be opened in Dose Level 4 
(Cohorts 4A and 4B). 
• 
On occasion, AUTO3 production may fail to generate sufficient cells for the current dose 
level. In this case, the patient can be treated on study but at a lower dose, however if 
production fails to generate ≥15 × 106 (approx. 0.2 × 106/kg) CD19/CD22 CAR -positive 
T cells, near the lowest known active dose of CD19 CAR-positive T cells 
(1.46 × 105 T cells/kg, approximately total dose of 10 × 106 T cells [patient UPENN 
chronic lymphocytic leukaemia 3, NCT0102936]), then the patient will not be treated on 
the study. Only patients treated at planned dose level will be evaluable for dose escalation 
decision making and primary efficacy analysis (+ 20% window). Additional patients will 
be treated to meet the minimum number needed to make the dose escalation decision 
• 
If emerging data suggest that escalation is appropriate to an intermediate dose, which is a 
lower than the planned dose, then it can be undertaken with Regimen A or B. Total number 
of patients of Phase I may also be increased if necessary. 
• 
If emerging safety and efficacy data suggest further dose escalation is warranted, any doses 
higher than 900 × 106 CD/19/CD22 CAR T cells will not be undertaken without a 
substantial protocol amendment.  
Note: The dose determination is based solely upon the genetically modified cells 
(i.e. CD19/CD22 CAR-positive T cells). A patient may be eligible for a planned dose level if 
the dose is within ±20% of the prescribed CD19/CD22 CAR-positive T cells dose. 

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3.4 
PHASE I – Expansion Cohort 
In this cohort, the safety and tolerability of AUTO3 at the RP2D or dose range will be assessed 
in an outpatient/ambulatory care setting following declaration of RP2D or dose range in the 
dose escalation part. Approximately 20 patients will be treated. There will be no inter-patient 
dosing interval. 
Patients enrolled in this cohort will be monitored for at least 10 days in an 
outpatient/ambulatory care setting, or until all AUTO3-non-haematological related toxicities 
have returned to Grade ≤1 or baseline, or longer as clinically necessary. During the 10 days 
following AUTO3 infusion, the patients are monitored at a minimum every 2 to 3 days (in the 
UK, at least once a day evaluation by a physician or qualified designee). In addition, it is 
recommended for the patient to have a daily verbal communication with qualified 
nurse/medical personnel (phone call). Patients will also need adequate caregiver support (in 
line with institutional outpatient transplant guidelines). Patients enrolled or treated in this 
cohort can be admitted to the inpatient setting as necessary for the management of AEs or 
toxicity at any time. Patients can also be admitted based on Investigator discretion should they 
consider it inappropriate to treat or monitor an already enrolled patient in an 
outpatient/ambulatory setting. Physicians may also admit patients for social reasons. In all 
cases the reason for admission should be documented. 
3.5 
PHASE II 
Once the RP2D(s) or dose range is/are determined, the Phase II part of the study will open with 
two cohorts. This part will treat approximately up to 101 patients on the RP2D(s). Cohort 1 
will comprise approximately 81 patients with DLBCL subsets and transformed FL, Cohort 2 
will comprise approximately 20 patients with PMBCL and DLBCL transformed from other 
indolent histologies. Patients treated at a dose lower than the RP2D(s) will not be evaluable for 
primary efficacy endpoint analysis but will be evaluable for secondary efficacy endpoints and 
safety analysis. Once Phase II starts, patients can be dosed simultaneously at the declared RP2D 
dose(s) without inter-patient intervals. 
3.6 
DOSE LIMITING TOXICITY 
Toxicities will be graded for severity according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0. CRS and neurological toxicity will be graded 
according to the American Society for Transplantation and Cellular Therapy/American Society 
for Blood and Marrow Transplantation (ASTCT/ASBMT) consensus grading (Lee et al. 2019). 
DLT criteria takes into consideration the single dose nature of AUTO3 treatment (unlike repeat 
dose treatments of usual anti-cancer agents), the potential for differential expansion of CARs 
post-infusion in different patients and inclusion of consolidation or pre-conditioning therapy. 
As well as features inherent to CAR therapy such transient fever due to low grade cytokine 
release syndrome in the setting of pre-conditioning induced cytopenias/neutropenia seen in 
most patients and which are not necessarily classical neutropenic fevers resulting from 
infection. 
The DLT evaluation period will be 28 days after the infusion of AUTO3, or 14 days after the 
first dose of pembrolizumab, if administration of first pembrolizumab dose is delayed. 

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Dose limiting toxicity will be defined as: 
• 
Any new non-haematological AE of Grade 3 or higher toxicity using the NCI CTCAE 
(Version 5.0), which is probably or definitely related to AUTO3 therapy, which occurs 
within the DLT evaluation period, and which fails to resolve to Grade 2 or better within 
14 days, despite appropriate supportive measures. 
• 
A Grade 4 CRS, NT, or cerebral oedema, or Grade 3 NT that lasts >72 hours. 
• 
Grade >3 Disseminated Intravascular Coagulation (DIC) 
• 
Grade >2 Infusion Reaction with AUTO3 infusion 
• 
Any other fatal event (Grade 5) or life-threatening event (Grade 4) that cannot be managed 
with conventional supportive measures or which in the opinion of the SEC necessitates 
dose reduction or other modification to trial treatment to avoid a similar hazard in future 
patients. Effort should be made to perform an autopsy in case of a fatal event where the 
aetiology is unclear. 
• 
Any event that in the opinion of treating Investigators and or medical monitor put patient 
at undue risk may also be considered a DLT. 
Reporting Requirements for DLT 
All DLTs must be reported to the Sponsor as serious adverse events (SAEs) within 24 hours of 
site staff becoming aware of them (see Section 12.3.5). The Sponsor will notify all DLTs to 
the SEC and IDMC. 
Maximum Tolerated Dose: The MTD is defined as the highest dose level of AUTO3 at which 
≤one patient out of six patients experience a DLT during the DLT evaluation period. If two or 
more out of six patients at a dose level experience a DLT during the DLT evaluation period, 
the MTD has been exceeded. If the MTD is exceeded due to a specific toxicity that can be 
managed with supportive care, an additional three patients may be treated at the dose level that 
exceeded the MTD with establishment of supportive care measures. A summary of available 
safety data and a description of the plans for supportive care measures with further enrolment 
at that dose level will be provided to Independent Ethics Committees/Institutional Review 
Boards (IECs/IRBs) prior to dosing. 
Maximum Administered Dose: The planned MAD for this study is 900 × 106 CD19/CD22 
CAR-positive T cells in the event the MTD is not defined. The MAD may be lower based on 
emerging data. 
Recommended Phase II Dose: The RP2D(s) will be either identical to the MTD or MAD or 
a lower dose level of AUTO3, selected on the basis of a cumulative review of safety, 
persistence of the CAR T cells and clinical activity. The RP2D(s) dose level(s), or dose cohorts 
(on Regimen A and or B) may be expanded to an additional six patients (total n=12) to further 
characterise safety. Similarly, if a RP2D dose range is selected a total of up to 12 patients may 
be enrolled to obtain additional safety and cellular kinetics data. 
3.7 
SAFETY STOPPING CRITERIA FOR THE CLINICAL TRIAL 
The study could be stopped by the SEC or the IDMC upon occurrence of any of the following 
events: 

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• 
Unexpected and related SAEs that exposed patients participating to the study to 
unacceptable risk of harm (class related toxicities such as CRS and neurotoxicities will not 
automatically result in stopping unless they are exposing patients to risk above what is 
generally seen with similar therapies). 
• 
Uncontrolled SAEs related to identified risks. 
• 
The occurrence of non-haematological Grade 4 toxicity in three patients unless in the 
opinion of the IDMC (after review), it is likely manageable with the institution of 
appropriate supportive care.  
• 
Death of a patient at any time after therapy that is definitely related to CAR T cell therapy. 
• 
The occurrence of a second malignancy at any point after therapy that is definitely related 
to the CAR T cell therapy. 
The study may be restarted after appropriate preventive or management guidelines have been 
instituted and a substantial protocol amendment has been approved by the regulatory 
authorities and ethics committees. 
3.8 
STUDY DURATION 
The total study duration is estimated to be approximately 7 years from first patient enrolled to 
the end of the study. The end of the study (EOS) is defined as the LPLV expected to be 36 
months after the last patient’s AUTO3 dose or earlier in the event of patient death or consent 
withdrawal. 
In the event of disease progression prior to the end of the study, patients will continue to be 
monitored for safety and survival in order to collect Health Authority requested data 
(e.g. delayed AEs) until the end of the study or until time of early withdrawal or death. The 
survival follow-up can be conducted via telephone contact if necessary. 
3.9 
EARLY STUDY TERMINATION 
The study can be terminated at any time at the discretion of the Sponsor. If the study is 
terminated prematurely, the Health Authorities will be notified per applicable guidelines. The 
Sponsor, or the Investigator will be responsible for informing IRBs and/or IECs of the early 
termination of the study, in accordance with local requirements. 
The Investigator may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patients’ interests. In the event of early 
termination, patients should receive local standard of care at the physician’s discretion. For 
patients who have received AUTO3, a long-term follow-up study for safety should continue 
under a separate protocol for up to 15 years post infusion as per Health Authority guidelines.  
3.10 
NUMBER OF PATIENTS 
It is anticipated that approximately 171 patients will be enrolled (consented) into the study and 
approximately 151 patients receiving the treatment as outlined below: 
• 
Phase I: A dose escalation and expansion cohort involving approximately 50 treated 
patients in total (up to 6 patients per dose cohort, dose level 1 may include up to 
12 patients).  

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• 
Phase II: A Phase II involving up to a total of 101 patients; 81 with DLBCL subsets and 
transformed FL in Cohort 1, additionally, 20 patients with primary mediastinal large B cell 
lymphoma and those with lymphoma transformed from other indolent histologies in 
Cohort 2. 
The sample size for Phase II of the study will follow Simon’s 2-stage optimal design as 
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4 SCIENTIFIC RATIONALE FOR STUDY 
4.1 
DESIGN RATIONALE 
This single-arm dose-escalation Phase I/II study is designed to assess safety, tolerability, and 
optimum RP2D(s) and MTD, if an MTD exists, for AUTO3. Considering the experience the 
field has with targeting CD19 and CD22 individually, the novelty of targeting both CD19 and 
CD22 with a single construct expressing two CARs, as well as incorporation of consolidation 
or pre-conditioning treatment with an anti-PD-1 antibody (pembrolizumab), a cautious dose 
escalation design encompassing four dose levels is considered appropriate. A rolling 6 dose 
escalation design in the Phase I has been chosen, as it will facilitate dosing an adequate number 
of patients prior to evaluation of safety and biological activity, and to facilitate better decision 
making of the Phase II dose. In addition, considering that time required to manufacture 
individual products and the risk of rapid disease progress in these patients, a rolling 6 design is 
more optimal. 
A dose escalation with ≤half log increase over the previous dose is appropriate considering the 
in-vivo expansion of the CAR T cells, other studies have used half-log/300% (Brudno and 
Kochenderfer 2016) to a log/1000% (Turtle et al. 2016) increase in dose. The proposed dose 
levels of 50 × 106, 150 × 106, 450 × 106 and 900 × 106 CD19/CD22 CAR-positive T cells are 
conservative and designed to identify a safe and efficacious dose or dose range for the Phase II. 
The rationale for starting dose levels and dosing schedule is outlined in detail in Sections 4.2 
and 4.4. 
Considering the first in human nature of the study, dosing an adequate number of patients at 
the starting dose without consolidation before initiating consolidation therapy is necessary and 
is incorporated into the design (Section 3.2). The rationale for pre-conditioning or 
consolidation with anti-PD-1 antibody (pembrolizumab) is further described in Section 4.6. 
The timing of initiation of anti-PD-1 consolidation therapy considers the time to peak 
expansion of the infused CAR T cells which is around 7 days (range 2 to 14 days) (Schuster et 
al. 2016), following which the number of circulating CAR T cells decreases over the next few 
weeks due to activation-induced cell death as well as exhaustion (Long et al. 2015). 
Additionally, CRS which occurs within the first week of T cell infusion in all patients (Schuster 
et al. 2014) is expected to have resolved in most patients by Day 14 (Lee et al. 2015). It is 
necessary to dose anti-PD-1 antibody before significant contraction of the CAR T cell 
compartment. Additionally, based on emerging data from the ZUMA-6 study involving 
axicabtagene ciloleucel in combination with atezolizumab which was administered starting on 
Day 1 (in addition to Day 21 and 14), no apparent exacerbation or recurrence of axicabtagene 
ciloleucel–related toxicity following atezolizumab infusion was observed (Jacobson et al. 
2018). In another study with anti-CD19 CAR T therapy JCAR014 and the anti PD-L1 agent 
durvalumab, patients have been dosed with durvalumab one day prior to JCAR014 infusion. 
This combination and dosing regimen at escalating doses of durvalumab has been well tolerated 
to date (Hirayama et al. 2018). It is likely, based on the emerging safety profile of AUTO3 in 
this study and the AMELIA study (Amrolia et al. 2018), that early dosing of pembrolizumab 
is likely to be tolerable. Moreover, as PD-1 overexpression has been observed in CAR T cells, 
which possibly leads to exhaustion and hypofunction, early dosing of pembrolizumab on 
Day -1 may improve CAR T cell expansion, persistence, and functional killing. An additional 
reason for early dosing of pembrolizumab on Day -1 is to help CAR T cells engage tumour 
cells with de novo PD-L1 upregulation, which can be seen in 10% to 30% of patients with 

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DLBCL (Andorsky et al. 2011, Chen et al. 2013, Rossille et al. 2014, Kiyasu et al. 2015, Dong 
et al. 2016, Menter et al.)  
The limited number of doses of anti-PD-1 antibody consolidation (three doses in total, given 
every 21 days) is considered adequate to facilitate induction of CRs which happen early with 
CAR T cell therapy, usually with in the first three months (Neelapu et al. 2016). This will also 
reduce the risk for any cumulative toxicity. An alternative approach, in which 1 dose of 
anti-PD-1 is administered during pre-conditioning, will be explored in Regimen B. Since most 
clinical responses occur in the first month and the maximal expansion and contraction of CAR 
T cells also happen during the same period, maintaining CAR T cell function over that period 
with a single dose of pembrolizumab may be adequate for optimal activity of the CAR T cells 
on the tumour. For these reasons we will explore Regimen B with a single dose of 
pembrolizumab on Day -1. 
The option for delaying, withholding or withdrawing anti-PD-1 therapy based on emerging 
data is designed to add to safety.  
During Phase I cell dose escalation, a minimum dosing interval of 2 weeks between patients is 
incorporated to reduce the risk of inducing severe adverse effects in more than one patient. 
During evaluation of alternative regimens of pembrolizumab at the same dose of CAR T cells, 
the inter-patient dosing interval of 7 days is considered adequate. Based on the totality of data 
from the current study, the study in paediatric ALL (Amelia study) (see Section 1.7), the risk 
of patients deteriorating during the inter-patient interval, and the safety of AUTO3 at previous 
dose levels and regimens, a 7-day inter-patient dosing interval is likely to be adequate. 
Additionally, close monitoring for up to 10 days after AUTO3 and up to 3 days after the first 
dose of anti-PD-1 therapy is designed to add to safety. A DLT assessment window of 28 days 
is incorporated and is appropriate as the therapy involves a single dose of AUTO3 and the 
majority of toxicities happen within the first few weeks (Davila et al. 2014). Considering the 
extensive clinical experience with these agents, this window is considered adequate even with 
the use of anti-PD-1 consolidation or pre-conditioning as it is unlikely to significantly increase 
AEs. Additionally, the DLT period will be extended to 2 weeks after the first dose of 
pembrolizumab in case the dosing of pembrolizumab is delayed and to capture any additive 
toxicity. 
The rationale for Simon’s 2 -stage optimal design for the Phase II (Cohort 1) part of the study 
is to allow for the termination of the study at interim analysis after 27 patients if the true 
response rate is 10% or less. The rationale for dosing up to 81 patients is to detect early signs 
of efficacy in addition to generating additional safety data at the RP2D(s).  
4.2 
POPULATION RATIONALE 
AUTO3 is designed to specifically target CD19 and/or CD22, which are only expressed on 
normal and malignant B lymphocytes. The patient population for this study is DLBCL and 
large B-cell lymphoma subsets, and will include:  
• 
DLBCL, not otherwise specified (NOS), per World Health Organisation classification and 
DLBCL with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit). 
• 
Transformed DLBCL from FL. 
• 
Transformed 
DLBCL 
from 
other 
indolent 
lymphomas 
(excluding 
Richter’s 
transformation). 

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• 
High-grade B cell lymphoma with MYC expression (excluding Burkitt’s lymphoma). 
• 
Primary mediastinal large B cell lymphoma.  
In addition, since this is an experimental therapy, the study patient population will be restricted 
to patients with chemotherapy-refractory disease, or relapse after at least two lines of therapy 
(including an anti-CD20 monoclonal antibody and an anthracycline cycle), or after ASCT, and 
have PET-positive disease (for efficacy assessment).  
Patients with lymphoma and history of central nervous system (CNS) involvement may also 
be included in the study. Tisagenlecleucel is a CAR T cell product approved by the European 
Medicines Agency and the FDA for the treatment of relapsed/refractory DLBCL. Both the 
pivotal Phase II trial (Schuster et al. 2019) and the Phase Ib (PORTIA; (NCT03630159 2018)) 
study allowed prior history of CNS disease and only excluded patients with active 
disease. Lisocabtagene maraleucel, another CD19 CAR T cell product, is currently being 
studied in two trials involving DLBCL (NCT02631044 2015, NCT03484702 2018). Both trials 
allow patients with prior as well as active CNS disease. Data presented thus far from 
NCT02631044 show Grade 3/4 CRS at 1% and Grade 3/4 NT at 12% (Abramson et al. 2018). 
Additionally, data from studies with anti CD19 CAR T therapies in relapsed/refractory ALL 
show no increased risk of NT in patients with CNS involvement by malignancy (Talekar 2017, 
Zhang 2018) and in a Phase I AUTO3 paediatric B-ALL trial that allows patients with CNS 
involvement with disease there have been no reports of Grade 3/4 NT attributed to AUTO3 
(see Section 1.7 (Amrolia et al. 2018). Finally, in the ongoing AUTO3 trial in DLBCL, there 
has been one case of Grade 3 NT that resolved (Ardeshna et al. 2018). 
As outlined in Section 1.1, the prognosis for patients who relapse after ASCT, or fail initial 
salvage is particularly poor. In patients with DLBCL that has progressed after ASCT, median 
OS is <10 months (Vose et al. 1992, Nagle et al. 2013). The median OS of patients requiring 
third-line treatment is 4.4 months (Van Den Neste et al. 2016). The prognosis of patients with 
histological transformation and FL Grade 3B is also poor (Section 1.1). Also, for patients with 
primary mediastinal lymphoma, cure rates are low for those who relapse or progress (Dunleavy 
and Wilson 2015)(Zelenetz 2019)(Crump et al. 2017)(Mills et al. 1995, Villela et al. 2001, 
Telio et al. 2012, Hitz et al. 2015)(Coiffier et al. 2002, Feugier et al. 2005)(Telio et al. 2012, 
Hitz et al. 2015). These patients are appropriate candidates for clinical trials, and data from 
existing trials of second-generation CD19 CAR T cells therapies in similar patient populations 
have been very promising with approved products in these subtypes (Kochenderfer et al. 2015, 
Kochenderfer et al. 2016, Neelapu et al. 2016). Dual targeting of CD19 and CD22 followed by 
consolidation or pre-conditioning with anti-PD-1 therapy is likely to improve outcomes further. 
4.3 
STARTING DOSE RATIONALE 
The primary consideration for selection of a starting dose for the proposed trial is the safety of 
the patient. Considerations for CAR T cell dosing are challenging. Chimeric antigen receptor 
T cells are a “living therapy” i.e. they can engraft within the study patient, they can expand and 
they have no half-life in the standard conception of the term (Ghorashian et al. 2015). Efficacy 
and toxicity appears related to the magnitude and kinetics of engraftment (Maude et al. 2014). 
A wide range of doses have been utilised in existing studies of CD19 CAR T cell therapy in 
leukaemia and lymphomas (5 × 105 to 1.7 × 107 CAR T cells/kg), with no clear correlation 
between cell dose administered and efficacy, reflecting the fact that infused CAR T cells can 
expand by several logs after transfer to a lymphodepleted host. Consequently, the correlation 
between CAR T cell dose and toxicity is much less clear than the correlation with standard 

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small molecule or protein-based therapeutics. The findings are obscured by differences in CAR 
design and CAR T cell production processes. A dose in the order of millions of CAR T cells/kg 
appears generally optimal. 
Considering the incorporation of consolidation or pre-conditioning therapy with anti-PD-1 
antibody in this lymphoma study, the proposed starting dose of 50 × 106 CD19/CD22 
CAR-positive T cells (AUTO3) is appropriate. It is approximately a third of the dose of 2 × 106 
CD19 (CD28z) CAR-positive T cells/kg considered to be the MTD in the National Institute of 
Health and Kite Pharma studies in B cell lymphomas (Neelapu et al. 2016). This is also 
significantly lower than the UPENN’s CTL019, a CD19 (41BB-ζ) CAR dose, where a higher 
dose of up to 500 × 106 (5.10 - 6.75 × 106 cells/kg) was considered tolerable and the RP2D 
(Maude et al. 2014).  
Dual targeting of CD19 and CD22 is not anticipated to result in more activity or toxicity over 
a CD19 or a CD22 CAR alone for several reasons: firstly, CD22 is significantly less densely 
expressed than CD19 on lymphoma cell lines so the cumulative targetable antigen density will 
not be significantly increased (Lee et al. 2014, Shah et al. 2015). Secondly, little if any synergy 
is anticipated from signalling through both of the TNF-family receptor endodomains, as a 
signal through either OX40 or 41BB is likely to saturate the common signalling pathway. In 
the absence of a CD28 co-stimulatory domain, less rapid proliferation is expected. 
Furthermore, no increase in cytotoxicity is observed in vitro between CD19 and CD19/CD22 
CAR constructs with CD19-positive/CD22-positive target cells (IB Section 4.4.3). Only in 
situations where the targets lose expression of CD19 do we expect continued cytotoxicity with 
the CD19/CD22 CAR. 
The proposed dose is lower than the starting doses of AUTO3 in paediatric ALL (1 × 106 CAR 
T cells/kg or approx. 75 × 106 CAR T cells) and similar to that used in other recent CAR studies 
in lymphoma i.e. 50 × 106 CAR T cells with JCAR017, a CD19 (41BB-ζ) CAR (Abramson et 
al. 2016) and 0.66 × 106 CAR T cells/kg (approx. 50 × 106 CAR T cells in total) with 
HuCAR-19, a CD19 (CD28-ζ) CAR (Brudno et al. 2016). The treatment of the first three 
patients at the starting dose without consolidation will provide additional clarity to the safety 
profile of the starting dose. The rationale for consolidation or pre-conditioning therapy is 
further discussed in Section 4.6. Moreover, the available data indicates that incorporation of 
anti-PD-1 antibody is unlikely to significantly increase proliferation, cytokine production or 
toxicity (IB Section 4.6 and (Cherkassky et al. 2016). In the single patient treated with this 
combination, no substantial CAR T cell proliferation or cytokine production was noted and, 
other than fever, therapy was well tolerated (Chong et al. 2016) and resulted in clinically 
significant anti-tumour response. The use of limited number of doses in the consolidation 
approach or single dose in the pre-conditioning approach is also likely to limit any potential 
additive toxicity.  
In summary, considering the experience the field has with targeting CD19 and CD22 
individually, the novelty of targeting both CD19 and CD22 with a single construct expressing 
two CARs, as well as incorporation of consolidation or pre-conditioning treatment with an anti-
PD-1 antibody (pembrolizumab), the proposed starting dose of 50 × 106 CD19/CD22 CAR-
positive T cells is considered appropriate. 
4.4 
RATIONALE FOR DOSING SCHEDULE 
CAR T cell therapies are generally administered once, undergo significant expansion in vivo 
upon contact with the target antigen expressed on tumour cells and, particularly where a 

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41BB-ζ co-stimulatory domain is incorporated in to the CAR, persist long-term in a proportion 
of patients (Maude et al. 2014). It is anticipated that AUTO3 will have similar expansion and 
persistence in vivo to the CD19 CAR-positive T cells utilised in the UPENN studies, rendering 
the need for re-dosing unnecessary (Schuster et al. 2016). On occasion, a re-treatment dose 
may be given if the patient meets the criteria for re-treatment (Section ).  
All patients will receive a single dose of AUTO3. Cytokine surge, especially IL-15, observed 
during post-conditioning chemotherapy with fludarabine and cyclophosphamide (FLU-CY) 
occurs in the first few days and returns to baseline around 10 days later (Rossi et al. 2015). It 
may be ideal to dose the CAR T cells early within this window, as IL-15 is necessary for CAR 
T cell expansion, engraftment, and resulting efficacy (Xu et al. 2014). 
The timing rationale for consolidation and pre-conditioning with pembrolizumab is described 
in Section 4.1. The pembrolizumab dose of 200 mg for consolidation is based on the prescribed 
label dose for other solid tumours. The dosing frequency of every 3 weeks (Regimen A: 
Days 14, 35 and 56 [±3 days]) is also based on the prescribed label for solid tumours. The total 
number of doses is limited to only three doses (Regimen A), and the rationale is based on the 
hypothesis that CAR responses happen early and limited duration of anti-PD-1 is adequate to 
induce CRs, and thus further continuation of pembrolizumab is likely unnecessary. For 
Regimen B, we chose a single pembrolizumab dose of 200 mg to be given on Day -1 as part of 
the pre-conditioning regimen. The peak expansion and the peak anti-tumour effect of CAR T 
cells generally occur in the first 2 weeks (Neelapu et al. 2017, Schuster et al. 2019). We have 
also observed this in Study AUTO3-DB1 (Ardeshna et al. 2018). Cytokine production and 
PD-1 upregulation also generally occur 2 weeks post-CAR T cell infusion (Kochenderfer et al. 
2015, Locke et al. 2017). In addition, the majority of clinical responses are achieved within the 
first month post-CAR T infusion (Neelapu et al. 2017, Schuster et al. 2019). All CRs were 
achieved in 1 month in AUTO3-DB1 (Ardeshna et al. 2018). Given that the half-life of 
pembrolizumab is 23 days, a single dose of pembrolizumab on Day -1 prior to CAR T infusion 
is likely sufficient to minimise both the exhaustion of CAR T cells during expansion and the 
immune escape effect of PD-L1. Moreover, based on data from other studies, it is less likely 
that there will be an additional safety concern for dosing at Day -1. In a study with JCAR014 
(NCT02706405 2016), patients were dosed with durvalumab safely on Day -1 prior to 
JCAR014 therapy (Hirayama et al. 2018) followed by multiple additional doses. For these 
reasons as well as for patient convenience, we plan to explore Regimen B of single dose 
pembrolizumab on Day -1 instead of 3 doses of pembrolizumab (Regimen A).  
After treatment with AUTO3, safety will be monitored closely (both in hospital and as an 
outpatient/ambulatory care setting), and efficacy will be assessed periodically as described in 
the Schedule of Assessments. The timing of assessments is designed to capture early signs of 
toxicity and efficacy. 
4.5 
FLUDARABINE AND CYCLOPHOSPHAMIDE 
Pre-conditioning strategies that deplete host lymphocytes prior to adoptive transfer of tumour 
specific T-lymphocytes is thought to enhance treatment efficacy by eliminating regulatory 
T cells and increasing access of the transfused CAR T cells to activating cytokines (Klebanoff 
et al. 2005, Wrzesinski and Restifo 2005). Cyclophosphamide has an established history in 
lymphodepleting regimens used prior to adoptive cell immunotherapy (Sporn et al. 1993, Curti 
et al. 1998, Brentjens et al. 2011, Chu et al. 2012). It is used alone or often used in combination 
with other agents (Dudley et al. 2008, Laurent et al. 2010, Geller et al. 2011) such as FLU 

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(Louis et al. 2011). The FLU-CY combination is well tolerated in chronic lymphocytic 
leukaemia (Hallek 2013). 
Cyclophosphamide and FLU based pre-conditioning have become the preferred regimen for 
CAR T therapies and have been used in multiple studies (Lee et al. 2014, Kochenderfer et al. 
2015, Ali et al. 2016). In terms of overall efficacy, the FLU-CY combination is also considered 
to be superior to CY alone (Lee et al. 2016, Turtle et al. 2016). 
The exact dose regimens used for lymphodepletion prior to CAR T cell therapy are variable 
(IB Section 7.2). The regimen utilised in this study (FLU 30 mg/m2/day for 4 days + CY 
500 mg/m2/day for 2 days) is similar to that evaluated in multiple clinical studies across 
institutions and appears both safe and active (Lee et al. 2014, Ali et al. 2016, Fry 2016, 
Kochenderfer et al. 2016, Neelapu et al. 2016, Turtle et al. 2016). See Section 7.2 of the IB for 
further background information relating to the pre-conditioning treatment. 
In the current study, we propose to start at a low dose of 50 × 106 CD19/CD22 CAR-positive 
T cells combined with low dose FLU-CY (FLU 30 mg/m2/day for 4 days and CY 
500 mg/m2/day for 2 days) based pre-conditioning regimen and titrate the CAR T dose up based 
on emerging safety data. A 3-day washout period prior to infusion of AUTO3 is also 
incorporated, taking into consideration the 20-hour half-life of FLU. FLU and CY will both 
start on Day -6. We also propose to include pembrolizumab 200 mg × 1 dose at Day -1 as part 
of pre-conditioning as this will be done prior to AUTO3 infusion (Regimen B). 
In summary, given the nature of the patient population and the role of FLU-CY and 
pembrolizumab in enhancing the clinical efficacy of CAR T cells, the proposed dose and 
regimen is justified.  
4.6 
ANTI-PD-1 CONSOLIDATION / PRE-CONDITIONING RATIONALE 
As described in Section 1.4 and in Section 7.7 of the IB, increases in PD-L1 expression by 
tumour cells is a crucial part of the tumour’s adaptive resistance to T cell mediated immune 
response including adoptively transferred engineered T cells.  
In addition, early CAR T cell exhaustion can potentially limit the effectiveness of the therapy 
and pre-clinical data suggest CAR T cell function can be restored by using an anti-PD-1 
antibody (Section 1.4). Similarly, we have observed that CD19/22 CAR T cells become 
exhausted after repeated stimulation. Our pre-clinical data also show that repeated antigen 
stimulation leads to PD-1 as well as PD-L1 overexpression on CD19/CD22 CAR T cells. These 
cells generate fewer cytokines compared with fresh unstimulated CD19/CD22 CAR T cells 
and induce less cytotoxicity when compared with fresh CD19/CD22 CAR T cells in PD-L1 
expressing tumours, suggesting exhaustion. The addition of anti-PD-1 antibody restored both 
AUTO3 cytokine production and cytotoxicity in DLBCL in in vitro systems. 
Clinically, pembrolizumab and other PD-1/PD-L1 inhibitors have also been used to improve 
CAR T cell function. Several Investigators have added PD-1 or PD-L1 inhibitors to CAR T 
cells in order to mitigate the effect of exhaustion and to enhance expansion, persistence, or 
restore tumour killing. Maude et al showed that all 4 patients with B ALL who progressed after 
tisagenlecleucel treatment, demonstrated re-expansion of CAR T cells following 
pembrolizumab treatment (Maude et al. 2017). This translated into objective responses in 
4 patients with extramedullary relapse and re-establishment of B cell aplasia in 3/6 patients (Li 
et al. 2018). Chong et al observed a re-expansion of CD19 CAR T cells with pembrolizumab 
in 8/11 patients with DLBCL who progressed after tisagenlecleucel administration (Chong et 

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al. 2018). This translated into an ORR of 25%. Jacobson et al showed that addition of 
atezolizumab to axicabtagene ciloleucel led to a doubling of CAR T cell expansion, measured 
by the area under the curve (AUC) compared to patients treated with axicabtagene ciloleucel 
alone (Jacobson et al. 2018). In this study, relapsed or refractory DLBCL patients were 
administered atezolizumab every 21 days for 4 doses starting on Day 21, 14, or on 
1 post-axicabtagene ciloleucel infusion. Severe toxicity such as Grade ≥3 CRS and neurologic 
events occurred in 3 (25%) and 6 (50%) patients, respectively. This was not significantly 
different from that seen with axicabtagene ciloleucel alone in the ZUMA-1 study, despite >2-
fold higher AUC in ZUMA-6 than the median observed in patients treated with axicabtagene 
ciloleucel alone in ZUMA-1. In another study in similar patients with relapsed/refractory B 
cell lymphomas, the PD-L1 inhibitor durvalumab was dosed at Day -1 prior to JCAR014 
(NCT02706405 2016). Up to 10 doses of durvalumab were administered at 4-week intervals 
until toxicity or disease progression. CRS and NT were seen in 38% and 8% of patients, 
respectively. The early results indicate that Day -1 dosing of durvalumab prior to JCAR014 
appears to be safe (Hirayama et al. 2018). 
The data from AUTO3 in DLBCL, when combined with 3 doses of pembrolizumab, also have 
not shown any Grade 2 or higher CRS and no neurotoxicities have been reported in patients 
treated with AUTO3 and pembrolizumab. These data provide evidence to support the safe 
combination of pembrolizumab with CAR T cells with no additive toxicity, severe CRS or NT 
in relapsed refractory DLBCL patients. In our preliminary Phase I data, at the lowest dose level 
of 50 × 106 CD19/22 CAR-positive T cells, where 4 patients did not receive pembrolizumab 
and 3 patients received pembrolizumab 14 to 21 days after AUTO3 infusion, we observed that 
the only patients who received pembrolizumab had persistent CAR T cells at 2 months. None 
of the patients who did not receive pembrolizumab had persistence of CAR T cells at 2 months. 
It is likely that early dosing of pembrolizumab will further reduce CAR T cell exhaustion.  
These data suggest that the addition of pembrolizumab to CAR T cell therapy is likely to be 
tolerable and unlikely to significantly worsen the safety profile of AUTO3. Moreover, 
considering the pre-clinical data, the timing and kinetics of CAR T cell expansion and 
contraction in patients (median time to peak is 14 days), dosing with pembrolizumab on Day -1 
prior to AUTO3 infusion should be explored. This would also allow pembrolizumab to engage 
with tumour cells expressing de novo PD-L1 in addition to prevent early exhaustion and 
improve overall expansion and engraftment of CAR T cells. This is likely to complement the 
impact of FLU-CY pre-conditioning, which induces an IL-7 and IL-15 surge to increase CAR 
T cell engraftment and expansion.  
For safety reasons, pembrolizumab will be first introduced after peak expansion of CAR T cells 
and should that regimen (Regimen A - consolidation) be safe, then it will be given prior to 
CAR T cell infusion (Regimen B - pre-conditioning) to optimise the impact of pembrolizumab 
on CAR T cell exhaustion.  
Based on the rationale described above in Section 1.4 and considering the low starting dose 
and cautious study design, the proposed incorporation of limited duration (3 doses, Section 4.4) 
anti-PD-1 (pembrolizumab) consolidation or pre-conditioning is justified. 
4.7 
BIOMARKER COLLECTION AND ASSESSMENT RATIONALE 
Current experience with CAR T cell therapies indicate that the safety depends on the disease 
burden, CAR T proliferation, and cytokine release, and efficacy depends on CAR T 
proliferation and persistence. To this end, the current biomarker strategy is designed to assess 

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blood cytokine levels and CAR T levels and persistence at various time points after AUTO3 
infusion. In addition, BM sampling will be performed to assess disease status and expression 
of CD19/CD22 CAR Tpositive cells, which will help evaluate efficacy as well as resistance 
Additional optional samples may be collected to assess CY and/or FLU drug levels. 

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5 RISKS AND MITIGATION STRATEGY 
This exploratory study is designed to assess the safety and biological activity of different doses 
of AUTO3 in a limited number of patients. Given the treatment novelty, this study will involve 
patients whose disease has progressed after treatment with the main approved classes of agents. 
Such patients are considered to have poor prognosis and are candidates for promising 
experimental therapies. 
5.1 
LEUKAPHERESIS 
This is necessary for enrolling onto this study, as it is a prerequisite for preparing AUTO3. Cell 
production efficiency of at least 80% is anticipated and is dependent on the quality of the 
leukapheresate. AUTO3 infusion may or may not provide clinical benefit to these patients. 
Risks of leukapheresis are summarised in Table 9. 
Table 9: 
Leukapheresis – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Pain and bruising due to insertion of cannula/ 
central venous access. 
Experienced clinicians/nurses performing the procedure, 
analgesics to be used as needed for pain. 
Bacterial bloodstream infections associated 
with the insertion of access and return venous 
access devices. 
The procedure will be carried out by trained and 
experienced personnel and risks will be minimised by 
strict adherence to aseptic measure. 
Symptoms of hypocalcaemia e.g. muscle 
cramps due to chelation by anticoagulants used 
to prevent clotting. 
Patients will be monitored for symptoms of 
hypocalcaemia, the rate of citrate infusion to the patient 
and duration of the procedure will be controlled by 
experienced personnel. Calcium supplements will be 
given as needed. 
5.2 
FLU-CY PRE-CONDITIONING CHEMOTHERAPY 
Pre-conditioning with CY and FLU will only be undertaken after confirmation of the successful 
production of AUTO3. The risks of pre-conditioning with chemotherapy are summarised in 
Table 10. Please refer to the Summary of Product Characteristics (SmPC) or United States 
Prescribing Information (USPI) for more details. 

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Table 10: 
Pre-conditioning Chemotherapy – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Myelosuppression resulting in anaemia, 
thrombocytopenia, and lymphopenia, are the most 
common toxicities. Moderate to severe 
myelosuppression is possible. Nadir for granulocyte 
is 1 to 2 weeks and platelets 2 to 4 weeks after 
chemotherapy, with recovery usually within 4 to 
6 weeks. Neutropenic fever, infections, sepsis, and 
septic shock may occur and may sometimes be 
fatal.  
The FLU and CY chemotherapy given is milder 
compared to general chemotherapy received by 
patients and will be given only once (one cycle, given 
over 4 days). Anti-microbial prophylaxis (including 
pneumocystis prophylaxis and acyclovir) may be 
given to prevent infections and if infections arise, 
these will be treated as per institutional guidelines. 
Blood, platelet and fresh frozen plasma transfusions 
will be given as per standard institutional guidelines. 
All sites have extensive expertise in managing these 
complications. 
Cyclophosphamide associated toxicities including, 
but not limited to haemorrhagic cystitis, pyelitis, 
myocarditis and myo-pericarditis, pneumonitis and 
pulmonary fibrosis; veno-occlusive liver disease 
(per approved label) may also occur. 
Given the low dose and short duration of treatment, 
these toxicities are unlikely. Patients will be given 
anti-emetic prophylaxis and hydration during 
lymphodepletion as per institutional policy. If 
haemorrhagic cystitis occurs, i.v. fluids and mesna 
will be given. Other toxicities will be managed as per 
standard institutional policy and by trained personnel. 
Fludarabine is generally well tolerated: the most 
common side effects are lymphopenia and 
infection. Serious and sometimes fatal infections, 
including opportunistic infections and reactivations 
of latent viral infections such as Herpes zoster, 
Epstein-Barr virus, and progressive multifocal 
leukoencephalopathy, have been reported in 
patients treated with higher doses and for much 
longer durations. Neurotoxicity can occur but 
generally at higher doses. Other associated 
toxicities (as per the label) include but are not 
limited to autoimmune disorders, hepatic 
impairment, neuro-toxicity, and renal impairment. 
Given the low dose and short duration of treatment, 
these toxicities are less likely to occur. Toxicities will 
be managed as per standard institutional policy and by 
trained personnel. 
CY=cyclophosphamide; FLU=fludarabine; i.v.=intravenous 
5.3 
AUTO3 INFUSION 
Risks associated with the infusion of AUTO3 are presented in Table 11. 
Table 11: 
AUTO3 Infusion – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Infusion reactions may occur with the infusion of 
AUTO3. 
The product is autologous and the risk is likely 
to be low. Patients will be pre-medicated with 
diphenhydramine/chlorpheniramine and 
paracetamol/acetaminophen (Section 10.3). 
Cytokine-release syndrome is a recognised toxicity 
associated with CAR T cell therapies. Clinical symptoms 
indicative of CRS includes culture negative fever, but may 
also include myalgia, nausea/vomiting, tachycardia, 
hypoxia, hypotension, headache, confusion, tremor, and 
delirium. Potentially life-threatening complications of 
CRS may include cardiac dysfunction, acute respiratory 
distress syndrome, renal and/or hepatic failure, and 
Patients will be monitored for CRS and 
appropriate treatment will be given in the event 
of the occurrence (Section 10.4).  

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Risks  
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disseminated intravascular coagulation (DIC). The clinical 
features may overlap with macrophage activation 
syndrome. 
Neurotoxicity has been seen in patients with lymphoma 
after treatment with CAR T cell therapy and is now 
referred to as ICANS. The cause of NT is not well-
understood, although it is generally reported to be fully 
reversible. Although symptoms can vary, the early 
manifestations of ICANS are often tremor, dysgraphia, 
mild difficulty with expressive speech especially naming 
objects, impaired attention, apraxia, and mild lethargy. 
Other symptoms can include confusion, depressed level of 
consciousness/encephalopathy, hallucinations, dysphasia, 
ataxia, apraxia, cranial nerve palsies, and seizures. 
Headache is a non-specific symptom, frequently occurring 
during fever or after chemotherapy; thus, headache alone 
is not a useful marker of ICANS. Expressive aphasia, on 
the other hand, appears to be a very specific symptom of 
ICANS. 
The patient will be closely monitored for 
neurological signs and symptoms, and 
neuroimaging will be performed as appropriate. 
Appropriate treatment, including 
dexamethasone, will be provided in the event of 
severe NT, including cerebral oedema and 
seizures (Section 10.6). 
Cytopenia (neutropenia, thrombocytopenia and 
anaemia) has been seen in patients with leukaemia and 
lymphoma after treatment with CAR T cell therapy, 
though is often confounded by the patient’s prior 
treatments, disease state at the time of treatment and the 
pre AUTO3 lymphodepletion chemotherapy. The 
cytopenia may be prolonged but resolves in most 
individuals (Locke et al. 2019). 
Patients should be supported according to local 
institutional practice. Patients with low 
neutrophil counts will receive prophylactic 
antibiotics and antiviral medications if 
clinically appropriate and in accordance with 
local practice. All patients with fevers and 
neutropenia will have blood cultures drawn and 
broad-spectrum antibiotic coverage initiated 
promptly. 
Off-tumour toxicity could be due to either on-target (due 
to expression of the antigen on non-tumour cells) or off-
target (recognition of a molecular target other than CD19 
or CD22) interactions. Historically, there have been 
reports of on-target/off-tumour toxicity with CAR therapy 
as well as T cell receptor engineered T cells; the details are 
described in the IB.  
Pre-clinical toxicology indicates the risk to be 
low as CD19 and CD22 expression is largely 
limited to the B cell lineage. Ongoing CD19 
and or CD22 CAR studies have not shown 
significant off-target toxicity. Considering the 
body of knowledge concerning targeting CD19 
and CD22, this risk is likely to be low. 
Tumour lysis syndrome (TLS) may occur on treatment 
with AUTO3 due to rapid destruction of malignant cells in 
the context of a high tumour burden, although this is rarely 
seen after CD19 CAR-positive T cell therapy in 
lymphoma. 
If TLS occurs, all sites have extensive 
experience in managing this complication and 
supportive care will be initiated rapidly as per 
standard institutional protocols. (See 
Section 10.7). 
Hypogammaglobulinaemia may occur because of 
depletion of normal B cells by AUTO3. Potentially this 
may increase the risk of infections. The degree of 
hypogammaglobulinaemia and its duration are variable 
depending on the persistence of CAR T cells. 
B cell recovery and Ig levels will be monitored 
regularly following AUTO3 infusion. Patients 
with recurrent infections and persistent, severe 
hypogammaglobulinaemia will receive i.v. 
Ig replacement (Section 10.8). 
Sepsis: Sepsis leading to death has been noted in 
three patients treated with very high doses (5 × 108 CAR T 
cells) of CD19 CAR in a study done at UPENN. 
Gradual titration of dose, prophylactic 
antibiotics and antiviral medications, close 
monitoring of patients and early intervention is 
likely to reduce the risk. 
Insertional mutagenesis: Disruption of the cellular 
transcriptome by retroviral-mediated insertional 
mutagenesis has, in rare cases and in haematopoietic stem 
cell gene therapy trials, given rise to haematopoietic stem 
T cells that have been transduced with a 
retrovirus have, to date, been proven safe. 
Unlike haematopoietic stem cells, T cells are 
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Risks  
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cells with elevated expression of growth-related genes, 
which subsequently resulted in T cell leukaemia and/or 
lymphoma. 
transformation. The patients will be monitored 
for secondary malignancy and survival in a 
long-term follow-up protocol for up to 15 years 
following treatment with AUTO3 (see Section 
8.7). 
Risks associated with a replication competent 
retrovirus (RCR): There is a risk that a recombination 
event may occur during vector production that results in an 
RCR, which may be pathogenic in humans. 
All vector lots are tested for RCR prior to 
release to sites. The risks of an RCR are 
unknown. To date, no patient has developed an 
RCR with a retroviral based CAR T cell 
therapy. Patients will be monitored for RCR by 
polymerase chain reaction (PCR) during their 
scheduled follow-up visits. If a positive signal 
is confirmed, additional testing will be 
performed and medical and research experts 
will be consulted for the optimal treatment 
approach should any complication arise. 
Immunogenicity 
Evaluations to assess immunogenicity will be 
performed in this study. 
Anti-CAR antibodies or anti-CAR T cell 
response could be neutralising; reduced 
efficacy is possible in patients who develop 
them due to either neutralisation or enhanced 
clearance (Section 9.3.4)  
Dimethyl sulfoxide (DMSO), which is part of 
cryopreservative buffer, may cause an abnormal taste at 
the time of infusion and body odour lasting 1 to 2 days 
afterwards. At high doses, DMSO may cause nausea, 
vomiting, abdominal pain, headache, and haemolysis. 
Rarely, patients may experience mild or severe cardiac, 
pulmonary, renal, or neurological symptoms. 
Most patients are likely to be exposed to a 
small dose of DMSO; even at the highest dose, 
the median amount of DMSO exposure is likely 
to be 13 g and maximum 26 g, which is 
significantly lower than the general institutional 
maximum limit of 70 g. Additionally, at these 
dose levels, the side effects are likely to be mild 
and short lasting. 
Safety oversight of the patients dosed with AUTO3 in 
an outpatient/ambulatory care setting: After CAR T 
cells infusion, patients require monitoring while they are at 
risk for the development of CRS or ICANS.  
The sites selected have experience with either 
outpatient CAR T administration and/or 
outpatient stem cell transplantation to ensure 
adequate management follow-up of patients 
dosed with AUTO3. In addition, toxicities will 
be managed as per standard institutional policy 
and by trained personnel. Exclusion criteria 
have also been implemented specifically for the 
outpatient cohort.  
ALL=acute lymphoblastic leukaemia; CAR=chimeric antigen receptor; CD19=cluster of differentiation 19; CD22=cluster of 
differentiation 22; CRS=cytokine release syndrome; DIC=disseminated intravascular coagulation; DMSO=dimethyl 
sulfoxide; ECHO=echocardiogram; g=gram; IB=Investigator’s Brochure; ICANS=immune effector cell-associated 
neurotoxicity syndrome; Ig=immunoglobulin; i.v.=intravenous; MUGA=multigated acquisition; PCR=polymerase chain 
reaction; RCR=replication competent retrovirus; TLS=tumour lysis syndrome; UPENN=University of Pennsylvania. 
5.4 
ANTI-PD-1 
(PEMBROLIZUMAB) 
(PRE-CONDITIONING 
or 
CONSOLIDATION) THERAPY 
Administration of anti-PD-1 antibody during pre-conditioning or after CD19/CD22 
CAR-positive T cells (AUTO3) is thought to prevent tumour cell escape due to upregulation 
of PD-L1. The consolidation therapy regimen starting after AUTO3 administration will be 
undertaken after any CRS and NT have resolved. The risks associated with anti-PD-1 

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(pembrolizumab) are presented in Table 12. Please refer to the SmPC or USPI for more details. 
Use of a single dose of pembrolizumab as part of a modified pre-conditioning regimen may 
have a lower risk of immune toxicity. 
Table 12: 
Anti-PD-1 AUTO3 Consolidation or Pre-conditioning Therapy – Risks and 
Mitigation Strategy (per SmPC) 
Risks  
Mitigation Strategy  
Immune-mediated 
pneumonitis, including death 
Monitor patients for signs and symptoms of pneumonitis. Evaluate patients 
with suspected pneumonitis with radiographic imaging and administer 
corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, 
followed by a taper) for Grade 2 or greater pneumonitis. Withhold 
pembrolizumab for moderate (Grade 2) pneumonitis, and permanently 
discontinue pembrolizumab for severe (Grade 3) and life-threatening 
(Grade 4) pneumonitis. 
Immune-mediated colitis 
Monitor patients for signs and symptoms of colitis. Administer 
corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent 
followed by a taper) for Grade 2 or greater colitis. Withhold pembrolizumab 
for moderate (Grade 2) or severe (Grade 3) colitis, and permanently 
discontinue pembrolizumab for life-threatening (Grade 4) colitis. 
Immune-mediated hepatitis 
Monitor patients for changes in liver function. Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg/day [for Grade 2 hepatitis] and 1 to 
2 mg/kg/day [for Grade 3 or greater hepatitis] prednisone or equivalent 
followed by a taper) and, based on severity of liver enzyme elevations, 
withhold or discontinue pembrolizumab. 
Immune-mediated 
endocrinopathies including, 
hypophysitis, thyroid 
disorders and Type 1 
diabetes mellitus 
Monitor for signs and symptoms of hypophysitis (including hypopituitarism 
and adrenal insufficiency). Administer corticosteroids and hormone 
replacement as clinically indicated. Withhold pembrolizumab for moderate 
(Grade 2) hypophysitis and withhold or discontinue pembrolizumab for 
severe (Grade 3) or life-threatening (Grade 4) hypophysitis. 
Monitor patients for changes in thyroid function (at the start of treatment, 
periodically during treatment, and as indicated based on clinical evaluation) 
and for clinical signs and symptoms of thyroid disorders. Administer 
replacement hormones for hypothyroidism and manage hyperthyroidism with 
thioamide and beta-blockers as appropriate. Withhold or discontinue 
pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) 
hyperthyroidism 
Monitor patients for hyperglycaemia or other signs and symptoms of 
diabetes. Administer insulin for Type 1 diabetes; withhold pembrolizumab 
and administer an anti-hyperglycaemic in patients with severe 
hyperglycaemia. 
Immune-mediated nephritis 
and renal dysfunction 
Monitor patients for changes in renal function. Administer corticosteroids 
(initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a 
taper) for Grade 2 or greater nephritis. Withhold pembrolizumab for 
moderate (Grade 2), and permanently discontinue pembrolizumab for severe 
(Grade 3) or life-threatening (Grade 4) nephritis. 
Other immune-mediated 
adverse reactions 
For suspected immune-mediated adverse reactions, ensure adequate 
evaluation to confirm aetiology or exclude other causes. Based on the 
severity of the adverse reaction, withhold pembrolizumab and administer 
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Infusion-related reactions: 
pembrolizumab can cause 
severe or life-threatening 
infusion-related reactions, 
which have been reported in 
0.2% of patients receiving 
pembrolizumab 
Monitor patients for signs and symptoms of infusion-related reactions 
including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, 
hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) 
infusion-related reactions, stop infusion and permanently discontinue 
pembrolizumab. 
Embryo-foetal toxicity, 
based on its mechanism of 
action, pembrolizumab can 
cause foetal harm when 
administered to a pregnant 
woman 
Advise females of reproductive potential to use highly effective 
contraception during treatment with pembrolizumab and for 4 months after 
the last dose of pembrolizumab (or 12 months after AUTO3 whichever is 
longer). 
5.5 
UNKNOWN LONG-TERM RISKS OF GENE THERAPY 
Following completion of this study, all patients will be invited to enrol in a long-term follow-up 
study and monitored for up to 15 years for AUTO3 treatment-related SAEs, AEs of interest, 
including new secondary malignancies, and survival. 

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6 PATIENT POPULATION 
Patients will be eligible for the trial if all the inclusion criteria are met and none of the exclusion 
criteria applies. There will be no exception to the eligibility requirements at the time of 
registration. Ensuring patient eligibility is the responsibility of the Principal Investigator or 
other delegated Investigator(s). 
6.1 
INCLUSION CRITERIA 
Patients must meet all the following criteria for study entry: 
1. Male or female, aged ≥18 years. 
2. Willing and able to give written, informed consent to the current study. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1. 
4. Histologically confirmed DLBCL and large B cell lymphoma subsets, including: 
Phase I and Phase II Cohort 1: 
a. 
DLBCL, not otherwise specified (NOS), per World Health Organisation classification 
and DLBCL with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit).  
b. Transformed DLBCL from FL. High-grade B cell lymphoma with MYC expression 
(excluding Burkitt’s lymphoma). 
Phase I and Phase II Cohort 2: 
c. 
Transformed DLBCL from other indolent lymphomas (excluding Richter’s 
transformation). 
5. Chemotherapy-refractory disease, defined as one or more of the following: 
a. 
Stable disease (duration of stable disease must be less than or equal to 12 months) or 
progressive disease as best response to most recent chemotherapy containing regimen. 
Refractory disease after frontline chemo-immunotherapy is allowed. 
b. Disease progression or recurrence in ≤12 months of prior ASCT.OR 
6. Relapse after at least two lines of therapy or after ASCT. At a minimum: 
a. 
Patients must have received rituximab or another anti-CD20 monoclonal antibody 
(unless Investigator determines that tumour is CD20-negative) and an 
anthracycline-containing chemotherapy regimen. 
b. Patients must have either failed ASCT, or be ineligible for or not consenting to ASCT. 
c. 
Patients with transformed DLBCL must have received at least one line of therapy after 
transformation to DLBCL. 
7. PET-positive disease per Lugano classification. 
8. For females of childbearing potential (defined as <24 months after last menstruation or 
not surgically sterile), a negative serum or urine pregnancy test must be documented at 
screening, prior to pre-conditioning and confirmed before receiving the first dose of 
study treatment.  
For females who are not postmenopausal (<24 months of amenorrhea) or who are not 
surgically sterile (absence of ovaries and/or uterus), two methods of contraception 

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comprising of one highly effective method of contraception together with a barrier 
method must be used during the treatment period and for at least 12 months after the last 
dose of study treatment. They must agree not to donate eggs (ova, oocytes) for the 
purposes of assisted reproduction during the study and for 12 months after receiving the 
last dose of study drug (please refer to Appendix 3). 
9. For males, it must be agreed that two acceptable methods of contraception are used 
(one by the patient – usually a barrier method, and one highly effective method by the 
patient’s partner as defined in Appendix 3) during the treatment period and for at least 
12 months after the last dose of study treatment and that sperm will not be donated 
during the treatment period and for at least 12 months after the last dose of study 
treatment.  
10. Adequate renal, hepatic, pulmonary, and cardiac function defined as: 
a. 
Creatinine clearance ≥40 cc/min. 
b. Serum alanine aminotransferase/aspartate aminotransferase ≤2.5 × upper limit of 
normal (ULN). 
c. 
Total bilirubin ≤1.5 × ULN, except in patients with Gilbert’s syndrome. 
d. LVEF ≥50% (by echocardiogram [ECHO] or multigated acquisition scan [MUGA]) 
unless the institutional lower limit of normal is lower.  
e. 
Baseline oxygen saturation >92% on room air and ≤Grade 1 dyspnoea. 
11. Patient has adequate BM function without requiring ongoing blood product or 
granulocyte-colony stimulating factor support and meets the following criteria: 
a. 
Absolute neutrophil count ≥1.0 × 109/L. 
b. Absolute lymphocyte count ≥0.3 × 109/L (at enrolment and prior to leukapheresis). 
c. 
Haemoglobin ≥80 g/L. 
d. Platelets ≥75 × 109/L. 
12. No contra-indications for leukapheresis. 
6.2 
EXCLUSION CRITERIA 
Patients meeting any of the following exclusion criteria must not be enrolled into the study: 
1. Prior allogeneic haematopoietic stem cell transplant. 
2. Females who are pregnant or lactating. 
3. History or presence of clinically relevant CNS pathology such as epilepsy, paresis, 
aphasia, stroke within 3 months prior to enrolment, severe brain injuries, dementia, 
Parkinson’s disease, cerebellar disease, organic brain syndrome, uncontrolled mental 
illness, or psychosis. 
4. Patients with active CNS involvement by malignancy. Patients with history of CNS 
involvement with malignancy may be eligible if CNS disease has been effectively treated 
and provided treatment was at least 4 weeks prior to enrolment (at least 8 weeks prior to 
AUTO3 infusion). 

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5. Clinically significant, uncontrolled heart disease (New York Heart Association Class III 
or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
sick-sinus syndrome, or electrocardiographic evidence of acute ischaemia or Grade 3 
conduction system abnormalities unless the patient has a pacemaker) or a recent (within 
12 months) cardiac event. 
• 
Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are 
not excluded). 
• 
Evidence of pericardial effusion. 
6 
Patients with a history (within 3 months) or evidence of pulmonary embolism requiring 
ongoing therapeutic anticoagulation at the time of pre-conditioning. 
7 
Patients with active gastrointestinal (GI) bleeding. 
8 
Patients with any major surgical intervention in the last 3 months. 
9 
Active bacterial, viral or fungal infection requiring systemic treatment. Active or latent 
hepatitis B infection or hepatitis C infection. Testing positive for human 
immunodeficiency virus, human T cell lymphotropic virus (HTLV1 and 2) or syphilis. 
10. History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, systemic lupus) 
resulting in end organ injury or requiring systemic immunosuppression/systemic disease 
modifying agents within the last 24 months. 
11. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or 
inflammatory disease affecting the CNS. 
12. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or 
history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising 
pneumonia (e.g. bronchiolitis obliterans), or idiopathic pneumonitis. Prior radiation 
pneumonitis in the radiation field (fibrosis) is allowed (if >24 weeks since the event). 
13. History of other malignant neoplasms unless disease free for at least 24 months 
(carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal 
therapy allowed). 
14. Prior treatment with PD-1, PD-L1, or cytotoxic T lymphocyte-associated 
protein 4 targeted therapy, or TNF receptor superfamily agonists including CD134 
(OX40), CD27, CD137 (41BB), and CD357 (glucocorticoid-induced TNF receptor 
family-related protein) within 6 weeks prior to AUTO3 infusion (excluding study 
treatment with pembrolizumab on Day -1).  
15. Prior treatment with investigational or approved gene therapy or cell therapy products 
until a dose level has treated at least three patients and has been declared safe. 
16. Prior CD19 or CD22 targeted therapy.  
17. The following medications are excluded: 
• 
Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or 
72 hours prior to AUTO3 administration. However, physiological replacement, 
topical, and inhaled steroids are permitted. 
• 
Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior 
to leukapheresis or AUTO3 infusion.  

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• 
Cytotoxic chemotherapies within 2 weeks of AUTO3 infusion and 1 week prior to 
leukapheresis (2 weeks for lymphodepleting chemotherapy). 
• 
Antibody therapy use including anti-CD20 therapy within 2 weeks prior to AUTO3 
infusion, or 5 half-lives of the respective antibody, whichever is shorter. 
• 
Granulocyte-colony stimulating factor less than 10 days prior to leukapheresis. Live 
vaccine ≤4 weeks prior to enrolment. 
• 
Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other intrathecal 
chemotherapy (e.g. Ara-C) within 2 weeks prior to starting pre-conditioning 
chemotherapy. 
18. Prior limited radiation therapy (e.g. radiation to bone metastasis for pain control) within 
4 weeks of AUTO3 infusion or chest/mediastinal radiation within 24 weeks of AUTO3 
infusion. 
19. Research participants receiving any other investigational agents, or concurrent 
biological, chemotherapy, or radiation therapy. 
20. Known allergy to albumin, dimethyl sulphoxide (DMSO), CY or FLU, pembrolizumab 
or tocilizumab. 
21. Any contraindications to receive anti-PD-1 antibody pembrolizumab will be excluded 
from cohorts requiring administration of pembrolizumab. 
22. Patients, who in the opinion of the Investigator, may not be able to understand or comply 
with the safety monitoring requirements of the study. 
23. Any other condition that in the Investigator’s opinion would make the patient unsuitable 
for the clinical trial. 
Phase I Expansion Cohort: 
24. Subjects who do not have caregiver support (in line with institutional outpatient 
transplant guidelines) for outpatient/ambulatory care setting. 
25. Subjects who are staying greater than 60 minutes (or whatever is permissible per 
institutional outpatient transplant guidelines) from the clinical trial site at the time of 
treatment. 
PATIENT ELIGIBILITY TO RECEIVE AUTO3: Patients meeting any of the following 
criteria must not initiate pre-conditioning or infusion with AUTO3 (or pembrolizumab on 
Day -1) or must have the AUTO3 infusion delayed until they no longer meet these criteria:  
1. Severe intercurrent infection. 
2. Requirement for supplementary oxygen or active pulmonary infiltrates.  
3. Clinical deterioration of organ function (renal and hepatic) exceeding the criteria set at 
study entry.  

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7 ATIMP: AUTO3 
7.1 
AUTO3 DESCRIPTION 
AUTO3 is an ATIMP consisting of autologous enriched T cells retrovirally transduced to 
express two CARs, targeting CD19 and CD22, both on the same cell. AUTO3 also contains 
non-transduced autologous lymphocytes as a product-related impurity.  
AUTO3 is presented in a CryoMACS® bag as a suspension in saline/human albumin 
solution/DMSO. The final product, AUTO3, may consist of one or more CryoMACS® bags 
for i.v. infusion.  
7.2 
AUTO3 MANUFACTURING 
The Sponsor is responsible for the manufacturing of the drug product, AUTO3, according to 
Good Manufacturing Practice (GMP) principles and guidelines applicable to ATIMPs. The 
starting material for generation of AUTO3 is an unstimulated leukapheresate from the patient, 
which will be performed at the study site apheresis collection unit. This may require insertion 
of central venous access and is a day case procedure to collect peripheral blood mononuclear 
cells (PBMCs) only. Sites will be responsible for ensuring that the patient biological screening 
and leukapheresis procedures, including the labelling and issue of the leukapheresis product 
are carried out per the Human Tissue (Quality and Safety for Human Application) Regulations 
(SI 2007/1523) and in line with local procedures. 
The leukapheresis procedure will be performed by the apheresis unit staff as described in 
Section 8.2. The collected PBMCs will be transported to the Sponsor Manufacturing Unit for 
generation of AUTO3, under aseptic GMP conditions. Further details regarding this process 
can be found in the Investigational Medicinal Product Dossier (IMPD) or in Module 3 of the 
Investigational New Drug (IND).  
AUTO3 will be generated by ex vivo transduction of activated PBMCs using an engineered 
murine leukaemia virus-derived retroviral vector 
 containing the CD19/CD22 CAR 
expression cassette. The retroviral vector is produced under GMP conditions by 
 
cotransfection of HEK293T cells and subsequent harvest and purification of the culture 
supernatant. In brief, cells from the leukapheresate are washed and activated with mitogenic 
ligands and cytokines. After activation, cells are transduced in bags with the retroviral vector. 
Post-transduction, cells are expanded for between 3 and 6 days to produce adequate dose. The 
appropriate dose of cells is then transferred to a CryoMACS® bag and formulated with a 
saline/human albumin solution/DMSO buffer. Full release testing will be performed to 
pre-defined specifications. AUTO3 manufacture and release will take approximately 4 weeks. 
AUTO3 will be cryopreserved in a sealed CryoMACS® bag and stored in a vapour-phase liquid 
nitrogen environment prior to administration. Further details regarding this process can be 
found in the IMPD or in Module 3 of the IND. All AUTO3 products will be released by a 
Qualified Person (QP) (see also Section ). 
Please refer to the AUTO3 IB, IMPD or in Module 3 of the IND, and CHM for further details 
on the manufacture of AUTO3, shipment, storage, and handling. 
7.3 
PACKAGING AND LABELLING 
AUTO3 is supplied as a cryopreserved cell suspension in a sealed CryoMACS® bag containing 
the required number of CD19/CD22-CAR-positive T cells for the planned dose level. Each 

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AUTO3 CryoMACS® freezing bag will be labelled and will include all the required 
information, including the exact cell content, as applicable per local regulations. 
CryoMACS® freezing bags are single use, sterile, containers intended for a single cycle of 
freezing, storage (down to -196°C), and subsequent thawing (at 37°C) of AUTO3 cells. The 
CryoMACS® freezing bags are comprised of a freezing bag (with access ports) as the primary 
containment for AUTO3 and an overwrap bag as secondary containment. Additionally, the 
CryoMACS® freezing bag has a built-in label pocket, which allows for the insertion of the 
patient label to include patient identification and product specifications for AUTO3. As part of 
the bag assembly, two spike ports are available which allow access to the bag contents for 
therapeutic use of the product (via attachment of a sterile transfusion assembly). 
All AUTO3 products supplied will be released by a QP in line with national and/or EU 
requirements.  
7.4 
SUPPLY AND STORAGE 
Cryopreserved AUTO3 will be supplied to the study sites (authorised to receive genetically 
modified organisms, in accordance with local requirements) by the Sponsor. Transport of 
AUTO3 to the study site will be performed in validated shippers under controlled temperature 
conditions below -150°C. In the case of a temperature excursion occurring during transit, the 
disposition of AUTO3 will be decided following the review of the temperature data by the 
responsible QP or their designee. All temperature excursions outside the storage conditions 
specified in the IMPD/Module 3 of the IND/Labels/Trial-Specific Procedures for receipt and 
storage of AUTO3 must be documented and reported to the Sponsor via the Clinical Research 
Associate as per the CHM. The Sponsor must be informed immediately if a patient has been 
administered AUTO3 where a temperature excursion has occurred.  
The Investigator/pharmacist/designated personnel will take an inventory and acknowledge 
receipt of all shipments of the study product to confirm the shipment condition and content.  
AUTO3 must be stored at below -150°C, under controlled temperature and alarmed conditions, 
in a secure storage area with restricted access until ready for thawing and preparation as 
specified in the CHM. The study site will be responsible for the receipt, storage, and issue of 
AUTO3, and will comply with trial-specific procedures and the CHM.  
AUTO3 supplied for the AUTO3-DB1 trial is specific for each patient. 
7.5 
ACCOUNTABILITY AND DESTRUCTION 
Study drug accountability and traceability records will be maintained at the site at all times. 
The identification number of the patient, the administration date, batch number, expiry date 
and dose of AUTO3 dispensed will be recorded on the appropriate inventory forms.  
The Sponsor may authorise unused AUTO3 and any product contact materials to be disposed 
of as standard clinical waste (typically autoclaving). The site must obtain authorisation from 
the Sponsor before any AUTO3 is destroyed, and AUTO3 destruction must be documented on 
the appropriate form. Further details can be found in the CHM. Documented evidence of 
destruction will be made available to the Sponsor. Ancillary supplies are not required to be 
returned to the Sponsor. Accurate records of all AUTO3 received at, dispensed from, returned 
to, and disposed of by the study site should be recorded on the ATIMP accountability log. 

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8 STUDY PROCEDURES AND TREATMENT 
8.1 
CONSENT, SCREENING AND REGISTRATION 
Consent: All patients must sign an informed consent form (ICF) prior to the conduct of any 
study-related procedures. Sites are responsible for assessing a patient’s capacity to give 
informed consent. 
Sites must ensure that all patients have been given the current approved version of the patient 
information sheets (PIS), are fully informed about the trial, and have confirmed their 
willingness to take part in the trial by signing the current approved consent form. Sites must 
assess a patient’s ability to understand verbal and written information in English or the local 
language, and whether an interpreter would be required to ensure fully informed consent. If a 
patient requires an interpreter and none is available, the patient should not be considered for 
the trial.  
The Investigator, or, where delegated by the Investigator, other appropriately trained site staff, 
is required to provide a full explanation of the trial and all relevant treatment options to each 
patient prior to trial entry. During these discussions, the current approved PIS for the trial 
should be discussed with the patient. Sufficient time must be allowed for the patient to consider 
and discuss participation in the trial. Written informed consent on the current approved version 
of the ICF for the trial must be obtained before any trial-specific procedures are conducted. 
The discussion and consent process must be documented in the patient notes. 
Patient Assignment: After providing written informed consent, the patient will be issued with 
a unique patient identification number. The patient identification number will be used to 
identify the patient for the duration of the study. Patient identification numbers will not be 
reassigned or reused. 
The screening phase begins when the first screening assessment is conducted. During the 
screening phase, eligibility criteria will be reviewed, demographic data obtained, and a 
complete clinical evaluation will be performed. Screening procedures will be performed up to 
12 weeks before AUTO3 is administered (see Schedule of Assessments). If an assessment was 
performed as part of the patient’s routine clinical evaluation and not specifically for this study, 
it does not need to be repeated after signed informed consent has been obtained provided that 
the assessments fulfil the study requirements and are performed within the specified timeframe 
prior to the AUTO3 administration. Retesting of abnormal screening values that lead to 
exclusion is allowed during the screening phase (to reassess eligibility). The measurements 
collected at the time closest to, but prior to, the administration of AUTO3 will be defined as 
the baseline values for safety assessment and treatment decisions. Adverse events associated 
with screening procedures will be collected. Baseline data will be collected during screening 
as described in the Schedule of Assessments.  
Infectious Disease Screening: Patients will be tested by the site (in accordance with the site’s 
Human Tissue Authority license for human application) for infectious diseases as outlined 
below prior to (but within 30 days of) leukapheresis. If required, an additional infectious 
disease test will be done on the day of leukapheresis (or within 7 days of leukapheresis). 
Table 13 lists the tests that must be performed as a minimum requirement.  

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Table 13: 
Infectious Disease Screening 
Pathogen  
Test  
HIV 1 and 2  
Anti-HIV-1 and 2  
Hepatitis B  
Hepatitis B surface antigen, anti-hepatitis B core antibody 
Hepatitis C  
Anti-hepatitis C virus antibody  
Syphilis  
Syphilis serology (chemiluminescent microparticle immunoassay)*  
HTLV 1 and 2  
Anti-HTLV-1 and 2  
HIV=human immunodeficiency virus; HTLV=human T cell lymphotropic virus. 
* A validated testing algorithm must be applied to exclude the presence of active infection with Treponema pallidum. A 
non-reactive test, specific or non-specific, can allow tissues and cells to be released. When a non-specific test is performed, a 
reactive result will not prevent procurement or release if a specific Treponema confirmatory test is non-reactive. A patient 
whose specimen tests reactive on a Treponema-specific test will require a thorough risk assessment to determine eligibility 
for clinical use. 
A screening log must be maintained by the site and filed in the Investigator Site File. 
PATIENT REGISTRATION: Patient registration will be performed prior to commencement 
of any trial treatment. Following screening evaluations , confirmation of eligibility and consent 
of a patient at a site, the registration form must be fully completed and then sent to Autolus 
Limited. The patient information will be reviewed and registration will be approved by the 
medical monitor.  
After registration of patients, the site will coordinate with Autolus Limited on timing of 
leukapheresis to generate the ATIMP, AUTO3. 
8.2 
LEUKAPHERESIS 
Following informed consent, confirmation of eligibility and registration to the study, patients 
will undergo an unstimulated leukapheresis for the generation of AUTO3. 
Leukapheresis must be performed within 30 days of infectious disease testing and will be done 
following the standard institutional processes. In general, leukapheresis should be performed 
at least 35 days before the planned AUTO3 dosing date, as AUTO3 manufacture and release 
takes approximately 1 month. Based on emerging data this window may change. If required, 
an additional infectious disease test will be done on the day of leukapheresis (or within 7 days 
of leukapheresis). The leukapheresis may be repeated if an inadequate number of cells have 
been collected, the leukapheresate is contaminated, or additional leukapheresate is necessary 
for re-treatment. 
The leukapheresate is the starting material for the manufacture of the ATIMP, AUTO3. The 
total cell number that is required for successful manufacture varies according to the dose level. 
Typically, a double volume leukapheresis will be performed. The target collection is 1.6 × 109 
PBMCs. If the collection is insufficient, the Sponsor will advise as to the feasibility of 
successful manufacture. If collection is determined to be inadequate, then collected cells may 
be used for the Sponsor’s research purposes as per the consent. The leukapheresate will be 
transported to the Sponsor for generation of AUTO3 at a temperature of 2 to 8°C as soon as 
possible and within 48 hours, ideally within 24 hours. Further details regarding this process 
can be found in the CHM. 
Bridging chemotherapy may be prescribed to the patient during the AUTO3 manufacturing 
period at the discretion of the Investigator and in accordance with the exclusion criteria and 

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washout periods outlined in the eligibility criteria (see Section 6.2). Each leukapheresate will 
be identified by a unique patient identification number plus any additional patient identifiers 
as allowed per local regulations (typically initials and date of birth). 
Upon QP release of AUTO3 product, and if the patient continues to meet the eligibility criteria 
for entry to the study (as outlined in Section 6), the site will liaise with the manufacturer to 
arrange transfer of the AUTO3 product to the participating site. Further details are provided in 
the CHM. 
If a patient after successful leukapheresis and manufacture of AUTO3, re-enrols on the study 
and is eligible for treatment, repeat leukapheresis and manufacturing of AUTO3 may not be 
necessary and should be discussed with the Sponsor. 
8.3 
PRE-CONDITIONING CHEMOTHERAPY 
Patients that still meet eligibility requirements for the study and in whom AUTO3 has been 
QP-released will proceed to receive a standard lymphodepleting pre-conditioning treatment 
with FLU and CY before AUTO3 infusion. Patients on Regimen B will receive modified 
pre-conditioning that will include a single dose of pembrolizumab. The pre-conditioning phase 
will begin with administration of chemotherapy and will end with the beginning of treatment 
with AUTO3 infusion. During this phase, AEs associated with pre-conditioning chemotherapy 
as well as use of concomitant medications will be collected.  
Prior to administration of pre-conditioning chemotherapy, patients will undergo clinical and 
laboratory assessments as per the Schedule of Assessments and the site Investigator or 
Designee will determine if the patient is fit to receive pre-conditioning chemotherapy. If 
considered to be fit, patients will proceed to receive a standard lymphodepleting 
pre-conditioning treatment with CY and FLU for 4 days (starting Day -6), and timed to end 
3 days (-1 day) before AUTO3 infusion The pre-conditioning treatment will be administered 
with a single dose of pembrolizumab on Day -1 for Regimen B. 
8.3.1 
Pre-conditioning Dose and Regimen 
Fludarabine-CY dosing is described below; FLU will be given first. 
Regimen A (Standard Pre-conditioning Regimen): 
• 
Day -6: FLU 30 mg/m2 followed by CY 500 mg/m2. 
• 
Day -5: FLU 30 mg/m2 followed by CY 500 mg/m2.  
• 
Day -4: FLU 30 mg/m2  
• 
Day -3: FLU 30 mg/m2.  
Regimen B (Modified Pre-conditioning Regimen): 
• 
Day -6: FLU 30 mg/m2 followed by CY 500 mg/m2. 
• 
Day -5: FLU 30 mg/m2 followed by CY 500 mg/m2.  
• 
Day -4: FLU 30 mg/m2. 
• 
Day -3: FLU 30 mg/m2.  
• 
Day -1: Pembrolizumab 200 mg. 

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The pre-conditioning chemotherapy should be completed a minimum of 3 days (-1 day) prior 
to AUTO3 infusion.  
Fludarabine will be given by i.v. infusion over approximately 30 minutes in sodium chloride 
0.9%. For patients with renal impairment (glomerular filtration rate 30 to 60 mL/min/1.73 m2 
[corrected]), the dose of FLU should be reduced per routine clinical practice (generally by 
25%). When patients receive both CY and FLU, FLU will be given first. 
Cyclophosphamide will be given by i.v. infusion over approximately 30 minutes. Adequate 
pre- and post-hydration for up to 4 to 6 hours (or as per institutional practice) should be given 
post-infusion to induce diuresis. Use of mesna for the prescribed dose is generally considered 
unnecessary but may be considered based on institutional practice. Cyclophosphamide dose 
may be reduced if the leukocyte count is <2500 cells/μL with 6 hours post-hydration.  
Anti-emetic prophylaxis will be given as per standard institutional policy. Prophylaxis for 
tumour lysis syndrome (TLS) with allopurinol and i.v. fluids may be given if clinically 
necessary.  
For additional information, please refer to the FLU and CY SmPCs/USPIs. 
Pembrolizumab: Refer to the SmPC/USPI for additional information regarding 
pembrolizumab. 
8.3.2 
Supply of Pembrolizumab 
Pembrolizumab is being used as pre-conditioning therapy prior to treatment with AUTO3. The 
proposed use is not an authorised indication for this drug, and duration of use for 
pre-conditioning therapy is limited to one dose (Regimen B) compared to continuous use until 
progression for other authorised indications. 
Pembrolizumab is authorised and commercially available in the UK, US and EU. The Sponsor 
will provide appropriately labelled pembrolizumab to the hospital sites. Sufficient quantities of 
pembrolizumab will be dispensed to cover the prescribed dose and will be labelled for the 
study, and prepared as per site Standard Operating Procedures and according to manufacturer 
recommendations and standard local practice. Good aseptic practice must be employed when 
preparing pembrolizumab solutions for infusion. 
8.3.3 
Supply of Fludarabine and Cyclophosphamide 
Fludarabine and CY are non-investigational medicinal products (NIMPs) as they are not being 
tested or used as a comparator in this trial. Fludarabine and CY will be used to induce 
lymphodepletion in the current study as a pre-conditioning treatment, prior to AUTO3 
treatment. Both drugs are authorised and commercially available in the UK, US and EU. 
Investigators will be responsible for their own supply of FLU and CY, sourced from their 
institution. Sufficient quantities of FLU and CY will be dispensed to cover the prescribed dose 
and will be prepared as per site Standard Operating Procedures and according manufacturer 
recommendations. Fludarabine and CY are cytotoxic and must be handled with care in 
accordance with local policy. Good aseptic practice must be employed when preparing FLU 
and CY solutions for infusion. Further details may be found in the USPI/SmPCs for FLU and 
CY.  

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8.3.4 
Accountability 
of 
Fludarabine 
and 
Cyclophosphamide 
and 
Pembrolizumab 
Pharmacy records of the pembrolizumab dispensed to trial patients should be kept. The expiry 
date, batch number used, and manufacturer should be recorded as well as details of vials 
dispensed and returned. 
Pharmacy records of the FLU and CY dispensed to trial patients should also be kept. 
8.4 
AUTO3 TREATMENT AND PATIENT MONITORING 
The treatment phase will involve infusion of AUTO3 on Day 0. Patients will be monitored for 
up to 10 days (inpatient or ambulatory care setting), or longer if clinically necessary. 
8.4.1 
Assessment Prior to AUTO3 Infusion 
Prior to administration of AUTO3 patients will undergo clinical and laboratory assessments 
and the site Investigator or designee will determine if the patient is eligible to receive AUTO3 
as per protocol Section 6 (see Schedule of Assessments for details). For patients who receive 
bridging therapy, baseline disease assessment with positron emission tomography (PET)/CT 
should be done after completion of bridging therapy and before pre-conditioning and AUTO3 
infusion. 
If patients are not eligible to receive infusion of AUTO3 (Section 6.2), the infusion will be 
delayed. Infusion at a later date may be performed as per dose delay guidelines (Section 8.4.4) 
or cancelled.  
8.4.2 
AUTO3 Administration 
AUTO3 (upon successful QP release) will be administered as a single rapid i.v. infusion on 
Day 0 in an in-patient setting. Full details will be provided in the CHM. Only the Investigator 
or Investigator’s designee will dispense the study product.  
Premedication with diphenhydramine/chlorpheniramine and paracetamol/acetaminophen may 
be given prior to infusion of AUTO3 as per standard institutional practice (see Section 10.2), 
but steroids should not be given as part of premedication 
The Investigator or Investigator’s designee or a study research nurse experienced in the 
administration of cellular blood products as per the trial-specific procedure will verify that the 
patient details (Unique Patient Number) on the AUTO3 label matches the recipient, check the 
dose of cells, volume, and number of cryobags to be infused and prescribe the AUTO3 on a 
blood product chart. Details of the exact dose, volume (from label), time of completion of 
thawing and time of completion of infusion will be documented in the applicable study records. 
AUTO3 will be infused as described in the CHM. In brief, AUTO3 will be thawed in a 37°C 
water bath under sterile conditions, the bag will be gently massaged until the cells have just 
thawed. There should be no frozen clumps left in the bag. The entire contents of the bag will 
be given as an i.v. infusion using a syringe or gravity aided infusion through a central or 
peripheral venous line over 5 to 15 minutes (max under 30 mins) through an 18-gauge blood 
set. A leukodepleting filter must NOT be used for the infusion of the T cell product. The 
infusion line and the bag should be flushed as described in the CHM to ensure all cells have 

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been administered. If the AUTO3 cell product appears to have a damaged or leaking bag, or 
otherwise appears to be compromised, it should not be infused. 
Although not routinely practiced, there may be circumstances (e.g. when AUTO3 is 
administered by a site for the first time), when Sponsor representatives may be present to 
observe the thawing and/or dosing of AUTO3. These individuals will have no participation in 
the preparation of the product nor in any part in the patient’s medical care. This will only occur 
if the practice is allowed by local IRB Ethics Committee and institutional guidelines and the 
consent of the patient. This may also allow the sponsor to collect best practices and further 
refine dose administration.  
The time between completion of thawing and completion of infusion should not exceed 
30 minutes. 
8.4.3 
Monitoring During and After Drug Administration 
8.4.3.1 
During Phase I – Escalation  
Patients will be monitored (inpatient or ambulatory care setting) for up to 10 days (or until all 
AUTO3 related non-haematological toxicities have returned to Grade ≤1 or baseline) following 
the cell infusion (longer if clinically necessary). Monitoring will include temperature, pulse, 
blood pressure, respiratory rate, and oxygen saturations immediately prior to and every 
30 minutes (±10 minutes) for 4 hours after AUTO3 infusion. Any clinically significant changes 
in vital signs should be recorded and reported as an AE as appropriate. In the event of allergic 
adverse reactions, anti-histamines may be administered, as well as oxygen and salbutamol in 
the event of respiratory distress. 
During hospitalisation/ambulatory care, patients will be monitored daily and will undergo 
blood tests (see Schedule of Assessments) for signs of toxicity, in particular for CRS, TLS and 
neurological disturbance. Transfusions of blood products, antibiotics, analgesics, and intensive 
care will also be provided as clinically indicated. Prophylaxis for TLS may be initiated if the 
risk is considered high or for all new patients if TLS occurs at a certain dose level. Urate levels 
will be monitored and treatment started if indicated.  
Data regarding intensity of care will be collected on a periodic basis e.g. duration of inpatient 
stay or ambulatory care admission, intensive care unit/intensive therapy unit stay, duration of 
pressor support, mechanical ventilation, dialysis. 
Patients may be discharged from hospital when clinically appropriate or following successful 
management of CRS, even if it is prior to 10 days post-AUTO3 infusion, if deemed appropriate 
by the treating Investigator. The in-patient stay may be extended if deemed necessary by the 
treating physician. 
Following discharge from the hospital, the patient will be closely monitored for AEs and 
laboratory abnormalities, at least on a weekly basis. The required study procedures and 
assessments to be conducted during the Treatment Stage are outlined in the Schedule of 
Assessments. Clinical evaluations and laboratory studies may be repeated more frequently, if 
clinically indicated. Provided that all criteria are satisfied (see Section 8.4.7), patients may 
receive re-treatment (2nd cycle) of AUTO3.  
Patients will also receive consolidation treatment (Section 8.5). Patients will be monitored 
(inpatient or ambulatory care setting) for up to 3 days after the first dose of consolidation 
treatment with pembrolizumab on Day 14 (applicable to Regimen A). Safety and efficacy 

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assessments described in the Schedule of Assessment will be performed and AEs and 
concomitant medications will be documented.  
After being discharged, patients will attend the clinic on a regular basis as described in the 
Schedule of Assessments (Table 1). At the end of the treatment phase (Day 28), a complete 
evaluation of disease response will be performed as outlined in Schedule of Assessments 
Table 1 and described in Section 9.4. Clinical evaluations and laboratory assessments may be 
repeated more frequently including neurological examination and coagulation as clinically 
indicated. 
After completing the study the patients will be followed on a separate long-term follow-up 
protocol (AUTO-LT1). 
8.4.3.2 
During Phase I Expansion Cohort 
Patients will be infused and monitored in an outpatient/ambulatory care setting. The monitoring 
guidelines are the same as described in Section 8.4.3.1, except during the 10 days following 
AUTO3 infusion, the patients are assessed by a healthcare professional at a minimum every 2 
to 3 days instead of daily. In addition, it is recommended for the patient to have a daily verbal 
communication with qualified nurse/medical personnel (phone call). Note:  in the UK, the 
patients are to be assessed at least once a day for 10 days by a physician or qualified designee. 
Based on emerging safety finding patients may be admitted as deemed appropriate by the 
medical personnel. 
8.4.4 
Dose Delay 
If the pre-conditioning regimen is interrupted for intercurrent illness or other reasons, the 
patient may complete or recommence the pre-conditioning regimen after recovery, or proceed 
with partial pre-conditioning according to the Investigator’s judgment after consultation with 
the Sponsor. Patients will be closely monitored during and after the conditioning regimen. 
If a patient is unable to be dosed on the planned day with AUTO3, they may undergo delayed 
dosing, and be re-pre-conditioned (if appropriate) if they continue to meet the study enrolment 
criteria. If AUTO3 infusion is delayed and time between end of pre-conditioning chemotherapy 
and AUTO3 infusion is more than 8 days, infusion of AUTO3 should not proceed without 
consultation with the Sponsor. Imaging studies may not need to be repeated if the patient has 
not received any other anti-lymphoma therapy in the interim (excluding steroids and pre-
conditioning chemotherapy). Patients undergoing delayed dosing may be evaluable for dose 
escalation decision making if the SEC so concludes.  
If the patient is deemed unsuitable to receive AUTO3, they will be discontinued from the 
clinical trial (see Section 15.2) and replaced. Each case will be discussed with the Sponsor. 
Dose delays with pembrolizumab should be managed as per the prescribed dosing windows in 
the protocol and SmPC/USPI. 
8.4.5 
Interruption of Infusion 
In the event of severe infusion reaction, the FLU-CY or AUTO3 or pembrolizumab infusion 
should be stopped and the patient treated as clinically indicated. When the patient has 
recovered, the infusion may be restarted. 

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Interruption of AUTO3 should not be greater than 30 minutes after thawing of AUTO3. If an 
infusion is interrupted for mechanical, technical or any other reason, then this should be dealt 
with per local practice and the infusion restarted as soon as possible. In case of uncertainty, 
individual cases should be discussed with the Sponsor.  
If the patient develops an allergic reaction to the drugs in the pre-conditioning regimen, 
alternative drugs as per the institutional practice may be considered after discussion with the 
Sponsor. 
8.4.6 
Duration of Treatment 
In most patients, it is expected that AUTO3 will be given once. However, if a patient has 
sufficient AUTO3 remaining from the original manufacture and meets the re-treatment criteria, 
a second treatment may be given (see re-treatment of patient Section 8.4.7). 
8.4.7 
Re-treatment of Patients 
It is expected that most patients will receive a single dose of AUTO3 as part of their treatment. 
However, some patients may have sufficient AUTO3 leftover for a re-treatment, or 
leukapheresate, which can be used to manufacture AUTO3, or they may be eligible for repeat 
leukapheresis. Such patients may receive a re-treatment (as single infusion) of their own stored 
AUTO3. Prior to re-treatment, the patient needs to meet the following criteria: 
1. Patient shows evidence of low AUTO3 survival (<0.2 × 109/L) and no significant 
anti-tumour effect (no CR) after the first dose, and the first treatment dose is considered 
to be sub therapeutic. 
OR 
2. There was objective clinical evidence of anti-tumour activity following the previous 
AUTO3 infusion (i.e. Stable Disease or better).  
OR 
3. The patient has evidence of progressive disease in the context of declining levels of 
AUTO3. Circulating levels AUTO3 cells must be low (<0.2 × 109/L) for at least 2 weeks 
prior to the second infusion.  
AND all of the following: 
4. The patient has adequate cryopreserved AUTO3 available for a second dose (≤highest 
safe dose). 
5. The patient tolerated the first infusion without dose-limiting or other severe or 
unmanageable toxicity for a follow-up period of at least 28 days.  
6. The patient still fulfils the trial entry criteria required to tolerate another pre-conditioning 
treatment and AUTO3 infusion.  
Patients undergoing a second AUTO3 infusion should receive the same pre-conditioning. The 
dose of AUTO3 can be at (or up to) the highest dose level cohort that has been declared safe 
after dosing at least three patients and has shown evidence of anti-tumour activity (CR or PR). 
These patients who are being re-treated will not contribute to dose escalation decisions in that 
dose cohort, unless a DLT occurs as per DLT criteria in Section 3.6. Patients that have or have 
not received consolidation or pre-conditioning therapy with anti-PD-1 antibody with the earlier 

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dose may receive consolidation or pre-conditioning following re-treatment with AUTO3. 
Depending on the number of cells available, an intermediate dose may also be administered if 
considered appropriate. The decision to re-treat a patient will be made by the treating 
Investigator and Sponsor in consultation with the SEC. Patients re-treated will be monitored in 
a similar way to patients being treated for the first time. 
8.5 
CONSOLIDATION THERAPY 
Anti-PD-1 Antibody: Pembrolizumab 
Consolidation therapy with anti-PD-1 antibody pembrolizumab will be administered after 
AUTO3 and following resolution of key toxicities such as CRS (resolution to  Grade 1) and 
NT. 
8.5.1 
Pembrolizumab Dose and Regimen 
Pembrolizumab (200 mg) will be infused over 30 minutes: 
• on Day 14 (±3 days) and repeated every 3 weeks for a total of 3 doses i.e. on Day 35 
(±3 days) and Day 56 (±3 days) (Regimen A only)  
Administration of pembrolizumab may be delayed by up to 14 days until any ongoing CRS or 
NT has resolved, with a minimum dosing interval of 21 days between doses.  
Based on emerging data, the Investigator may consider additional doses on a case-by-case basis 
and in consultation with the medical team. Pembrolizumab should be prepared and infused in 
accordance with the USPI/SmPC. 
Administration of pembrolizumab should be withheld if any of the following occur:  
• ≥Grade 2 pneumonitis.  
• ≥Grade 2 colitis.  
• ≥Grade 3 endocrinopathies.  
• ≥Grade 2 nephritis.  
• Aspartate aminotransferase or alanine aminotransferase >3 and up to 5 × ULN or total 
bilirubin >25 µmol/L (1.5 mg/dL) and up to 3 × ULN. 
• Any other severe or Grade 3 treatment-related adverse reaction. 
Refer to the SmPC/USPI for additional information regarding pembrolizumab. 
8.5.2 
Supply of Pembrolizumab 
Pembrolizumab is being used as consolidation therapy following treatment with AUTO3. The 
proposed use is not an authorised indication for this drug, and duration of use for consolidation 
therapy is limited to three doses in total, with one dose every 3 weeks (Regimen A) and one 
dose in Regimen B (compared to continuous use until progression for other authorised 
indications). 
Pembrolizumab is authorised and commercially available in the UK, US and EU. The Sponsor 
will provide appropriately labelled pembrolizumab to the hospital sites. Sufficient quantities of 
pembrolizumab will be dispensed to cover the prescribed dose and will be labelled for the 

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study, and prepared as per site Standard Operating Procedures and according to manufacturer 
recommendations and standard local practice. Good aseptic practice must be employed when 
preparing pembrolizumab solutions for infusion. 
8.5.3 
Accountability of Pembrolizumab 
Pharmacy records should be kept of the pembrolizumab dispensed to trial patients. The expiry 
date, batch number used, and manufacturer should be recorded as well as details of vials 
dispensed and returned.  
8.6 
FOLLOW-UP PHASE 
Upon completion of consolidation treatment, for patients enrolled in Phase I in regimen A, or 
1 month after administration of AUTO3 for patients enrolled in Phase I regimen B and Phase 
II, all patients will enter the follow-up phase where they will continue to be monitored 
periodically as detailed in the schedule of assessments until the end of the study or until early 
withdrawal or death, whichever is the latest for the assessment of anti-tumour response and for 
safety evaluation. Adverse events that are considered related to the study medication will be 
recorded/reported as detailed in Section 12.3.  
8.6.1 
Efficacy and Safety Follow-up 
Following initial achievement of CR, stable disease, PR (and non-evaluable [NE] patients) at 
Month 1 or later, based on PET using [18F]-fluorodeoxyglucose (FDG), CT scans, magnetic 
resonance imaging (MRI), physical examination, including lymphoma B-symptoms, BM, and 
other procedures as appropriate, the patients will be followed up for efficacy and safety.  
Patients will have periodic monitoring of response (as per Appendix 1) based on PET using 
[18F]-FDG, CT scans, magnetic resonance imaging (MRI), as described in the schedule of 
assessments.   
Patients who proceed to transplant or other anti-cancer therapies while in remission will also 
be monitored for efficacy and safety until the EOS. 
Patients will be invited to participate in the long-term follow-up study at EOS.  
Relapse evaluation: If at any time during the Efficacy and Safety Follow-Up, a patient who 
was in remission relapses, a full disease evaluation will be completed. As soon as possible after 
being aware of a relapse, the patient will be scheduled for a visit, and have PET/CT and other 
assessments as clinically indicated (e.g. tumour biopsy).  
Once patients have completed the 36-month follow-up period post AUTO3 infusion, they will 
be monitored every 6 months until the end of study as per schedule of assessments (Table 2).  
Patients who have received AUTO3 and who are still responding will subsequently be 
followed-up for: 
• 
Survival, limited concomitant medication, all SAEs and AEs considered related to the 
AUTO3, AEs of special interest, and any new malignancy (Section 12.3) 
• 
Disease response until progression or end of the study  
• 
First subsequent therapy post-CAR-T and response if applicable 
• 
Once a year for AUTO3 vector persistence and RCR.  

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8.6.2 
Safety and Survival Follow-up 
Patients who fail to respond to treatment or who respond but subsequently progress will 
continue to be monitored for safety and survival until EOS as per the safety and survival 
schedule of assessments (Table 3). At EOS, the patients will complete an EOS visit and will 
be invited to participate in the long-term follow-up study. 
The first assessment for the safety and survival follow-up will happen at the next planned visit 
as per the safety and survival follow-up schedule of assessments e.g. if a patient progresses at 
Month 10, then the first visit in for safety and survival follow-up will be Month 12. 
During the safety and survival follow-up, patients will come to the site as per schedule of 
assessments. If a patient cannot attend a scheduled visit, the information can be collected 
remotely (e.g. over the phone) and the Investigator should attempt at a minimum to determine 
the survival status and whether the patient has started receiving additional antineoplastic 
therapies and associated response to new treatment.  
In the event that a patient still in remission is no longer willing to be followed up for efficacy 
and safety, but agrees to remain on study to be monitored for safety and survival until 
completion of the study, the Investigator should attempt at a minimum to determine the relapse 
status and whether the patient has started receiving additional antineoplastic therapies. The 
efficacy data collected as per the local standard of care may be recorded in the clinical database 
until they relapse or rollover to the long-term follow-up study.  
Selected AEs and concomitant medications will be recorded, please refer to Section 12.3.  
For patients who are lost to follow-up, the Investigator should show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. 
Once patients have completed the 36-month follow-up period post AUTO3 infusion, they will 
be monitored every 6 months until the end of study as per schedule of assessments.  
Patients who have received AUTO3 and subsequently progressed will be followed up for: 
• 
Survival, all SAEs and AEs considered related to AUTO3, AEs of special interest and any 
new malignancy (see Section 12.3) 
• 
First subsequent therapy post-CAR-T and response if applicable 
• 
Once a year for AUTO3 vector persistence and RCR  
If a patient misses a scheduled visit, or if the visit time-point where survival status is required 
does not align with a scheduled visit, survival status can be obtained via phone contact with 
the patient or correspondence with local health care provider.  
Any patient who had already completed their end of study visit on the main AUTO3-DB1 study 
may be re-enrolled if they wish to consent to the new schedule of assessments for long-term 
safety and survival follow-up (Table 3). 
8.7 
LONG-TERM FOLLOW-UP 
The aim of the long-term follow-up protocol is to assess for delayed consequences due to the 
use of a viral vector during the manufacture of AUTO3. Semi-annual and annual evaluations 
will be performed on all patients who have received AUTO3. At least once a year, patients will 
visit the clinic for a physical exam and medical history (including concomitant medications 

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and AEs) with careful attention to features possibly related to retrovirus associated events such 
as new malignancies, new incidence or exacerbation of autoimmune disorder. In addition, 
blood samples will be taken to evaluate routine safety endpoints, CAR-T persistence and RCR. 
All patients who have received AUTO3 will be eligible and asked for their consent to be 
enrolled onto a separate long-term follow-up protocol at EOS.  
Patients enrolled in the long-term follow-up study  will be monitored for all SAEs considered 
related to the study treatment, AEs of special interest, including any new malignancy, for a 
period of up to 15 years following treatment with AUTO3. Data regarding survival and 
subsequent therapies will be collected.  
 

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9 STUDY ASSESSMENTS 
9.1 
DEMOGRAPHIC AND BASELINE ASSESSMENTS 
The following will be collected at screening to determine eligibility and baseline status of the 
patient. 
9.1.2 
Demographic Data and Baseline Variables 
Demographic data 
• 
Demographic data will include self-reported race/ethnicity, age, gender, and height at 
screening visit prior to leukapheresis. 
Medical history/lymphoma 
• 
Medical history includes clinically significant diseases, surgeries, lymphoma history and 
treatment, lymphoma B-symptoms, all medications used by the patient and known 
allergies. Histological confirmation of disease diagnosis will be obtained (pathology 
report). 
Pregnancy test 
• 
Serum (β-human chorionic gonadotropin) or urine pregnancy testing will be performed for 
females of childbearing potential at the screening visit and will be repeated when the 
patient is admitted prior to starting lymphodepletion, prior to starting pre-conditioning 
treatment, and prior to AUTO3 infusion. Following AUTO3 infusion, pregnancy testing 
will be performed at Day 28, Day 56, Month 3, Month 6, Month 12, Month 18 and 
Month 24 (for patients on study), as described in the Schedule of Assessments. 
9.2 
SAFETY EVALUATIONS 
All patients who receive AUTO3 will be considered evaluable for toxicity assessment. Any 
clinically relevant changes occurring during the study must be recorded on the AE section of 
the electronic Case Report Form (eCRF). Safety assessments will be based on medical review 
of AE reports and the results of vital sign measurements, electrocardiograms (ECGs), physical 
examinations, clinical laboratory tests, and performance status assessments at specified time 
points as described in the Schedule of Assessments. Any clinically significant abnormalities 
persisting at the end of the study/early withdrawal will be followed by the Investigator until 
resolution, or until a clinically stable endpoint is reached. The study will be monitored by the 
SEC and IDMC (details regarding the SEC and IDMC are provided in Section 13). The study 
will include the following evaluations of safety and tolerability according to the time points 
provided in the Schedule of Assessments. 
9.2.1 
Adverse Events and Toxicity 
Adverse events will be noted by clinic staff or reported by the patient (or, when appropriate, 
by a caregiver, surrogate, or the patient's legally acceptable representative) for the duration of 
the study. Adverse event recording and reporting is described in detail in Section 12.3. 
Toxicity will be graded using the NCI CTCAE Version 5.0 criteria. The incidence of NCI 
Grade 3 to 5 toxicity and the frequency and severity of AEs occurring within 75 days of 
AUTO3 infusion will be determined. In particular, the incidence of Grade 3 to 5 CRS and 

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Grade 3 to 5 NT occurring within 75 days of AUTO3, according to the ASTCT/ASBMT 
consensus grading (Lee et al. 2019) will be determined (see Section 12).  
The incidence of AEs will be tabulated and reviewed for potential significance and clinical 
importance.  
9.2.2 
Clinical Laboratory Tests 
Blood samples for haematology, coagulation and biochemistry will be collected at each visit 
as specified in the Schedule of Assessments. Where appropriate, tests must be performed prior 
to receiving pre-conditioning treatment or AUTO3 infusion. More frequent clinical laboratory 
tests may be performed if indicated by the overall clinical condition of the patient or by 
abnormalities that warrant more frequent monitoring. Screening laboratory results must be 
available to the Investigator for evaluation before AUTO3 infusion and subsequent laboratory 
results should be available at the time of the patient’s evaluation by the treating physician. The 
Investigator must review the laboratory reports, document this review, and ensure that any 
clinically relevant changes occurring during the study are recorded in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. A summary of the tests 
that will be performed by the local laboratory is presented in Table 14.  
Table 14: 
Clinical Laboratory Tests 
Assessment 
Description 
Haematology 
Haemoglobin, red blood cell count, platelet count, white blood cell count with 
differential (neutrophils, eosinophils, lymphocytes, monocytes, and basophils). 
Coagulation 
Prothrombin time, international normalised ratio, activated partial thromboplastin 
time, fibrinogen. 
Biochemistry 
Sodium, phosphate, potassium, ALT, AST, uric acid, urea, creatinine, CPK, lactate 
dehydrogenase, total bilirubin, calcium, albumin. All tests must be performed prior 
to AUTO3 infusion on Day 0.  
Ferritin, C-reactive 
protein  
Ferritin, C-reactive protein. 
Pregnancy test 
Serum (β-human chorionic gonadotropin) or urine pregnancy testing for females of 
childbearing potential. 
Serology (at 
screening only) 
• 
HIV antibody. 
• 
Hepatitis B core antibody: if positive, further testing (DNA by PCR) to rule out 
active disease or chronic carrier. Must be confirmed negative prior to screening. 
• 
Hepatitis C virus antibody: if positive for hepatitis C virus, further testing (by 
ribonucleic acid PCR) should be performed to rule out active infection. 
• 
Anti-HTLV-1. 
• 
Anti-HTLV-2 
• 
Syphilis Serology 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; DNA=deoxyribonucleic 
acid; HIV=human immunodeficiency virus; HTLV=human T cell lymphotropic virus; PCR=polymerase chain reaction.  
9.2.3 
12-lead Electrocardiogram 
A 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart 
rate and measures PR, RR, QRS, QT, and corrected QT intervals. Refer to the Schedule of 
Assessments for details regarding the frequency of ECG assessments. At each time point, a 

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single 12-lead ECG will be performed by qualified site personnel. The clinical Investigator or 
designee will review the printout, including ECG morphology. The ECG should be repeated in 
triplicate if motion artefacts or clinically relevant abnormalities are noted. Additional 
cardiovascular assessments should be performed as clinically appropriate to ensure patient 
safety. If blood sampling or vital sign measurement is scheduled for the same time point as 
ECG recording, the procedures should be performed in the following order: ECG(s), vital signs, 
then blood draw. 
9.2.4 
Echocardiogram and Multigated Acquisition 
Echocardiogram is the preferred method to assess cardiac ejection fraction and cardiac valve 
abnormalities; MUGA is an acceptable alternative. Assessments should be performed at 
screening and additional assessments may be performed at the onset of CRS and/or when 
clinically indicated. Generally, for a patient, the same procedure should be performed at 
screening and at any follow-up assessment to allow direct comparison. 
9.2.5 
Vital Signs 
Vital signs will include temperature, pulse/heart rate, respiratory rate, blood pressure (systolic 
and diastolic), oxygen saturation and weight. Blood pressure and pulse/heart rate measurements 
should be recorded with the patient in a seated position or supine. Multiple time points (a 
minimum of three) will be collected prior to treatment to establish a good baseline blood 
pressure for the patient. Blood pressure and pulse/heart rate measurements will be assessed 
with an automated device. Manual techniques will be used only if an automated device is not 
available. 
9.2.6 
Physical Examination 
A complete physical examination will be conducted at screening as per the institutional 
standard practice. Thereafter, a symptom-directed physical examination will be conducted at 
subsequent visits. The schedule for physical examinations is provided in the Schedule of 
Assessments. Any clinically significant observations will be recorded and reported as an AE 
as appropriate. 
9.2.7 
ECOG Performance Status 
The ECOG scale provided in Appendix 2 will be used to grade changes in the patient’s daily 
living activities. The frequency of ECOG assessments is provided in the Schedule of 
Assessments. 
9.3 
PHARMACODYNAMICS AND BIOMARKER EVALUATION 
Blood-based pharmacodynamics biomarkers will be evaluated in all patients as described in 
the Schedule of Assessments. Peripheral blood biomarkers may be assessed pre- and post-
AUTO3 treatment. Assessment at additional time points may be performed based on emerging 
data to better understand the safety/efficacy of the CAR product. Details regarding sample 
collection and processing are provided in the lab manual. 

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9.3.1 
Evaluation of AUTO3 Persistence in Peripheral Blood and Bone Marrow 
Two validated assays will be used to measure the expansion/persistence of CD19/CD22 CAR-
positive T cells at the time points indicated in the Schedule of Assessments. Flow cytometry 
will be used to measure the frequency of CD19/CD22 CAR-positive T cells per microliter of 
whole blood and/or a polymerase chain reaction (PCR) assay will be used to quantify the 
number of copies of the CD19/CD22 CAR transgene per microgram of genomic 
deoxyribonucleic acid (DNA) or per 100 cells in peripheral whole blood. Please refer to the 
AUTO3-DB1 laboratory manual for the handling and storage of samples.  
9.3.2 
Evaluation of RCR in Peripheral Blood 
As per Health Authorities’ guidelines, tests will be performed to evaluate and monitor the 
presence of RCR by PCR in whole blood or PBMCs. Please refer to the AUTO3-DB1 
laboratory manual for the handling and storage of samples. 
9.3.3 
Insertional Mutagenesis 
Blood samples will be stored and archived before and after treatment (per Schedule of 
Assessments) with the intent to be analysed for insertional mutagenesis, should a patient 
develop a new malignancy. The result will allow identification of any potential relationship 
between AUTO3 treatment and the development of any new malignancy. Please refer to the 
AUTO3-DB1 laboratory manual for the handling and storage of samples. 
9.3.4 
B Cell Aplasia (Flow Cytometry) 
Blood samples will be collected for flow cytometry of B cells in accordance with the Schedule 
of Assessments for the assessment of B cell aplasia. Samples will be analysed in local hospital 
laboratories as per local practice. 
9.3.5 
Serum IgG Levels 
Blood samples will be collected in accordance with the Schedule of Assessments for the 
measurement of serum IgG, IgA and IgM levels. Samples will be analysed in local hospital 
laboratories. 
9.3.6 
Immunogenicity Analysis 
Detection of human anti-CAR T cell responses and antibodies, or related antibodies, may be 
measured in cryopreserved PBMCs and serum. Serum or plasma samples at selected time 
points, for example at Day 0, end of DLT evaluation period and Month 6, may be analysed if 
clinically indicated. Additional samples may be analysed if clinically indicated e.g. if AUTO3 
cells become undetectable or at relapse. The assays have not yet been developed but will be 
based on assays used to measure human anti-human antibodies in patients treated with 
monoclonal antibodies or on assays to measure T cell responses in cell therapy trials. The 
development of the assays may utilise plasma, serum or PBMCs collected during the trial, and 
data will not be reported if a suitable assay cannot be developed.  

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9.3.7 
Exploratory Biomarker Assessments 
Serum cytokine profile: The serum cytokine profile (using a minimum dataset of TNF-α, IFN-
γ, and IL-6) will be measured using a highly sensitive, reproducible, and validated cytokine 
assay at time points indicated in the Schedule of Assessments. Additional samples may be 
taken where clinically indicated, for example during CRS. Blood samples for cytokine 
measurements may be frozen and batched for analysis or assayed using fresh serum. Serum 
may also be used for measurement of other biomarkers as appropriate. 
Immunological/genomic phenotyping: PBMCs will be isolated from whole blood following 
standard procedures and cryopreserved in liquid nitrogen for later immunological assessment 
or assessed immediately. Samples will not be stored for more than 15 years. PBMCs may be 
used for various immunological assessments such as phenotyping by flow cytometry, genomic 
analysis and other assays as developed. Immunophenotyping or genotyping of PBMCs will be 
evaluated at selected time points (per Schedule of Assessments) and dependent upon a 
minimum frequency of CD19/CD22 CAR-positive cells.  
Biomarker expression: The expression of PD-L1, CD19 and CD22 or other immunological 
markers on lymphoma cells and/or the presence of CAR T cells will be evaluated by IHC and/or 
flow cytometry in available tissue (blood, BM, tumour tissue). 
If a patient is declared to have disease progression outside of scheduled time points, optional 
blood and tissue samples will be collected to help elucidate the reasons for primary or acquired 
resistance using appropriate methods.  
CSF Evaluation: CSF may be investigated for cytokine levels and/or evidence of tumour cells 
or CAR T cells or other parameters that may be determined by emerging data. 
9.4 
EFFICACY EVALUATION 
Response evaluations will be conducted as specified in the Schedule of Assessments and will 
include the following: PET using [18F]-fluorodeoxyglucose (FDG), CT scans, magnetic 
resonance imaging (MRI), physical examination, including lymphoma B-symptoms, BM, and 
other procedures as necessary. Examinations such as endoscopy may be performed if there is 
GI involvement at baseline. These assessments should be performed throughout the study at 
each time point using the same method of assessment used to assess disease at baseline. The 
baseline assessment should be performed within 35 days of starting pre-conditioning 
(approximately 40 days before receiving AUTO3). Patients receiving bridging therapy should 
have the baseline disease assessment after the bridging therapy is completed and prior to 
starting pre-conditioning. Response to treatment will be assessed by the Investigator at the site 
and the results will be recorded in the eCRF.  
It is important that instances and evidence of disease progression be reported to the Sponsor as 
soon as possible. The medical monitor will review the data to confirm that the criteria for 
disease progression have been met. If the medical monitor concurs, the Investigator will be 
notified and the patient will be withdrawn from the study. Whenever possible, subsequent anti-
cancer treatment should start once disease progression has been confirmed. 
9.4.1 
PET Scan 
Positron emission tomography using [18F]-FDG is important for the complete assessment of 
response and progression. Whole body [18F]-FDG-PET scan (skull base to the proximal femur) 

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is mandatory at screening; during the study PET scans will be performed as per the Schedule 
of Assessments. For patients who achieve a complete metabolic response (CMR), disease 
assessments after Month 6 can be based on CT scans alone, if clinically appropriate. If relapse 
occurs after CMR or disease progression is suspected (e.g. new or enlarging lesion(s) detected 
on CT scan), a PET scan is to be repeated to confirm relapse/progression.  
Assessment of PET results is based on published criteria. Visual assessment is considered 
adequate for determining whether a PET scan is positive, and use of the standardised uptake 
value is not necessary. A positive scan is defined as focal or diffuse [18F]-FDG uptake above 
background in a location incompatible with normal anatomy or physiology, without a specific 
standardised uptake value cut-off. Other causes of false-positive scans should be ruled out. 
Exceptions include mild and diffusely increased [18F]-FDG uptake at the site of moderate- or 
large-sized masses with an intensity that is lower than or equal to the mediastinal blood pool, 
hepatic or splenic nodules 1.5 cm with [18F]-FDG uptake lower than the surrounding 
liver/spleen uptake, and diffusely increased BM uptake within weeks after treatment. 
During the study, disease response will be assessed using CT scans as per the Schedule of 
Assessments with i.v. contrast of the neck, chest, abdomen, pelvis and any other location where 
disease was present at screening, and whole body [18F]-FDG-PET scans. Patients who are 
intolerant of i.v. CT contrast agents will have CT scans performed with oral contrast.  
A separate CT scan and PET scan are preferred, but if the only available modality is 
combined/dual PET/CT scanner, then the CT portion of a PET/CT may be used in lieu of a 
dedicated CT; CT scanning must be done according to certain imaging requirements that ensure 
that an optimised CT examination is done.  
Magnetic resonance imaging may be used to evaluate sites of disease that cannot be adequately 
imaged using CT (in cases where MRI is desirable, the MRI must be obtained at baseline and 
at all subsequent response evaluations). For all other sites of disease, MRI studies do not 
replace the required neck, chest, abdomen, and pelvic CT scans. Brain MRI is only required if 
clinically indicated.  
Disease assessments will be performed as outlined in the Schedule of Assessments and 
scans/images will be collected and assessed by independent central review (Phase II only).  
9.4.2 
Bone Marrow Assessment 
Bone marrow aspirate is mandatory and biopsy is optional at screening. Patients with BM 
involvement at baseline must have a repeat BM evaluation at the time of CR (preferably within 
30 days of the initial documentation of CR). If BM involvement can be confirmed with 
morphology, IHC need not be performed. Only one BM examination is necessary for complete 
documentation of the CR. 
Portions of the BM aspirates collected at screening and at CR (if aspirate is collected at CR) 
may be used to for biomarker assessment such as persistence of CD19/CD22 CAR-positive T 
cells in the marrow, PD-L1 expression, and minimal residual disease. 
9.4.3 
Physical Examination 
Patients should have physical examination to evaluate possible presence of palpable lymph 
nodes, tumour masses or enlargement of spleen and liver at screening and other time points as 
specified in the Schedule of Assessments. Symptom-directed questions should be asked to 
evaluate for presence of lymphoma B-symptoms. 

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9.4.4 
Efficacy Criteria 
9.4.4.1 
Assessment of Disease Response and Progressive Disease 
Efficacy assessments for the purpose of the study result analyses will be performed by the 
Investigators and independent central radiology review (Phase II only) according to the Lugano 
Classification (Cheson et al. 2014) (Appendix 1). The primary efficacy analysis for Phase II 
will be based on the independent central review.  
9.4.4.2 
Appendix 1(Younes et al. 2017)(Cheson et al. 2014)Definition of 
Measurable and Assessable Disease 
Eligible patients must have PET-positive disease at baseline (FDG-avid disease corresponding 
with a 5-point scale score of 4 or 5). Patients who receive bridging therapy after study 
enrolment must have a PET/CT scan performed after completion of bridging therapy. Patients 
who do not have PET-positive disease (5-point scale score of 4 or 5) after bridging treatment 
will be excluded from the primary efficacy analysis. Patients with PET-positive disease at 
baseline but without measurable disease per CT scan will be included in the primary efficacy 
analysis.  
For radiological assessments based on CT scan (or MRI), measurable sites of disease are 
defined as lymph nodes, lymph node masses, or extranodal sites of lymphoma. Each 
measurable site of disease must be greater than 1.5 cm in the long axis regardless of short axis 
measurement, or greater than 1.0 cm in the short axis regardless of long axis measurement, and 
clearly measurable in two perpendicular dimensions. Measurement must be determined by 
imaging evaluation. All other sites of disease are considered assessable, but not measurable. 
Up to six measurable sites of disease, clearly measurable in two perpendicular dimensions, will 
be followed for each patient. Measurable sites of disease should be chosen such that they are 
representative of the patient’s disease (this includes splenic and extranodal disease). If there 
are lymph nodes or lymph node masses in the mediastinum or retroperitoneum larger than 
1.5 cm in two perpendicular dimensions, at least one lymph node mass from each region should 
always be included. In addition, selection of measurable lesions should be from as disparate 
regions of the body as possible.  
All other sites of disease will be considered assessable. Assessable disease includes objective 
evidence of disease that is identified by radiological imaging, physical examination, or other 
procedures as necessary, but is not measurable as defined above. Examples of assessable 
disease include bone lesions; mucosal lesions in the GI tract; effusions; pleural, peritoneal, or 
bowel wall thickening; disease limited to BM; and groups of lymph nodes that are not 
measurable but are thought to represent lymphoma. In addition, if more than six sites of disease 
are measurable, these other sites of measurable disease may be included as assessable disease. 
9.4.4.3 
Endpoints 
The efficacy endpoints are ORR, DOR, PFS, and OS:  
Overall response rate: Complete response or PR by the Criteria for Response Assessment of 
NHL (i.e. Lugano Classification)  
The proportion of patients achieving PR and CR at 1, 3, and 6 months post-AUTO3 infusion 
will also be determined. 

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Duration of response (DOR): DOR is defined as the time from the first observed CR or PR 
to documented disease progression or death due to underlying disease, for patients who are 
considered as responders. DOR will also be evaluated for CR and PR patients separately. 
Progression-free survival: PFS is defined as the time from first treatment of AUTO3 to 
documented disease progression or death due to any cause.  
Overall survival: OS is defined as the time from the first treatment of AUTO3 to death due to 
any cause. 
9.5 
BLOOD VOLUME COLLECTIONS 
In general, blood will be taken from a Hickman line or other central venous access for the first 
year after AUTO3 infusion so that venepuncture will not be needed. The maximum volume of 
blood collected for study related assessments on any one day is unlikely to exceed 76 mL. 
Additional samples may be collected as required to ensure the safety of the patient. Refer to 
the laboratory manual for the handling and storages of samples. 

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10 
GUIDELINES 
FOR 
PREVENTION, 
MONITORING, 
AND 
MANAGEMENT OF ADVERSE EVENTS 
The following guidelines are recommendations and should be modified according to local 
practice and the patient’s clinical need. 
10.1 
GENERAL SUPPORTIVE CARE GUIDELINES FOR PATIENTS 
RECEIVING CAR T CELL THERAPY 
Table 15: 
General Supportive Care Guidelines for Patients Receiving CAR T Cell 
Therapy 
Toxicity 
Preventive and Supportive Care Interventions 
General 
Administer paracetamol/acetaminophen for symptomatic management of fevers in 
patients with normal hepatic function; 
Provide cooling blankets for fevers >40°C; 
Appropriate personnel and appropriate resuscitation equipment should be available 
in or near the infusion room and a physician should be readily available during the 
infusion of study drug; 
Tocilizumab must be available at sites managing patients receiving CAR T cell 
products; 
Avoid corticosteroids and, if thrombocytopenic, NSAIDs. 
Infection Prophylaxis 
Patients should receive prophylaxis with antimicrobials due to the use of FLU and 
the potentially extended duration of lymphopenia and neutropenia; 
Patients should receive pneumocystis prophylaxis with 
trimethoprim-sulfamethoxazole or suitable alternative agents, and either acyclovir or 
valacyclovir for herpes virus prophylaxis from the start of conditioning 
chemotherapy until 3 to 6 months post-AUTO3 infusion; 
Additional anti-microbial (e.g. ciprofloxacin) and anti-fungal prophylaxis to be 
given as per institutional practice; 
All patients should be monitored for CMV by PCR weekly during admission or as 
necessary; 
All patients with fevers while neutropenic must have blood cultures drawn and 
receive broad-spectrum antibiotics as per institutional practice. 
Respiratory 
Monitor for oxygen saturation at every visit, a significant decrease in oxygen 
saturation at room air should be investigated and managed with supportive care 
including supplemental oxygen, anti-microbials and ventilator support as 
appropriate. Patients with an oxygen requirement of >40% (or lower based on 
emerging data) in setting of CRS should receive treatment with tocilizumab (see 
Section 10.4). 

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Toxicity 
Preventive and Supportive Care Interventions 
Cardiovascular 
Stop or taper antihypertensive medications prior to cell infusion; 
 
Monitor vital signs at least every 12 to 24 hours on an inpatient unit during hospital 
stay; 
Monitor vital signs every 2 hours in patients with fevers and tachycardia; 
Initiate replacement i.v. fluids for patients with poor oral intake or high insensible 
losses to maintain net even fluid balance; 
Administer i.v. fluid boluses for patients with systolic blood pressure less than their 
pre-infusion baseline; 
Patients with a systolic blood pressure <80% of their pre-infusion baseline and 
<100 mmHg (or as age appropriate) receive a 1 litre normal saline bolus; 
Patients with a systolic blood pressure <85 mmHg (or as age appropriate) receive a 
1 litre normal saline bolus regardless of baseline blood pressure; 
Patients receiving >1 i.v. fluid bolus (or as age appropriate) for hypotension or 
patients in the intensive care unit for toxicity management have a serum troponin 
drawn, and an ECG and an ECHO performed to evaluate for cardiac toxicity (see 
Section 10.4); 
Norepinephrine is the preferred first-line vasopressor for patients with hypotension 
initiated on vasopressor support. 
Haematologic 
Initiate allopurinol for TLS prophylaxis in patients without a contraindication prior 
to pre-conditioning chemotherapy; if indicated (see Section 10.7); 
Transfuse packed red cells for goal haemoglobin of ≥80 g/L; 
Transfuse platelets for a goal platelet count of ≥20,000/μL; 
Monitor complete blood count with differential at least daily. When absolute 
neutrophil count decreases to <500/μL; initiate granulocyte-colony stimulating 
factor support. Continue until absolute neutrophil count increases to ≥1500 μL; 
Transfuse fresh frozen plasma with a goal of normalisation of PTT in patients with a 
partial thromboplastin time (PTT) >1.5-fold above the ULN; and 
Transfuse cryoprecipitate to maintain fibrinogen of ≥100 mg/dL if the patient is at 
risk of bleeding. If the patient is bleeding, a higher level of fibrinogen should be 
maintained. 
Neurologic 
The nursing staff conducts focused neurologic examinations at least every 4 to 
6 hours in patients experiencing neurologic toxicity (see Section 10.6); 
Perform brain MRI in any patient experiencing neurologic toxicity; 
Perform lumbar puncture to evaluate for infectious pathogens, cytokine levels, and 
CAR T cell levels in patients experiencing neurologic toxicity whenever feasible; 
Consider a neurology consultation for any patient experiencing neurologic toxicity; 
and 
Standard antiepileptic medications for patients with active seizures. Prophylactic 
antiepileptic medications are not required. 
CAR=chimeric antigen receptor; CMV=cytomegalovirus; ECG=electrocardiogram; ECHO=echocardiogram; 
i.v.=intravenous; MRI=magnetic resonance imaging; NSAIDs=non-steroidal anti-inflammatory drugs; PCR=polymerase 
chain reaction; PTT=partial thromboplastin time; TLS=tumour lysis syndrome; ULN=upper limit of normal. 
Taken from: (Brudno and Kochenderfer 2016). 

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10.2 
PRE- AND POST-CAR T INFUSION SUPPORTIVE THERAPY 
AUTO3 is an autologous product, with humanised scFv CARs and is less likely to be 
immunogenic and induce an infusion or hypersensitivity reaction compared to murine scFv 
CARs. However, the following medications should be given 30 minutes before the study drug 
infusion: oral paracetamol/acetaminophen and an antihistamine (diphenhydramine/ 
chlorpheniramine or equivalent). These medications may be discontinued based on emerging 
data. In addition, pre-infusion medications listed in Table 16 may also be administered if 
necessary. 
Post-infusion medication listed in Table 16 may be considered following FLU-CY or AUTO3 
infusion if necessary, and such medication(s) may be continued for up to 48 hours after the 
infusion. Use of additional supportive care measures may be instituted as clinically necessary 
at the discretion of the Investigator. 
Table 16: 
Pre- and Post-infusion Medications 
Medication 
Dose 
Administration 
Pre-
infusion 
Post-
infusion 
Antihistamine 
Diphenhydramine/chlorpheniramine 
(10 to 20 mg) or equivalent. 
Oral – administer at least 
1 hour prior to study drug. 
I.v. or as appropriate – 
administer at least 30 minutes 
prior to study drug. 
Yes 
Optional 
Diphenhydramine/chlorpheniramine 
(8 to 16 mg) or equivalent. 
Oral - as clinically indicated. 
- 
Optional 
Antipyretic 
Paracetamol/acetaminophen 
(500 mg to 1000 mg) or equivalent. 
Oral - administer at least 
30 minutes prior to study 
drug. 
Yes 
Optional 
H2-antagonist 
Ranitidine (50 mg) or equivalent. 
I.v. - start infusion 
30 minutes prior to study 
drug. 
Optional 
- 
Antiemetic 
Ondansetron (16 mg) or equivalent. 
I.v. - start infusion 
30 minutes prior to study 
drug. 
Optional 
- 
Ondansetron (8 mg) or equivalent 
(long or short acting agents). 
Oral - as clinically indicated. 
- 
Optional 
i.v.=intravenous. 
Note: Steroids may be used in case of severe reactions not controlled by other measures.  
10.3 
TREATMENT OF AUTO3 INFUSION-RELATED REACTIONS 
Patients who experience infusion-related reactions (to pre-conditioning or AUTO3) that 
manifest as wheezing, flushing, hypoxemia, fever, chills, rigors, bronchospasm, headache, 
rash, pruritus, arthralgia, hypo- or hypertension or other symptoms, should have the symptoms 
managed according to the recommendations provided in Table 17 or as per institutional 
practice. All NCI CTCAE Grade 3 or 4 infusion-related reactions should be reported within 
24 hours to the Sponsor. If the event meets the criteria of an SAE, SAE reporting criteria in 
Section 12.3.5 should be followed. 

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Table 17: 
Guidelines for the Management of Infusion-related Reactions 
NCI CTCAE 
Grade 
Treatment/Intervention 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated. 
No intervention indicated; 
Monitor patient as medically indicated until 
recovery from symptoms. 
May consider 
diphenhydramine/chlorpheniramine 
10 to 20 mg or equivalent and or 
paracetamol/acetaminophen 500 to 
1000 mg if not instituted (see 
Table 16). 
Grade 2  
Moderate reaction; 
requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment. 
Interrupt infusion 
Start i.v. fluids; give 
diphenhydramine/chlorpheniramine 50 mg (or 
equivalent) i.v. and/or 
paracetamol/acetaminophen 500 to 1000 mg; 
consider bronchodilator therapy; may also 
consider corticosteroids if necessary; monitor 
patient closely until recovery from symptoms. 
Restart infusion if AUTO3 dose has not been 
fully administered.  
Symptoms recur: Stop and discontinue 
further infusion. 
The approximate amount of AUTO3 infused 
must be recorded on the eCRF. 
Diphenhydramine/chlorpheniramine 
10 to 20 mg or equivalent and/or 
paracetamol/acetaminophen 500 to 
1000 mg if not instituted (see 
Table 16). 
Grade 3 or 4 
Severe reaction;  
Grade 3: prolonged 
(i.e. not rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalisation 
indicated for other 
clinical sequelae 
(e.g. renal 
impairment, 
pulmonary 
infiltrates). 
Grade 4: 
life-threatening; 
pressor or ventilator 
support indicated 
Stop Infusion  
Start i.v. saline infusion; recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of a 
1:10000 solution injected slowly for 
i.v. administration, and/or 
diphenhydramine/chlorpheniramine 50 mg 
i.v. with methylprednisolone 100 mg i.v. (or 
equivalent), as needed, and other drugs as 
appropriate. 
Patients should be monitored until the 
Investigator is comfortable that the symptoms 
will not recur. Investigators should follow 
their institutional guidelines for the treatment 
of anaphylaxis. In the case of late-occurring 
hypersensitivity symptoms (e.g. appearance 
of a localised or generalised pruritus within 
1 week after treatment), symptomatic 
treatment may be given (e.g. oral 
antihistamine or corticosteroids), as 
appropriate.  
Grade 3: Discuss with Sponsor 
medical monitor about merits of 
completing AUTO3 infusion if full 
dose has not been administered.  
Grade 4: Permanently discontinue 
administration of any remaining 
AUTO3. 
General 
Appropriate personnel and appropriate resuscitation equipment should be available 
in or near the infusion room and a physician should be readily available during the 
infusion of study drug.  
CTCAE=Common Terminology Criteria for Adverse Events; eCRF=electronic Case Report Form; i.v.=intravenous; 
NCI=National Cancer Institute. 

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10.4 
GRADING 
AND 
MANAGEMENT 
OF 
CYTOKINE 
RELEASE 
SYNDROME  
Cytokine Release Syndrome is a recognised toxicity with CAR T cell therapies and, for some 
CAR T therapies, can be severe (Grade 3 or 4; 40% of patients with ALL and 20% of patients 
with DLBCL) (Kymriah (tisagenlecleucel) EU SmPC 2018, Kymriah US Prescribing 
Information 2018). Clinical symptoms indicative of CRS include culture negative fever, 
myalgia, nausea/vomiting, tachycardia, hypoxia, hypotension, headache, confusion, tremor, 
and delirium. Potentially life-threatening complications of CRS may include cardiac 
dysfunction, acute respiratory distress syndrome, renal and/or hepatic failure, and DIC (Brudno 
and Kochenderfer 2016). Symptoms usually present within the first 1 to 2 weeks following 
infusion (Neelapu et al. 2018). 
Some studies have suggested several possible risk factors for severe CRS, such as higher peak 
expansion level of CAR T, tumour burden, baseline high lactate dehydrogenase level, early 
onset CRS (within 3 days of infusion) and elevation of some cytokine levels after infusion (Hay 
et al. 2017, Locke et al. 2017, Santomasso et al. 2018). 
Macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) 
may occur in some patients for whom CAR-mediated inflammatory responses continue to 
evolve. The clinical syndrome of MAS is characterised by high grade non-remitting fever, 
cytopenias affecting at least two of three lineages, and hepatosplenomegaly (see Section 10.5). 
It is associated with biochemical abnormalities, such as high circulating levels of serum ferritin, 
soluble IL-2 receptor (sCD25), and triglycerides, together with a decrease of circulating natural 
killer cell activity. Other findings include variable levels of transaminases up to signs of acute 
liver failure and coagulopathy with findings consistent with DIC. 
Following the first AUTO3 infusion, patients should be closely monitored for early signs and 
symptoms indicative of CRS, with clinical review and blood tests including C-reactive protein, 
serum ferritin levels, and clotting. Serum cytokines should be obtained periodically as indicated 
in the schedule of assessments. Clinical personnel should be trained in the diagnosis and 
management of CRS.  
Grading for CRS is provided in Table 18, with recommendations regarding treatment provided 
in Table 19. 

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Table 18: 
Severity Grading of Cytokine Release Syndrome (ASTCT/ASBMT CRS 
Consensus Grading and CTCAE Version 5.0) (Lee et al. 2019) 
CRS 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever† 
Temperature 
≥38°C 
Temperature 
≥38°C 
Temperature ≥38°C 
Temperature ≥38°C 
With either: 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring one vasopressor 
with or without vasopressin 
Requiring multiple 
vasopressors (excluding 
vasopressin) 
And/or‡ 
Hypoxia 
None 
Requiring 
low-flow nasal 
cannula^ or 
blow-by 
Requiring high-flow nasal 
cannula^, facemask, 
non-rebreather mask, or 
Venturi mask 
Requiring positive 
pressure (e.g. CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
ASTCT/ASBMT=American Society for Transplantation and Cellular Therapy/American Society for Blood and Marrow 
Transplantation; BiPAP=bi-level positive airway pressure; CPAP=continuous positive airway pressure; CRS=cytokine 
release syndrome; CTCAE=Common Terminology Criteria for Adverse Events. 
Note: organ toxicities associated with CRS may be graded according to CTCAE Version 5.0 but they do not influence CRS 
grading. 
† Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive 
anti-pyretics or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS 
severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
‡ CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with a temperature of 39.5°C, hypotension requiring one vasopressor and hypoxia requiring low-flow 
nasal cannula is classified as having Grade 3 CRS. 
^ Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, 
sometimes used in paediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Table 19: 
Management of Cytokine Release Syndrome 
CRS Grade (CTCAE Version 5.0) 
Treatment 
Grade 1 
Symptoms are not life-threatening and 
require symptomatic treatment only (e.g. 
fever, nausea, fatigue, headache, myalgia, 
and malaise or organ toxicity) 
Supportive care per institutional standards including analgesics 
and antipyretics, assess and treat for neutropenic infections.  
Consider tocilizumab for persisting (>3 days) and/or refractory 
fever (persistent fever of ≥39°C despite antipyretics for 10 
hours) (Lee et al. 2014, Neelapu et al. 2018). 
Grade 2 
Symptoms require and respond to 
moderate intervention 
Supportive care including fluid substitution is recommended. 
Low-flow-oxygen (<40% fraction of inspired oxygen). 
Give tocilizumab. 
Grade 3 
Symptoms require and respond to 
aggressive intervention 
Intensive care should be considered. 
Oxygen (flow ≥40% fraction of inspired oxygen).  
Vasopressors as needed (see Table 20). 
Treat with tocilizumab see Table 20. 
Add siltuximab as necessary if not previously administered. 
Add steroids if unresponsive within 24 hours.  
CRS associated with MAS or haemophagocytosis may also be 
treated with anakinra, an IL-1 receptor antagonist (Shah et al. 
2017). 
Also, consider anti-TNF antibodies as clinically appropriate. 

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CRS Grade (CTCAE Version 5.0) 
Treatment 
Grade 4  
Life-threatening symptoms  
Intensive care. 
Treat with tocilizumab see Table 20. 
Add siltuximab as necessary if not previously administered. 
Treat with corticosteroids (see Table 20). 
CRS associated with MAS or haemophagocytosis may also be 
treated with anakinra, an IL-1 receptor antagonist (Shah et al. 
2017). 
Consider alternative agents such as anti-TNF, and other agents 
as appropriate. 
Grade 5  
Death 
Not applicable. 
CRS=cytokine release syndrome; CTCAE=Common Terminology Criteria for Adverse Events; IL=interleukin; 
MAS=macrophage activation syndrome; TNF=tumour necrosis factor. 
An overview of CRS management is presented in Figure 4. 
Figure 4: 
CRS Management Overview 
 
CRS=cytokine release syndrome; MAS=macrophage activation syndrome. 
Details of supportive medication and steroid doses are presented in Table 20.  

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Table 20: 
Pharmacologic Management of CRS 
Drug 
Indication 
Dose 
Vasopressor  
Hypotension not responsive to fluid resuscitation alone. 
Vasopressor use according to local institutional practice. 
Noradrenaline/norepinephrine is the preferred first-line 
vasopressor (Brudno and Kochenderfer 2016). Recommended 
doses provided (Lee et al. 2014). Vasopressor should be used for 
at least 3 hours. 
Note: Vasopressin is not available in all countries. 
Noradrenaline/norepine
phrine monotherapy 
≥0.2 μg/kg/minute 
Dopamine 
monotherapy 
≥10 μg/kg/minute 
Adrenaline 
monotherapy 
≥0.1 μg/kg/minute 
If on vasopressin: 
Vasopressin+noradrena
line/ norepinephrine 
equivalent of 
≥10 μg/min*. 
If on a combination 
vasopressors (not 
vasopressin): 
Noradrenaline/norepine
phrine equivalent of 
≥20 μg/min*. 

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Drug 
Indication 
Dose 
Anti-IL-6 
therapy 
Anti-IL-6 therapy may be given according to local institutional 
practice. 
Use of anti-IL-6 treatments is not currently believed to impair 
the efficacy of CAR T cell therapy, (Davila et al. 2014, Lee et 
al. 2015, Brudno and Kochenderfer 2016, Neelapu et al. 2018) 
Brudno and Kochenderfer (Brudno and Kochenderfer 2016) 
recommended the use of anti-IL-6 therapy (specifically 
tocilizumab) in the event of the following associated with CRS 
(CRS Grade ≥2 with associated conditions): 
• 
Left ventricular ejection fraction 40% by ECHO; 
• 
Creatinine >2.5-fold higher than the most recent level 
prior to CAR T cell infusion; 
• 
Norepinephrine requirement at a dose >2 mg/min for 
48 hours since the first administration of 
norepinephrine, even if administration is not 
continuous; 
• 
SBP of 90 mm Hg that cannot be maintained with 
norepinephrine; 
• 
Oxygen requirement of fraction of inspired oxygen 
50% or more for more than 2 hours continuously; 
• 
Dyspnoea that is severe enough to potentially require 
mechanical ventilation; 
• 
Activated PTT >2 × ULN; 
• 
Clinically-significant bleeding;  
• 
Creatine kinase >5 × ULN for longer than 2 days. 
Use of tocilizumab may also be considered for persistent fever 
of ≥39°C despite anti-pyretics for 10 hours, persistent/recurrent 
hypotension after initial fluid bolus, and initiation of oxygen 
supplementation (Lee et al. 2014, Neelapu et al. 2018). 
Tocilizumab 
Tocilizumab is approved in the US and Europe for the 
management of CRS patients (Actemra Prescribing Information 
2018, RoActemra SmPC 2018). 
Refer to local prescribing information. 
Note: organ dysfunction secondary to CRS and cytopenias due 
to disease/chemotherapy will not constitute a contraindication to 
tocilizumab. 
Siltuximab 
Siltuximab is an alternative to tocilizumab (Grupp et al. 2013, 
Calabrese and Rose-John 2014, Maude et al. 2014, Teachey et 
al. 2018) and may be used according to local institutional 
guidance. Siltuximab has been approved to treat Castleman’s 
disease (Neelapu et al. 2018, Siltuximab EU SmPC 2019, 
Siltuximab US Prescribing Information 2019).  
Siltuximab may be added if there is no response to 
tocilizumab±corticosteroids (Neelapu et al. 2018, Teachey et al. 
2018). 
Tocilizumab: 
The recommended 
dosing of tocilizumab 
for the treatment of 
CRS given as a 60-
minute i.v. infusion is 
8 mg/kg in patients 
weighing greater than 
or equal to 30 kg or 12 
mg/kg in patients 
weighing less than 
30 kg (Maude et al. 
2015).  
Tocilizumab can be 
given alone or in 
combination with 
corticosteroids. If no 
clinical improvement in 
the signs and symptoms 
of CRS occurs after the 
first dose, up to 3 
additional doses of 
tocilizumab may be 
administered. The 
interval between 
consecutive doses 
should be at least 8 
hours. Doses exceeding 
800 mg per infusion are 
not recommended in 
CRS patients (Actemra 
Prescribing Information 
2018, RoActemra 
SmPC 2018).  
Refer to local 
prescribing information 
and institutional 
guidance. 
Siltuximab: 
11 mg/kg over 1 hour 
as a single i.v. infusion 
(Neelapu et al. 2018, 
Siltuximab EU SmPC 
2019, Siltuximab US 
Prescribing Information 
2019). 

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Drug 
Indication 
Dose 
Corticosteroids 
Corticosteroids should generally be avoided in patients who 
have received CAR T cell therapy, due to concerns of the effect 
on the T cells (Neelapu et al. 2018), though, some studies have 
shown a clinical response to CAR T therapy after high doses of 
methylprednisolone (Maude et al. 2015, Mueller et al. 2018). 
Corticosteroids are indicated in Grade 4 CRS and Grade 3 CRS 
refractory to anti-IL-6 therapy. Corticosteroids are also indicated 
in patients with NT (ICANS) Grade 2 and above (see 
Section 10.6). Patients with ICANS in the absence of CRS 
should receive corticosteroids prior to anti-IL-6 therapy (Riegler 
et al. 2019). 
Dosing and choice of corticosteroid should be tailored to the 
individual patient and according to local institutional guidance 
(if specified). Commonly used initial doses include 
methylprednisolone. 
For patients with suspected ICANS, dexamethasone may be 
more suitable, due to more efficient penetration of the blood 
brain barrier (Mitchell et al. 2005) (see Section 10.6). 
Patients on i.v. steroids may be switched to an equivalent dose 
of oral corticosteroids (e.g. prednisone) at the start of tapering or 
earlier, once sustained clinical improvement is observed.  
Prophylactic antibiotics or other antimicrobials as clinically 
appropriate. 
Rigorous control of blood pressure and electrolytes (particularly 
calcium and magnesium). 
Methylprednisolone: 
2 mg/kg i.v. every 
12 hours weaned over 
5 days. 
Dexamethasone: 
10 mg i.v. every 
6 hours (if refractory 
can increase to 20 mg 
every 6 hours) 
(Neelapu et al. 2018). 
Anti-TNF 
therapy 
Infliximab (anti-TNFα antibody)  
Etanercept (soluble TNFα receptor) 
These agents have also demonstrated efficacy in the setting of 
CRS, MAS and other syndromes (Prahalad et al. 2001, 
Flammiger et al. 2012, Gabay et al. 2014, Ruella et al. 2017) 
Refer to local 
prescribing 
information. 
Anti-IL-1 
Therapy 
Anakinra 
Uncontrolled MAS or haemophagocytosis may also be treated 
with anakinra, an IL-1 receptor antagonist (Brudno and 
Kochenderfer 2016, Shah et al. 2017, Liu and Zhao 2018). 
100 mg by 
subcutaneous injection, 
to be repeated daily as 
clinically indicated. 
CAR= chimeric antigen receptor; CRS=cytokine release syndrome; ECHO=echocardiogram; EU=European Union; 
ICANS=immune effector cell-associated neurotoxicity syndrome; IL=interleukin; i.v.=intravenous; MAS=macrophage 
activation syndrome; PTT=prothrombin time; SBP=systolic blood pressure; SmPC=Summary of Product Characteristics; 
TNF=tumour necrosis factor; ULN=upper limit of normal; US=United States. 
* VASST Trial (Russel et al 2008) vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine 
(μg/min)] + [dopamine (μg/kg/min) ÷ 2] + [epinephrine (μg/min)] + [phenylephrine (μg/min) ÷10]. 
10.5 
MANAGEMENT MACROPHAGE ACTIVATION SYNDROME (MAS) 
Macrophage activation syndrome and HLH encompass a group of severe immunological 
disorders characterised by hyperactivation of macrophages and lymphocytes, proinflammatory 
cytokine production, lymphohistiocytic tissue infiltration, and immune-mediated multiorgan 
failure. 
Haemophagocytic lymphohistiocytosis and/or MAS may occur in some patients for whom 
CAR-mediated inflammatory responses continue to evolve. The clinical syndrome of MAS is 
characterised by high grade non-remitting fever, cytopenias affecting at least two of 
three lineages, and hepatosplenomegaly.  

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A patient might have HLH/MAS if they have a peak serum ferritin level of >10,000 ng/mL 
during the CRS phase of CAR T cell therapy and subsequently developed any two of the 
following (Neelapu et al. 2018): 
• 
CTCAE Grade ≥3 increase in serum bilirubin, aspartate aminotransferase, or alanine 
aminotransferase levels; 
• 
CTCAE Grade ≥3 oliguria or increase in serum creatinine levels; 
• 
CTCAE Grade ≥3 pulmonary oedema; 
• 
Presence of haemophagocytosis in bone marrow or organs based on histopathological 
assessment of cell morphology and/or CD68 immunohistochemistry. 
Haemophagocytic lymphohistiocytosis/MAS may be refractory to anti-IL-6 therapy and can 
be associated with high mortality if not treated promptly. Patients with suspected HLH/MAS 
should be treated with anti-IL-6 therapy and corticosteroids (Neelapu et al. 2018) 
(see Table 20). If the patient has no clinical or serological improvement within 48 hours, 
consider etoposide 75 to 100 mg/m2 as appropriate (Jordan et al. 2011, Schram and Berliner 
2015, Tamamyan et al. 2016). Intrathecal cytarabine can be considered in patients with 
HLH-associated NT (Neelapu et al. 2018). 
Uncontrolled HLH/MAS may also be treated with anakinra, an IL-1 receptor antagonist 
(see Table 20) (Brudno and Kochenderfer 2016, Shah et al. 2017, Liu and Zhao 2018).  
10.6 
GRADING AND MANAGEMENT OF NEUROTOXICITY (ICANS) 
Neurotoxicity has been seen in patients with leukaemia and lymphoma after treatment with 
CAR T cell therapy (Neelapu et al. 2018) and is now referred to as ICANS. The cause of NT 
is not well-understood, although it is generally reported to be fully reversible (Kymriah 
(tisagenlecleucel) EU SmPC 2018, Kymriah US Prescribing Information 2018). Enrichment of 
pro-inflammatory cytokines in the CNS, endothelial activation, and MAS have all been 
proposed as potential mechanisms (Karschnia et al. 2019). Transient neurological 
complications have also been reported with CD19 bispecific T cell engagers, suggesting that 
the target may have some relevance (Goebeler and Bargou 2016). 
Although symptoms can vary, the early manifestations of ICANS are often tremor, dysgraphia, 
mild difficulty with expressive speech (especially naming objects), impaired attention, apraxia, 
and mild lethargy. Other symptoms can include confusion, depressed level of 
consciousness/encephalopathy, hallucinations, dysphasia, ataxia, apraxia, cranial nerve palsies, 
and seizures. Headache is a non-specific symptom, frequently occurring during fever or after 
chemotherapy; thus, headache alone is not a useful marker of ICANS. Expressive aphasia, on 
the other hand, appears to be a very specific symptom of ICANS (Santomasso et al. 2018). 
In addition to more common NT symptoms such as encephalopathy, aphasia, delirium, tremor, 
and seizures; rare cases of rapid-onset and lethal diffuse cerebral oedema have occurred with 
some CAR T cell therapies (Gust et al. 2017, Locke et al. 2017, Gilbert 2018). 
There appears to be no correlation between ICANS and CRS/MAS and both can occur together 
or separately (Santomasso et al. 2018), although ICANS occurs more frequently in the presence 
of severe CRS. There is also some suggestion that patients with a high disease burden prior to 
treatment, higher peak CAR T cell expansion and early and higher elevations of serum 
cytokines may have a higher risk of NT (Santomasso et al. 2018). Of note, patients can develop 
ICANS even after treatment of anti-IL-6 therapy, after the resolution of CRS. 

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Patients will be monitored closely after the first AUTO3 infusion for neurological signs and 
symptoms of NT. If NT is observed, a neurology opinion should be sought, MRI imaging 
performed, and the patient will receive supportive care (e.g. anti-convulsant therapy), as 
appropriate (see Table 23).  
In general, as NT is transient and resolves spontaneously with no long-term sequelae, 
supportive care alone is sufficient in most patients. Steroids may be given for Grade 3 or 4 NT 
(see Table 23) or in the case of cerebral oedema or generalised seizures, but otherwise treatment 
with steroids should be avoided as this may be deleterious to the persistence of AUTO3.  
Neurotoxicity may also be caused by FLU but usually at higher doses than those being 
administered in this protocol (Helton et al. 2013). Symptoms of FLU including objective 
weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, optic neuropathy, 
blindness, and coma have been reported in patients with chronic lymphocytic leukaemia treated 
with multiple cycles of FLU.  
Neurotoxicity may also be associated with prior methotrexate treatment (either high dose or 
intrathecal) (Inaba et al. 2008, Bhojwani et al. 2014). Although neurological toxicities 
associated with methotrexate are usually acute, radiological abnormalities may persist 
(Bhojwani et al. 2014). 
Please see Table 21 for grading of NT as per the ASTCT/ASBMT guidelines for ICANS (Lee 
et al. 2019). 
Table 21:  
Assessment & Grading of ICANS 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE Score^ for 
Adults  
(see Table 22) 
7 to 9 
3 to 6 
0 to 2 
0 (patient is unarousable and 
unable to perform ICE) 
Depressed level 
of 
consciousness* 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to 
tactile stimulus 
Patient is unarousable or requires 
vigorous or repetitive tactile 
stimuli to arouse; stupor or coma 
Seizure 
N/A 
N/A 
Any clinical seizure, 
focal or generalised, 
that resolves rapidly; 
or non-convulsive 
seizures on EEG that 
resolve with 
intervention 
Life-threatening prolonged seizure 
(>5 minutes); or 
Repetitive clinical or electrical 
seizures without return to baseline 
in between 
Motor 
weakness§ 
N/A 
N/A 
N/A 
Deep focal motor weakness such 
as hemiparesis or paraparesis 

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Grade 1 
Grade 2 
Grade 3 
Grade 4 
Raised 
ICP/cerebral 
oedema 
N/A 
N/A 
Focal/local oedema 
on neuroimaging# 
Decerebrate or decorticate 
posturing; or cranial nerve VI 
palsy; or papilledema; or 
Cushing’s triad; or signs of diffuse 
cerebral oedema on neuroimaging 
ASTCT/ASBMT=American Society for Transplantation and Cellular Therapy/American Society for Blood and Marrow 
Transplantation; CTCAE=Common Terminology Criteria for Adverse Events; EEG=electroencephalogram; 
ICANS=immune effector cell-associated neurotoxicity syndrome; ICE=immune effector cell-associated encephalopathy; 
ICP=intracranial pressure; N/A=not applicable. 
Adapted from Lee 2019, ASTCT/ASBMT ICANS Consensus (Lee et al. 2019).  
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised 
ICP/cerebral oedema) not attributable to any other cause. 
^ A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is awake with global 
aphasia; however, a patient with an ICE score of 0 may be classified as having Grade 4 ICANS if the patient is 
unarousable. 
* Depressed level of consciousness should be attributable to no other cause (e.g. no sedating medication). 
§ Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE 
Version 5.0, but they do not influence ICANS grading. 
# Intracranial haemorrhage with or without associated oedema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE Version 5.0. 
Table 22:  
Immune Effector Cell-associated Encephalopathy (ICE) Scale 
Orientation: orientation to year, month, city, hospital 
4 points 
Following commands: ability to follow simple commands (e.g. “Show me 2 ﬁngers” or 
“Close your eyes and stick out your tongue”) 
1 point 
Naming: ability to name 3 objects (e.g. point to clock, pen, button) 
3 points 
Writing: ability to write a standard sentence (e.g. “Our national bird is the bald eagle”) 
1 point 
Attention: ability to count backwards from 100 by 10 
1 point 
Scoring 
10, no impairment; 
7 to 9, Grade 1 ICANS; 
3 to 6, Grade 2 ICANS; 
0 to 2, Grade 3 ICANS; 
0 due to patient unarousable and unable to perform ICE assessment. 
ICANS=immune effector cell-associated neurotoxicity syndrome; ICE=immune effector cell-associated encephalopathy. 
Patients may be managed as per the suggested guidelines below (Table 23) but may also be 
managed as per institutional management guidelines. 

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Table 23: 
Management of ICANS 
Grade 1 
Vigilant supportive care; aspiration precautions; i.v. hydration.  
Withhold oral intake of food, medicines and fluids, and assess swallowing.  
Convert all oral medications and/or nutrition to i.v. if swallowing is impaired.  
Avoid medications that cause CNS depression.  
Low doses of lorazepam (0.25 to 0.5 mg i.v. every 8 hours) or haloperidol 
(0.5 mg i.v. every 6 hours) can be used, with careful monitoring, for agitated 
patients.  
Neurology consultation.  
Fundoscopic exam to assess for papilledema.  
MRI of the brain with and without contrast; diagnostic lumbar puncture with 
measurement of opening pressure; MRI of the spine if the patient has focal 
peripheral neurological deficits; CT scan of the brain can be performed if 
MRI of the brain is not feasible.  
Consider daily 30 minute EEG until toxicity symptoms resolve; if no seizures 
are detected on EEG.  
Consider levetiracetam 750 mg every 12 hours (oral or i.v.) for a month for 
seizure prophylaxis. 
If EEG shows non-convulsive status epilepticus, treat as per the algorithm in 
Table 24. 
Consider anti-IL-6 therapy if NT is associated with concurrent CRS 
(see Section 10.4).  
Worsening: treat as ≥Grade 2. 
Grade 2 
Supportive care and neurological work-up as indicated for Grade 1.  
Anti-IL-6 therapy if associated with concurrent CRS (see Section 10.4). 
Dexamethasone 10 mg i.v. every 6 hours or methylprednisolone 1 mg/kg i.v. 
every 12 hours if refractory to anti-IL-6 therapy, or for NT without 
concurrent CRS.  
Consider transferring the patient to ICU if NT is associated with Grade ≥2 
CRS.  
Worsening: treat as Grade 3 to 4. 
Grade 3 neurologic 
toxicities  
(with the exception of 
headaches, that last 
continuously for 24 hours or 
longer) 
Supportive care and neurological work-up as indicated for Grade 1.  
ICU transfer is recommended.  
Anti-IL-6 therapy if associated with concurrent CRS, as described for 
Grade 2 NT and if not administered previously.  
Dexamethasone 10 mg i.v. every 6 hours or methylprednisolone 1 mg/kg i.v. 
every 12 hours if refractory to anti-IL-6 therapy, or for NT without 
concurrent CRS; continue corticosteroids until improvement to Grade 1 NT 
and then taper (see Table 20.Stage 1 or 2 papilledema with CSF opening 
pressure <20 mmHg should be treated as per the algorithm in Table 25. 
Consider repeat neuroimaging (CT or MRI) every 2 to 3 days if patient has 
persistent Grade ≥3 NT. 

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Grade 4 neurologic toxicity 
of any duration  
 
Any generalised seizures 
Supportive care and neurological work-up as outlined for Grade 1 NT. 
ICU monitoring; consider mechanical ventilation for airway protection.  
Anti-IL-6 therapy and repeat neuroimaging as described for Grade 3 NT.  
High-dose corticosteroids continued until improvement to Grade 1 NT and 
then taper; for example, methylprednisolone i.v. 1 g/day for 3 days, followed 
by rapid taper at 250 mg every 12 hours for 2 days, 125 mg every 12 hours 
for 2 days, and 60 mg every 12 hours for 2 days (see Table 20). 
For convulsive status epilepticus, treat as per the algorithm in Table 24. 
Stage ≥3 papilledema, with a CSF opening pressure ≥20 mmHg or cerebral 
oedema, should be treated as per the algorithm in Table 25. 
Worsening: May consider use of lymphodepleting drugs such as CY (Garfall 
et al. 2015) or other drugs (Klinger et al. 2016) if unresponsive to standard 
immunosuppressive therapies. 
Adapted from (Neelapu et al. 2018). 
CRS=cytokine release syndrome; CNS=central nervous system; CSF=cerebrospinal fluid; CT=computerised tomography; 
CY=cyclophosphamide; EEG=electroencephalogram; ICU=intensive-care unit; IL=interleukin; i.v.=intravenous; 
MRI=magnetic resonance imaging. 
Table 24:  
Recommendations for the Management of Status Epilepticus After CAR T 
Cell Therapy 
Event 
Management 
General 
Patients should be managed according to local institutional practice and with the 
consultation, or management, of a neurologist. 
Non-convulsive 
status epilepticus 
Assess airway, breathing, and circulation; check blood glucose.  
Lorazepam 0.5 mg i.v., with additional 0.5 mg i.v. every 5 minutes, as needed, up to 
a total of 2 mg to control electrographical seizures.  
Levetiracetam 500 mg i.v. bolus, as well as maintenance doses.  
If seizures persist, transfer to ICU and treat with phenobarbital loading dose of 
60 mg i.v. 
Maintenance doses after resolution of non-convulsive status epilepticus are as 
follows: lorazepam 0.5 mg i.v. every 8 hours for three doses; levetiracetam 1000 mg 
i.v. every 12 hours; phenobarbital 30 mg i.v. every 12 hours.  
Convulsive status 
epilepticus 
Assess airway, breathing, and circulation; check blood glucose.  
Transfer to ICU.  
Lorazepam 2 mg i.v., with additional 2 mg i.v. to a total of 4 mg to control seizures.  
Levetiracetam 500 mg i.v. bolus, as well as maintenance doses (as age appropriate).  
If seizures persist, add phenobarbital treatment at a loading dose of 15 mg/kg i.v. 
Maintenance doses after resolution of convulsive status epilepticus are: lorazepam 
0.5 mg i.v. every 8 hours for three doses; levetiracetam 1000 mg i.v. every 12 hours; 
phenobarbital 1 to 3 mg/kg i.v. every 12 hours.  
Continuous electroencephalogram monitoring should be performed, if seizures are 
refractory to treatment.  
Adapted from (Neelapu et al. 2018). 
CAR=chimeric antigen receptor; ICU=intensive-care unit; i.v.=intravenous. 
All indicated doses of medication are for adult patients. Please check local prescribing information. 

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Table 25:  
Recommendation for Management of Raised Intracranial Pressure After 
CAR T Cell Therapy 
Condition  
Management 
Stage 1 or 2 papilledema* 
with CSF opening pressure of 
<20 mmHg without cerebral 
oedema 
Acetazolamide 1000 mg i.v., followed by 250 to 1000 mg i.v. every 
12 hours (adjust dose based on renal function and acid–base balance, 
monitored 1 to 2 times daily).  
Stage 3, 4, or 5 papilledema*, 
with any sign of cerebral 
oedema on imaging studies, or 
a CSF opening pressure of 
≥20 mmHg 
Use high dose corticosteroids with methylprednisolone i.v. 1 g/day 
(see Table 20). 
Elevate head end of the patient’s bed to an angle of 30 degrees.  
Hyperventilation to achieve target partial pressure of arterial carbon dioxide 
of 28 to 30 mmHg but maintained for no longer than 24 hours. 
Hyperosmolar therapy with either mannitol (20 g/dL solution) or hypertonic 
saline (3% or 23.4%, as detailed below): 
• 
Mannitol: initial dose 0.5 to 1 g/kg; maintenance at 0.25 to 1 g/kg every 
6 hours while monitoring metabolic profile and serum osmolality every 
6 hours and withhold mannitol if serum osmolality is ≥320 mOsm/kg, 
or the osmolality gap is ≥40.  
• 
Hypertonic saline: initial 250 mL of 3% hypertonic saline; maintenance 
at 50 to 75 mL/hour while monitoring electrolytes every 4 hours, and 
withhold infusion if serum sodium levels reach ≥155 mEq/L. 
• 
For patients with imminent herniation: initial 30 mL of 23.4% 
hypertonic saline; repeat after 15 minutes, if needed.  
If patient has Ommaya reservoir, drain CSF to target opening pressure of 
<20 mmHg.  
Consider neurosurgery consultation and i.v. anaesthetics for 
burst-suppression pattern on electroencephalography.  
Metabolic profiling every 6 hours and daily CT scan of head, with 
adjustments in usage of the medications to prevent rebound cerebral 
oedema, renal failure, electrolyte abnormalities, hypovolemia, and 
hypotension.  
Adapted from (Neelapu et al. 2018). 
CAR=chimeric antigen receptor; CSF=cerebrospinal fluid; CT=computerised tomography; i.v.=intravenous. 
*papilledema grading should be performed according to the modified Frisén scale (Frisen 1982). 
10.7 
MANAGEMENT OF TUMOUR LYSIS SYNDROME 
Treatment with CAR T cells, such as AUTO3, can lead to rapid destruction of malignant 
B cells, which can be associated with a release of intracellular ions and metabolic by-products 
into the systemic circulation and can thus result in signs and symptoms indicative of TLS. 
Clinically, TLS can be characterised by rapid development of hyperuricemia, hyperkalaemia, 
hyperphosphataemia, hypocalcaemia, and potentially acute renal failure. 
Early recognition and monitoring of signs and symptoms of patients at risk for TLS, including 
identification of abnormal clinical and laboratory values, can lead to successful prevention of 
the serious clinical complications of the condition. Supportive care should be initiated 
according to the institutional standards and at the Investigator’s discretion. 
Management of TLS, including dehydration and management of abnormal laboratory test 
results such as hyperkalaemia, hyperuricemia, and hypocalcaemia, is highly recommended. It 
is also recommended that high-risk patients, i.e. those with a high tumour burden, be treated 

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prophylactically in accordance with local standards (e.g. rehydration, diuretics, allopurinol, 
rasburicase, and other medication to increase urate excretion). 
10.8 
HYPOGAMMAGLOBULINEMIA AND B CELL APLASIA 
Hypogammaglobulinaemia has been seen as a consequence of depletion of normal B cells by 
CAR T therapy (Doan and Pulsipher 2018). CAR T cell therapy targeting antigens found on 
the surface of B cells not only kills cancerous B cells but also normal B cells. Therefore, B cell 
aplasia (low numbers of B cells or absent B cells) is an expected result of successful 
CD19-specific CAR T cell treatment and has served as a useful indicator of ongoing CAR 
T cell activity. This effect results in reduced ability to manufacture the antibodies that protect 
against infection. Intravenous or subcutaneous Ig replacement therapy may be given with the 
aim of preventing infection. However, the degree and duration of this is likely to depend on the 
persistence of CAR T cells in the body and could last for months to years. At worst, the clinical 
consequences of therapeutic B cell elimination will resemble X-linked agammaglobulinaemia 
and patients with this disorder have a normal life expectancy when treated with regular i.v. Ig 
replacement. Immunoglobulin levels will be monitored regularly as per the Schedule of 
Assessments (Table 1 and Table 2) and patients with severe hypogammaglobulinaemia (serum 
IgG level is <4 g/L) persisting longer than 6 months are recommended to be treated with i.v. 
Ig administration until recovery of B cells and normal IgM levels, or lifelong if this does not 
occur.  
Management of Hypogammaglobulinaemia Associated with CAR T Therapy will be 
according to local institutional practice.  
10.9 
INFECTIOUS DISEASES 
Prophylactic anti-bacterial treatment, such as trimethoprim-sulfamethoxazole (or alternative 
drugs), for pneumocystis prophylaxis and prophylactic antivirals, such as acyclovir or 
valacyclovir, for herpes virus prophylaxis may be initiated prior to pre-conditioning 
chemotherapy and continued until lymphopenias have resolved or as clinically indicated. All 
patients with fevers and neutropenia should have blood cultures drawn and assessment for 
broad-spectrum antibiotics done per institutional practice. 
10.10 
MANAGEMENT OF IMMUNE RELATED ADVERSE EVENTS DUE 
TO ON-TARGET BUT OFF-TUMOUR TOXICITY  
Though it is unlikely that AUTO3 will cause immune-related AEs (irAEs) due to on-target but 
off-tumour toxicity, the patients will be closely monitored for signs and symptoms indicative 
of irAEs, which may allow for an early recognition of these events. Special attention will be 
paid to vital organs and for irAEs of any grade involving vital organs (e.g. lung, brain, and 
eyes), more aggressive monitoring and rapid institution of appropriate supportive care 
including systemic steroids, should be administered. In case of severe irAE, not successfully 
managed by general supportive care, treatment with steroids and other agents may be 
considered. 

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10.11 
MANAGEMENT 
OF 
PEMBROLIZUMAB 
RELATED 
IMMUNE 
TOXICITY 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic aetiology are outlined below. Where appropriate, these guidelines 
include the use of oral or i.v. corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
Attempts should be made to rule out other causes such as underlying disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines in this 
section are intended to be applied when the Investigator determines the events to be related to 
pembrolizumab. The SmPC/USPI for pembrolizumab should also be consulted for guidance 
on managing these associated events. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of the evaluation of the event. 
10.11.1 
Pneumonitis and Pulmonary AE 
Pulmonary AEs, including radiographic changes (e.g. focal ground glass opacities and patchy 
infiltrates) indicative of drug-related pneumonitis, have been observed in patients receiving 
immuno-oncology agents. These pulmonary AEs were either asymptomatic or associated with 
symptoms such as dyspnoea, cough, or fever. The initial occurrence of pulmonary AEs may be 
as early as after a single dose of pembrolizumab or delayed after prolonged therapy. Early 
recognition and treatment of pneumonitis is critical to its management. Patients should be 
advised to seek medical evaluation promptly if they develop new-onset dyspnoea, cough, or 
fever or if they have worsening of these baseline symptoms. 
Table 26: 
Management and Follow-up of Pulmonary Adverse Events 
Management and Follow-up of Pulmonary AEs 
Grade 1 
Monitor for symptoms every 2 to 3 days; consider pulmonary and infectious disease 
consult; re-image every 3 weeks. 
Worsening: treat as ≥Grade 2. 
Grade 2 
Monitor symptoms daily; re-image every 1 to 3 days; pulmonary and infectious disease 
consultation; consider bronchoscopy and lung biopsy; consider hospitalisation. 
Immediately: start 1.0 mg/kg/day methylprednisolone i.v. or oral equivalent; prophylactic 
antibiotics 
Persistence for 2 weeks or worsening: treat as Grade 3 to 4; 
Improvement to ≤Grade 1 or baseline: taper steroids over at least 1 month. 
Grade 3 to 4 
Hospitalise; pulmonary and infectious disease consultation; consider bronchoscopy and 
lung biopsy. 
Immediately: 2 to 4 mg/kg/day methylprednisolone or i.v. equivalent; add prophylactic 
antibiotics; 
Persistence for 2 days or worsening: add immunosuppression (e.g. infliximab, CY, i.v. Ig, 
or mycophenolate mofetil) 
Improvement to ≤Grade 2: taper steroids over at least 6 weeks. 

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Management and Follow-up of Pulmonary AEs 
General 
Patients on i.v. steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. The lower bioavailability of oral corticosteroids should be considered. 
AE=adverse event; CY=cyclophosphamide; Ig=immunoglobulin; i.v.=intravenous. 
10.11.2 
Diarrhoea/Colitis 
• 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhoea, abdominal pain, blood, or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
• 
All patients who experience diarrhoea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via i.v. infusion. For Grade 2 or higher diarrhoea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
Table 27: 
Management and Follow-up of Immune-related GI AEs 
Management and Follow-up of Immune-related GI AEs 
Grade 1 
Symptomatic treatment per institutional standards. 
Close monitoring; instruct patient to report worsening immediately and treat as Grade ≥2. 
Grade 2 
≤5 days: Symptomatic treatment per institutional standards. 
>5 days or recurrence: 0.5 to 1.0 mg/kg/d methylprednisolone; consider prophylactic 
antibiotics.  
Persistence or worsening despite steroids >3 days: treat as Grade 3/4. 
Improvement to ≤Grade 1: taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume study therapy per protocol. 
Grade 3 to 4 
Immediately: 1.0 to 2.0 mg/kg/d methylprednisolone i.v.; consider prophylactic 
antibiotics and lower endoscopy. 
Persistence >3 days or recurrence: add infliximab 5 mg/kg (if no contraindication such 
as perforation or sepsis). 
Improvement to ≤Grade 2 within ≤3 days: taper steroids over at least 1 month. 
General 
The oral corticosteroid equivalent of the recommended i.v. dose may be considered for 
ambulatory patients; the lower bioavailability of oral corticosteroids needs to be 
considered. 
Clinical caution should be exercised, for patients receiving concomitant medications of 
corticosteroids, non-steroidal anti-inflammatory drugs (NSAID), or opioid analgesics. In 
addition, be vigilant for signs and symptoms of potential perforation, especially in patients 
with known diverticular disease. Narcotics should be used with caution as pain medicines 
may mask the signs of colonic perforation. 
AE=adverse event; GI=gastrointestinal; Ig=immunoglobulin; i.v.=intravenous; NSAIDs=non-steroidal anti-inflammatory 
drugs. 
10.11.3 
Type 1 diabetes mellitus 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥Grade 3 
Hyperglycaemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA). 

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For type 1 diabetes mellitus or Grade 3 to 4 hyperglycaemia: 
• 
Insulin replacement therapy is recommended for type 1 diabetes mellitus and for Grade 3 
to 4 hyperglycaemia associated with metabolic acidosis or ketonuria.  
• 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
haemoglobin, and C-peptide. 
10.11.4 
Hypophysitis 
• 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• 
For Grade 3 to 4 events, treat with an initial dose of i.v. corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
10.11.5 
Hyperthyroidism or Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
Hyperthyroidism 
• 
Grade 2 hyperthyroidism events (and Grade 2 to 4 hypothyroidism): 
− In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
− In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyronine, is indicated per standard of care. 
• 
Grade 3 to 4 hyperthyroidism  
− Treat with an initial dose of i.v. corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
10.11.6 
Hepatic Events 
• 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). Treat with i.v. or oral corticosteroids. 
• 
For Grade 3 to 4 events, treat with i.v. corticosteroids for 24 to 48 hours.  
• 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
10.11.7 
Renal Failure or Nephritis 
• 
For Grade 2 events, treat with oral corticosteroids. 

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• 
For Grade 3 to 4 events, treat with systemic corticosteroids. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  
10.11.8 
Rash and Pruritus 
• 
For Grade 2 events, treat symptomatically and with oral corticosteroids.  
• 
For Grade 3 to 4 events, treat with systemic corticosteroids. consult dermatologist; 
consider skin biopsy. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  
10.11.9 
Management of Infusion Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Table 28 shows treatment guidelines for 
patients who experience an infusion reaction associated with administration of pembrolizumab. 
Table 28: 
Pembrolizumab Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated 
Increase monitoring of vital signs as medically indicated 
until the patient is deemed medically stable in the opinion of 
the Investigator. 
None. 
Grade 2 
Requires infusion 
interruption but 
responds promptly to 
symptomatic 
treatment (e.g. 
antihistamines, 
NSAIDs, narcotics, 
i.v. fluids); 
prophylactic 
medications 
indicated for 
≤24 hours 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is 
not limited to: 
i.v. fluids 
Antihistamines 
NSAIDs 
Paracetamol/acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the patient is deemed medically stable in the opinion of 
the Investigator. 
If symptoms resolve within 1 hour of stopping 
pembrolizumab infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 mL/hour to 
50 mL/hour). Otherwise dosing will be held until symptoms 
resolve and the patient should be pre-medicated for the next 
scheduled dose. 
Patients who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
Patient may be 
pre-medicated 
1.5 hours 
(±30 minutes) prior 
to infusion of 
pembrolizumab with: 
Diphenhydramine/ 
chlorpheniramine 
50 mg orally (or 
equivalent dose of 
antihistamine). 
Paracetamol/ 
acetaminophen 
500 to 1000 mg 
orally (or equivalent 
dose of antipyretic). 

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NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e. not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalisation 
indicated for other 
clinical sequelae (e.g. 
renal impairment, 
pulmonary 
infiltrates). 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated. 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
i.v. fluids 
Antihistamines 
NSAIDs 
Paracetamol/acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically indicated 
until the patient is deemed medically stable in the opinion of 
the Investigator. 
Hospitalisation may be indicated. 
Patient is permanently discontinued from further trial 
treatment administration. 
No subsequent 
dosing. 
GENERAL 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
CTCAE=Common Terminology Criteria for Adverse Events; i.v.=intravenous; NCI=National Cancer Institute; 
NSAIDs=non-steroidal anti-inflammatory drugs.  

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11 CONCOMITANT MEDICATIONS AND THERAPIES 
All concomitant medications taken or received by the patient from Day -6 until 75 days 
post-AUTO3 infusion must be recorded along with the reason for use and should include: 
• 
Dates of administration, including start and end dates. 
• 
Dosage information including dose and frequency. 
Only concomitant medication related to AEs attributed to AUTO3 or pembrolizumab treatment 
will be recorded from Day 75 post-AUTO3 infusion onwards. Concomitant medication may 
be given as medically indicated. Details of the concomitant medication/treatment given must 
be recorded in the patient’s medical records and details entered into the eCRF. Standard drugs 
required by the patient may be administered alongside the trial protocol.  
All safety management guidelines are only recommendations and deviations from this scheme 
are allowed according to the Investigator’s judgement and local institutional practice. 
11.1 
BRIDGING THERAPY 
Patients may receive bridging therapy while the product is being manufactured. The dates of 
bridging therapy, the chemotherapy agents and the doses given must be recorded in the eCRF. 
Additionally, the intent of bridging therapy, such as prevention of disease progression or 
induction of response in a rapidly progressing disease, should be documented in the eCRF. 
Cytotoxic chemotherapies should be stopped 2 weeks prior to AUTO3 infusion. Other therapies 
should also have an adequate washout as indicated in exclusion criterion 17. Patients should 
have a baseline PET/CT after the bridging chemotherapy is given and prior to starting 
pre-conditioning. 
11.2 
ALLOWED CONCOMITANT MEDICATIONS/THERAPIES 
Palliative radiotherapy: Palliative radiotherapy may be given concomitantly as clinically 
appropriate.  
Other permitted therapies: The following medications and supportive therapies are examples 
of support therapies that may be used during the study: 
• 
Anti-microbials including antivirals and supportive therapy as required to prevent 
infections. 
• 
Colony stimulating factors (use granulocyte-macrophage colony-stimulating factors 
[GM-CSF] with caution up to 3 weeks after AUTO3 infusion, due to the potential to 
worsen CRS symptoms. Granulocyte-colony stimulating factor (G-CSF) would be the 
preferred myeloid growth factor over GM-CSF, if medically indicated. The effects of 
G-CSF are unknown and can be used at the physician’s discretion). 
• 
Erythropoietin, and transfusion of platelets and red cells. 
Pre- and post-AUTO3 infusion supportive therapies: 
Please refer to Section 10.2. 

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11.3 
PROHIBITED AND CAUTIONARY THERAPIES 
Herbal, homeopathic agents or very high dose vitamins and mineral supplements: No 
herbal, homeopathic agents or very high dose vitamin and mineral supplements will be allowed 
between Day -10 and Day 56 following AUTO3 infusion, unless recommended by the 
Principal Investigator.  
Corticosteroids and immunosuppressant (except for managing treatment related 
toxicity): Patients should not be receiving corticosteroids at doses of >5 mg prednisolone or 
equivalent within 7 days of leukapheresis and 72 hours prior to the time of AUTO3 infusion. 
The use of immunosuppressants such as high dose corticosteroids should be avoided where 
possible, as these are likely to influence the efficacy and possibly safety of AUTO3. As per the 
exclusion criteria, immunosuppressants should be stopped ≥2 weeks prior to leukapheresis or 
AUTO3 infusion. Corticosteroids should also be avoided post-AUTO3 infusion if possible, 
although it is recognised that their use may be required in the context of development of CRS 
or infusion reactions. Physicians may use any medication as clinically appropriate and 
necessary to manage emerging AEs. The use of other immunosuppressants should be discussed 
with the Sponsor’s Medical Monitor. 
Anti-cancer therapies: In general, patients should not receive other anti-cancer therapy or any 
other investigational anti-cancer drugs after administration of AUTO3.Administration of other 
systemic anti-cancer therapy at any time will be considered an indicator of treatment failure 
(progressive disease). However, palliative radiotherapy for symptom control can be 
administered without necessarily indicating progressive disease. Patients who have been 
administered AUTO3 and subsequently require alternative anti-cancer therapy will complete 
the End of Study visit and roll on to a follow-up protocol. 
Investigators can use any medication based on their clinical judgement and local 
institutional practice to optimise patient’s safety. All medications should be recorded on the 
eCRF. 
11.4 
OVER-DOSAGE 
There is currently no experience of overdose of AUTO3 as no clinical studies have been 
performed to date. There is no specific treatment for an overdose of AUTO3. In the event of 
overdose, any adverse reactions should be treated symptomatically. In the event of 
unmanageable toxicity, steroids may be used to deplete AUTO3. 
AUTO3 cells will be provided in patient specific dose aliquots and will be administered by 
trained staff in a hospital setting; therefore, the chance of overdose is unlikely. 
11.5 
DIETARY AND LIFESTYLE RESTRICTIONS 
No dietary restrictions are recommended. A normal balanced diet is recommended; the patient 
may continue his/her normal diet as appropriate. 
Donating blood products and organs 
Patients should not donate blood, organs, tissue or cells to others after receiving AUTO3. 

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12 SAFETY AND PHARMACOVIGILANCE 
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of patients, Investigators, and the Sponsor, and are 
mandated by regulatory agencies worldwide. The Investigator or site staff will be responsible 
for detecting, documenting and reporting events that meet the definition of an AE or SAE. 
12.1 
DEFINITIONS 
12.1.1 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product which does not necessarily have a causal relationship with the treatment.  
An AE can therefore be any unfavourable and unintended sign (for example, an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.  
12.1.2 
Definition of an Adverse Reaction 
An adverse reaction is any untoward and unintended response to a medicinal product that is 
related to any dose administered. A causal relationship between a medicinal product and an AE 
is at least a reasonable possibility, e.g. the relationship cannot be ruled out.  
An unexpected adverse reaction is an adverse reaction in which the nature or severity of which 
is not consistent with the Reference Safety Information section outlined in the IB for AUTO3 
and SmPC for pembrolizumab. 
12.1.3 
Definition of a Serious Adverse Event 
A SAE is defined as an AE that meets any of the following criteria: 
• 
Results in death (death due to disease progression will not be considered as an SAE). 
• 
Life-threatening (the term ‘life-threatening’ refers to an event for which the patient was 
at risk of death at the time of the event. It does not include any AE that, had it occurred in 
a more severe form, might have caused death).  
• 
Requires in-patient hospitalisation or prolonged existing hospitalisation.  
• 
Results in persistent or significant disability/incapacity.  
• 
Congenital anomaly/birth defect.  
• 
Medically significant (e.g. important medical events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardise the patient or may 
require intervention to prevent one of the other outcomes listed above). 
If the event was initially non-serious, the onset of the SAE should be considered the time when 
the AE met the seriousness criteria. Resolution of the SAE should also be considered when the 
event is either a non-serious event or has resolved.  
Serious adverse events must be reported by the Investigator to the Sponsor within 24 hours of 
being made aware of their existence (see Section 12.3.5 for reporting instructions). 

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Protocol-Specific SAEs are as follows: 
• 
Grade 4 CRS and NT.  
• 
Any new primary cancers. 
• 
Significant cardiac dysfunction such as Grade 3 or higher decrease in left ventricular 
ejection fraction. 
• 
Grade 4 non-haematological laboratory abnormalities (not disease related) when 
considered clinically significant. 
Serious adverse events must be reported by the Investigator to the Sponsor within 24 hours of 
being made aware of their existence (see Section 12.3.5 for reporting instructions). 
Events NOT considered as SAEs: 
• 
A procedure requiring hospitalisation for protocol/disease-related investigations 
(e.g. surgery, scans, endoscopy, sampling for laboratory tests, BM sampling). However, 
hospitalisation or prolonged hospitalisation for a complication of such procedures remains 
a reportable SAE. 
• 
Hospitalisation for administration of pre-conditioning chemotherapy or conducting study 
procedures. 
• 
Routine treatment or monitoring of the indication not associated with any deterioration in 
condition. 
• 
The administration of blood or platelet transfusion as a routine treatment of the studied 
indication. However, hospitalisation or prolonged hospitalisation for a complication of 
such transfusion remains a reportable SAE. 
• 
Hospitalisation or prolongation of hospitalisation for technical, practical, or social reasons, 
in absence of an AE. 
• 
Hospitalisation of patients in the Phase I – expansion cohort being treated in the 
outpatient/ambulatory setting, where the Investigator feels the patient should be monitored 
as an inpatient for technical, practical, or social reasons (such as the lack of an adequate 
caregiver), in absence of AEs that meet the seriousness criteria (Section 12.1.3). 
• 
Hospitalisations not intended to treat an acute illness or AE (e.g. social reasons such as 
pending placement in a long-term care facility). A procedure that is planned (i.e. planned 
prior to starting of treatment on study), which must be documented in the source document 
and eCRF. Hospitalisation or prolonged hospitalisation for a complication remains a 
reportable SAE. 
• 
An elective treatment of a pre-existing condition unrelated to the studied indication. 
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
• 
An event that is part of the natural course of the disease under study (e.g. disease 
progression or hospitalisation due to disease progression, pain control, stabilisation of 
fractures) does not need to be reported as an SAE. Death due to the disease under study is 
to be recorded on the Death eCRF page. However, if progression of the underlying disease 
is greater than that which would normally be expected for the patient, or if the Investigator 

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considers that there was a causal relationship between treatment with study medication(s) 
and/or the disease progression, then this must be reported as an SAE. 
12.1.4 
Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction (SUSAR) is any suspected adverse reaction 
related to the study treatment that is both unexpected and serious (see Section 12.3.6). 
12.1.5 
Adverse Events of Special Interest 
The following are AEs of special interest.  
• Grade 3 or 4 AUTO3 infusion related reaction. 
• Grade 3 to 5 CRS. 
• Grade 3 to 5 NT (including depressed level of consciousness, dysphagia, ataxia, 
seizures, and cerebral oedema). 
• Any new malignancies (regardless of causality) including details of any applicable 
subtype and associated treatment 
• New incidence or exacerbation of a pre-existing Neurologic disorder 
• New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder 
• New incidence of a hematologic disorder 
Adverse events of special interest will be reported on an AESI/SAE form to the Sponsor within 
24 hours of becoming aware of the event. Events can be both an AESI and a SAE (Sections  
12.3.5 and 12.3.7). 
12.1.6 
Disease Progression 
Due to the nature of the disease under investigation, disease progression is an anticipated 
occurrence in many patients, due to the nature and prognosis of the disease. Disease 
progression is therefore not considered an AE, unless the disease progression is greater than 
that which would normally be expected for that patient, or if the Investigator considers that 
there was a causal relationship between treatment with study medication(s) or protocol 
design/procedures and the disease progression, then this must be reported as an SAE, due to 
the medical significance of the event. 
12.2 
ASSESSMENT OF ADVERSE EVENTS  
Adverse events will be elicited at each study visit as indicated in Schedule of Assessments and 
as clinically necessary. Patients will be instructed to report any AEs occurring between study 
visits to the study site. Adverse events will be assessed by the Investigator, or appropriately 
qualified designee, for severity, relationship to study treatment, action taken, outcome and 
whether the event meets criteria as an SAE according to the guidelines presented in 
Section 12.1.3. 

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12.2.1 
Severity of Adverse Events 
The severity of AEs will be graded according to the NCI CTCAE (Version 5.0). 
Adverse events that are not defined in the NCI CTCAE should be evaluated for severity 
according to the following scale: 
Table 29: 
Severity Grading of AEs Not Listed on the NCI CTCAE Grading System 
Grade 
Severity 
1 
Mild  
Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
2 
Moderate 
Mild to moderate limitation in activity, some assistance may be needed; no 
or minimal medical intervention/therapy required. 
3 
Severe 
Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalisation is possible. 
4 
Life-threatening 
Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required, hospitalisation or hospice care 
probable. 
5 
Fatal 
Death as a result of this AE. 
AE=adverse event. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 12.1.3. 
Grade 3 or 4 severity does not necessarily imply seriousness. Due to the nature of the patient’s 
disease and treatment, Grade 3 and 4 cytopenia (neutropenia, thrombocytopenia and anaemia) 
are common and are not usually considered medically significant in this context. For other 
events, there should be a low threshold in considering a Grade 3, and particularly a Grade 4 
event as serious. 
12.2.2 
Relationship of AEs to Treatment 
The Investigator must determine the relationship between the administration of the study drug 
and the occurrence of an AE/SAE as defined below: 
Relationship assessments classified as “Not Related” to study treatment:  
Not Related: 
The AE is not related to the investigational medicinal product. The patient 
either did not receive the investigational product or the event is related to 
aetiology other than the investigational product (the alternative aetiology 
must be documented in the study patient’s medical record). 
Unlikely Related: 
The AE is doubtfully related to the investigational product.  
The event is not clearly related to an identified aetiology other than the 
investigational product; but there is no plausible mechanism for the event 
to be related to the investigational product and/or there is no clear 
association between the event and the administration of the investigational 
product. 
Relationship assessments classified as “Related” to study treatment: 
Possibly Related: 
The AE may reasonably be related to the investigational product.  

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Probably Related: 
The AE is likely to be related to the investigational product.  
There is an association between the event and the administration of the 
investigational product, there is a plausible mechanism for the event to be 
related to the investigational product, the event is less likely to be 
explained by known characteristics of the patient’s clinical status, and an 
alternative aetiology is not apparent. 
Definitely Related: The AE is clearly related to the investigational product. 
If an event is assessed as related to a drug other than the investigational product, which has not 
been provided by the Sponsor, the name of the manufacturer must be provided when reporting 
the event.  
12.3 
REPORTING PROCEDURES 
12.3.1 
All Adverse Events  
The AE event term recorded in the eCRF, when possible and appropriate, should be the 
‘medical diagnosis’ using the most appropriate medical term. If a diagnosis is not known, then 
the signs and symptoms should be included. This can be updated later, when a diagnosis has 
been made. 
Signs and symptoms, or additional known associated events (e.g. febrile neutropenia with fever 
and neutropenia) do not need to be reported as additional event terms and should be described 
in the narrative. Signs, symptoms or other events, not normally associated with the reported 
event, should be added as additional events (e.g. febrile neutropenia and liver function 
abnormal). 
All measures required to manage an AE must be recorded in the patient’s medical notes and 
reported accordingly in the eCRF. 
Death is an outcome and should not be considered an AE, unless no other appropriate diagnosis 
can be made. This should be updated when a cause of death has been established. 
In principle all AEs, including SAEs should be collected from the time that the patient consents 
to the study. However, due to the long period between consent and treatment with AUTO3, 
any AEs/SAEs related to bridging chemotherapy that are not associated with study procedures 
do not require reporting as study AEs/SAEs. Any significant events should be added to the 
patient’s medical history. All AEs/SAEs related to study procedures (leukapheresis, bone 
marrow assessments etc) should be reported. 
All AEs/SAEs are to be recorded from admission for pre-conditioning chemotherapy (Day -7). 
Due to the patient’s disease state and expected effect of chemotherapy on laboratory values, 
not all laboratory value abnormalities will be considered as AEs (see Section 12.3.2). Changes 
to laboratory values are better assessed through individual laboratory measurements. 
The reporting period for all AEs is described in Table 30. 

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Table 30: 
Reporting Period for All AEs 
From: ICF signature 
Until: Day -6 
From: Day -6  
Until: Day 75 
post-AUTO3 infusion 
From: Day 75 post-AUTO3 
infusion  
Until: End of study/patient 
withdrawal 
OR, when patient initiates a 
new treatment for their disease 
• 
AEs/SAEs related to study procedures 
(leukapheresis, bone marrow 
assessments, lumbar punctures etc). 
Note: AEs/SAEs associated with bridging 
therapy prior to admission for conditioning 
chemotherapy, are not associated with study 
procedures and therefore do not need to be 
reported as AEs in this study. If significant, 
these should be included in the patient’s 
medical history.  
• 
All AEs. 
• 
All SAEs. 
• 
All AEs (regardless of 
grade) considered related to 
AUTO3. 
• 
All AEs of special interest 
(regardless of relationship 
to AUTO3) 
(Section 12.3.6). 
• 
All AEs related to study 
procedures (bone marrow 
assessments, lumbar 
punctures etc) regardless of 
relationship to AUTO3. 
All SAEs (regardless of 
relationship to AUTO3). 
If a patient starts a new 
treatment for disease 
progression or undergoes a stem 
cell transplant: 
• 
Only AEs (serious and 
non-serious) that are 
considered related to 
AUTO3 to be reported. 
AE=adverse event; ICF=informed consent form; SAE=serious adverse event. 
The Investigator should follow each AE until either: 
• 
The AE has resolved to baseline;  
• 
The AE is assessed as stable by the Investigator; 
• 
Patient is lost to follow-up; 
• 
Patient withdraws consent; 
• 
Death; 
• 
Study completion (or disease progression and patient withdrawn). 
If a drug-related AE and/or any SAE is ongoing at the time of study completion, the event will 
be followed until resolution, is assessed as stable by the Investigator, or one of the following 
apply: 
• 
Death; 
• 
Withdrawal of consent; 
• 
Start of new treatment/stem cell transplant; or  
• 
Patient lost to follow-up. 

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Patients who enter a long-term safety study will have their events considered as continuing at 
the completion of this study, and the event will be followed up, as applicable, in the long-term 
safety study. 
12.3.2 
Adverse Events Associated with Laboratory Values  
Anaemia, neutropenia, and thrombocytopenia requiring blood product support are anticipated 
(due to disease and pre-conditioning) and are therefore not considered AEs, unless they persist 
beyond Day 30 after CAR T cell infusion or are considered clinically significant and/or require 
advanced intervention above blood product and granulocyte-colony stimulating factor support. 
Grade 1 to 2 laboratory abnormalities, at any time point, are extremely frequent in this patient 
population and do not need to be considered AEs unless they are felt to be clinically significant 
by the Investigator.  
Whenever possible, AEs associated with laboratory values, should have these values included 
in the eCRF (e.g. reporting of AEs such as febrile neutropenia should be associated with 
temperature reading entry in vitals and absolute neutrophil counts in laboratory sections of the 
eCRF).  
It should be noted that a single laboratory measurement may not have any clinical significance 
and may need to be taken in the context of other observations. 
Abnormal laboratory values may be deemed clinically significant by the Investigator if either 
of the following conditions is met: 
• 
The abnormality suggests a disease and/or organ toxicity that is new or has worsened from 
baseline, in the context of the patient’s disease state and recent chemotherapy and/or CAR 
T cell therapy. 
• 
The abnormality is of a degree that requires additional active management (e.g. closer 
observation, more frequent follow-up assessments, or further diagnostic investigation). 
• 
Prolonged Grade 4 cytopenia lasting more than 60 days or those considered medically 
significant or requiring significant management in addition to transfusions and growth 
factor support (e.g. stem cell top up or transplant) should be reported as SAEs. 
If the abnormal laboratory value(s) indicate a specific medical condition or diagnosis, then this 
medical condition, rather than the laboratory result, should be used as the AE reported term 
(see Section 12.3.1). 
12.3.3 
Adverse Events Associated with Cytokine Release Syndrome  
As CRS can present with multiple signs and symptoms, it is important to assess the character 
and nature of these occurrences. Therefore, as well as entering the event of ‘Cytokine Release 
Syndrome’, with the appropriate grading (see Section 10.4) in the eCRF, please also add the 
associated AEs (or signs and symptoms), as separate AEs, with the appropriate CTCAE grading 
as applicable. Fever, hypotension and hypoxia are considered part of CRS, and should be 
entered in the CRS eCRF page, and therefore do not need to be added as separate AEs.  
12.3.4 
Adverse Events Associated with CAR T Neurotoxicity (ICANS) 
As ICANS can present with multiple signs and symptoms, it is important to assess the character 
and nature of these occurrences. Therefore, as well as entering the event of ‘ICANS’, with the 

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SAE follow-up reporting: 
After the initial SAE report, the Investigator is required to provide additional follow-up 
information on the SAE by submitting an updated SAE report form to the Sponsor (or 
designee). New significant information includes, but is not limited to, the following: 
• 
New signs or symptoms or a change in the diagnosis. 
• 
Significant new diagnostic test results. 
• 
Change in causality based on new information. 
• 
Change in the event’s outcome, including resolution. 
• 
Additional narrative information on the clinical course of the event. 
Serious adverse events must be followed through to resolution by the Investigator. Resolution 
is defined as a return to baseline status, Grade 1, or stabilisation of the condition with the 
expectation that it will remain chronic. For all SAEs, the Investigator may be requested to 
obtain additional information in an expedited manner. This additional information will allow 
for a complete medical assessment of the case and independent determination of possible 
causality. Information on other possible causes such as concomitant medication and illnesses 
must be provided. 
The Medical Monitor may specify a longer period of time, if required to assure the safety of 
the patient. 
12.3.6 
Suspected Unexpected Serious Adverse Reaction (SUSAR) Reporting 
If the event is evaluated as a SUSAR, i.e. unexpected events that are related (reasonable 
possibility) to the AUTO3, the Sponsor will submit the SUSAR to the regulatory authorities 
and the Research Ethics Committee, as soon as possible and within 7 calendar days for initial 
reports of fatal/life threatening events (with a follow-up report within a further 8 calendar days) 
and 15 calendar days for all other events. Where there are conflicting evaluations of causal 
relationship between the Investigator and the Sponsor, the more conservative will be used for 
reporting purposes.  
All reporting to regulatory authorities will be by the Sponsor, or through a Sponsor designated 
vendor. 
The Sponsor (or designee) will notify Investigators of all SUSARs and reportable SAEs. The 
Investigator must immediately review with the Investigator site team and retain the 
documentation in the Investigator Site File. 
12.3.7 
Adverse Events of Special Interests Reporting 
Adverse events of special interest occurring during the study should be reported to the Sponsor 
within 24 hours of becoming aware of the event using the AESI/SAE form. Additional or 
follow-up information should be submitted with relevant information promptly.  
The AESI/SAE form should be completed and faxed or emailed to the sponsor or designee (see 
Section 12.3.5) within 24 hours. 

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12.3.8 
Pregnancy Reporting and Management 
Pregnancies 
Female patients of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 12 months after the last dose 
of study treatment. Any pregnancies during this period must be reported to the Sponsor 
(or designee) within 24 hours of knowledge of the event using the pregnancy report form 
(fax numbers and email address are listed on the bottom of the form). 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs and must be reported to the Sponsor 
immediately using the AESI/SAE Form (i.e. no more than 24 hours after learning of the event). 
The Investigator must counsel the patient, discussing the risks of the pregnancy and the possible 
effects on the foetus. Monitoring of the patient should continue until conclusion of the 
pregnancy. 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed to immediately inform the Investigator if their partner becomes 
pregnant during the study or within 12 months after the last dose of study treatment. Any 
pregnancies during this period must be reported to the Sponsor (or designee) within 24 hours 
of knowledge of the event using the pregnancy report form (fax numbers and email address are 
listed on the bottom of the form). 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study treatment. The pregnant partner 
will be asked to sign an authorisation for use and disclosure of pregnancy health information. 
The Investigator may provide information on the risks of the pregnancy and the possible effects 
on the foetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
Outcome 
Additional information on the course and outcome of the pregnancy should be provided to the 
Sponsor (or designee) as soon as becoming available (i.e. no more than 24 hours after obtaining 
the information) using the paper pregnancy report form. The following pregnancy outcomes 
will be SAEs and should be reported according to the procedure in Section 12.3.5: 
• 
Spontaneous abortion (as the Sponsor considers spontaneous abortions to be medically 
significant events). 
• 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient. 
• 
All neonatal deaths occurring within 30 days of birth should be reported as SAEs, without 
regard to causality.  
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required. 

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12.3.9 
Overdose Reporting and Dosing Errors 
Safety information on the study drug may require expedited reporting and/or safety evaluation. 
This will include: 
• 
Overdose of a study drug (AUTO3 or pembrolizumab) 
• 
Suspected abuse/misuse of a study drug 
• 
Inadvertent or accidental exposure to a study drug 
• 
Medication error involving a study drug  
A study drug overdose is the accidental or intentional use in an amount higher than the dose 
being studied. An overdose or incorrect administration of study drug is not an AE unless it 
results in untoward medical effects. Any overdose or incorrect administration should be noted 
on the corresponding eCRF page. All AEs associated with an overdose or incorrect 
administration should be recorded on the AE eCRF page. If the associated AE fulfils the criteria 
for a SAE, the event should be reported immediately (i.e. no more than 24 hours after learning 
of the event; see Section 12.3.5). 

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13 OVERSIGHT COMMITTEES 
13.1 
SAFETY EVALUATION COMMITTEE  
Patient safety will be monitored throughout all parts of the study by a SEC established by the 
Sponsor. This committee will monitor treatment-emergent data on an ongoing basis throughout 
study conduct for the purpose of ensuring the continued safety of patients enrolled in this study. 
The SEC will be chaired by the Sponsor medical monitor and membership may include Study 
Investigators, a statistician and biomarker representative, along with additional Sponsor staff 
as appropriate. The team will meet at regular frequencies throughout study conduct:  
During Phase I, the SEC will meet:  
1. After the first patient in each cohort completes 2 weeks following AUTO3 infusion.  
2. After the third and/or sixth patient in each cohort completes the DLT evaluation period of 
28 days to make the dose escalation decision. 
3. Additional ad hoc meetings if safety stopping criteria is met.  
4. When clinically necessary based on emerging data. 
During Phase II, the SEC will meet:  
On a periodic basis (not exceeding 3 months until last patient has been enrolled and there after 
6 months) to assess cumulative safety data.  
2. After 10 and 27 patients (interim analysis) have completed 30 days following AUTO3 
infusion. 
The Sponsor will maintain documentation of meeting outcomes. Decisions with the potential 
to impact patient safety (e.g. an unfavourable change in the risk/benefit assessment) will be 
promptly communicated to Investigators, ethics committees and regulatory authorities as 
appropriate. Throughout the trial, information regarding all SAEs and potential DLTs will be 
sent to the SEC members. Dose limiting toxicities will be monitored centrally and the decision 
to assign the optimal dose will be taken by the SEC. 
Dose escalation decisions in Phase I of the study will be made by the SEC. The schedule of 
dose escalation meetings will depend on the time to completion of a cohort frequency of DLT 
and when (an) RP2D(s) is/are determined. The SEC may stop further enrolment into one or 
more of the cohorts if treatment-emergent toxicity is determined to result in an unfavourable 
change in patient risk/benefit. Decisions and/or recommendations made by the SEC will be 
communicated to the Principal Investigators at all active study centres and to the Sponsor.  
Mandatory SEC processes will be included in a SEC Charter. 
13.2 
INDEPENDENT DATA MONITORING COMMITTEE 
An IDMC consisting of two independent physicians and one statistician will be established by 
the Sponsor and they will review serious safety events. The decision of the IDMC will 
supersede that of SEC. The IDMC will meet upon occurrence of the following: 
• 
When any safety stopping, criteria (Section 3.7) are met. 
• 
During Phase I, once during Cohort 1 and once during Cohort 2 (via TC or 
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• 
Prior to opening Phase II. 
• 
At the interim analysis of Phase II (after enrolling 27 patients in Cohort 1) 
• 
Annually (6-monthly during active enrolment) during Phase II to review cumulative safety 
data. 
Throughout the trial, information regarding all SAEs and DLTs will be sent to the IDMC 
members to keep them informed on emerging safety findings. IDMC can ask for and will be 
provided any additional information relevant to the SAEs and DLTs. The IDMC will receive 
all dose evaluation/escalation meeting minutes (as soon as possible following the meeting) and 
will have the opportunity to review and can over-rule the SEC decision if clinically warranted 
and necessary.  
When an RP2D(s) decision is made by the SEC, the decision will need to be reviewed and 
endorsed by the IDMC prior to opening Phase II. 
Upon occurrence of any events as defined above, detailed event summaries and cumulative 
safety data will be sent to the IDMC. A recommendation to continue or to hold or modify the 
study will be made by the IDMC to the Sponsor. If and when a study is stopped, it will be 
restarted after a substantial protocol amendment has been approved by the regulatory 
authorities and ethics committees. 
Decisions and/or recommendations made by the IDMC will be communicated by the Sponsor 
to the Principal Investigators at all active study centres. 
Mandatory IDMC processes will be included in the IDMC Charter. 

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14 STATISTICS 
Further details of the statistical analysis of all the endpoints will be included in a separate 
Statistical Analysis Plan. Any analysis that deviates from the Statistical Analysis Plan will be 
documented and justified in the Clinical Study Report. 
14.1 
SAMPLE SIZE ESTIMATION 
Approximately 171 patients in total are expected to be enrolled (consented) into Phase I and 
Phase II of the study and approximately 151 patients in total are anticipated to be treated with 
AUTO3 therapy.  
Phase I (Escalation): Up to 30 patients treated (3 to 6 patients per dose cohort, with the 
exception of dose level cohort 1 one which may include up to 12 patients [up to 6 patients 
without anti-PD-1 treatment, and 6 patients with anti-PD-1 treatment]), following a rolling 6 
design (Skolnik et al. 2008). An additional 12 patients may be added to RP2D dose /dose range. 
Phase I Expansion Cohort: Approximately 20 patients will be treated in an 
outpatient/ambulatory care setting.  
At the end of Phase I (Escalation), assuming there at least 12 patients are treated, the study will 
terminate if the upper limit of the 2-sided 95% confidence interval in response rate is less than 
30%. This is equivalent to observing 0 response in 12 patients. The study will proceed to 
Phase II if the upper limit of the 2-sided 95% confidence interval in response rate exceeds 30%. 
Phase II: In Cohort 1, up to 81 evaluable patients will be analysed using Simon’s 2-stage 
optimal design. This will include 81 patients with DLBCL (and its defined subsets), and those 
with transformed FL (YESCARTA Prescribing Information 2017, Kymriah US Prescribing 
Information 2018). Additionally, 20 patients with primary mediastinal large B cell lymphoma 
and those with lymphoma transformed from other indolent histologies will be enrolled in 
Cohort 2.  
Simon's 2-stage design trial will be used in the Phase II Cohort 1 only. The null hypothesis that 
the true response rate is 30% will be tested against a 1-sided alternative. In the first stage, 27 
evaluable patients will be accrued. If there are nine or fewer responses in these 27 patients, the 
study will be stopped. Otherwise, 54 additional evaluable patients will be accrued for a total of 
81 in Cohort 1. The null hypothesis will be rejected if 31 or more responses are observed in 
81 patients. This design yields a type I error rate of 5% and 80% power when the true response 
rate is 45%. 
14.2 
DESCRIPTION OF ANALYSIS DATASETS 
14.2.1 
Screened Set 
The Screened Set comprises all patients who have signed informed consent and were screened 
in the study. 
14.2.2 
Enrolled Set 
The Enrolled Set consists of all patients enrolled into the study. 

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14.2.3 
Infused Set 
The Infused Set comprises all patients who received at least one infusion of AUTO3 treatment. 
14.2.4 
Safety Set  
The Safety Set comprises all patients who received at least one dose (complete or partial dose) 
of AUTO3 therapy. 
In addition, safety for patients who received pre-conditioning therapy but not AUTO3 therapy 
will also be summarized. 
14.2.5 
Efficacy Analysis Set 
All patients in the infused set with PET-positive disease prior to the start of pre-conditioning 
therapies will be included in the efficacy analysis set (EAS). Patients with PET-negative 
disease after bridging chemotherapy will not be included in the primary EAS.  
Further efficacy analysis sets of patients will be defined in the statistical analysis plan. 
14.3 
STATISTICAL ANALYSES AND METHODS 
Continuous data will be summarised using the mean, median, standard deviation, minimum 
and maximum, while frequency counts and percentages will be presented for discrete variables. 
Time-to-event endpoints will be summarised using the Kaplan-Meier method. Summary 
statistics will be presented for baseline characteristics. 
In all analyses, the Study Day refers to the day defined per Clinical Data Interchange Standards 
(CDISC) convention as: 
• 
(date of the event/assessment − date of first AUTO3 infusion + 1), if the event is on or 
after the date of first AUTO3 infusion 
• 
(date of the event/assessment − date of first AUTO3 infusion), if the event precedes the 
date of the first AUTO3 infusion. In this case, the study day will be negative. 
Note that the date of AUTO3 infusion will be Day 1 under the CDISC analysis convention.  
14.3.1 
Primary Endpoints 
The primary endpoints of the study are as follows: 
Phase I: Safety and RP2D(s) 
• 
Incidence of Grade 3 to 5 toxicity occurring within 75 days of AUTO3 infusion. 
• 
Frequency of DLT of AUTO3 
Phase I: Outpatient Cohort 
• Incidence of Grade 3 to 5 toxicity occurring within 75 days of AUTO3 infusion. 
Phase II: Anti-tumour effect  
• 
Proportion of patients in Cohort 1 treated at RP2D(s) and achieving objective response 
(CR, PR) per Lugano criteria, post-AUTO3 infusion, based on independent central 
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• 
Incidence of Grade 3 to 5 toxicity occurring within 75 days of AUTO3 infusion in Cohort 2 
at the RP2D(s). 
14.3.1.1 
Phase I: Safety 
Safety associated with AUTO3 administration (only those who received AUTO3). 
Summary statistics and analyses will be provided by dose level and overall. The safety analysis 
set will be used for the analysis of safety data. 
Safety evaluations will be based on the incidence, severity and type of AEs, and changes in the 
patient’s vital signs and clinical laboratory results. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) AE coding system for the purpose of summarisation. All AEs occurring in the 
study will be listed in by-patient data listings. Treatment-emergent AEs will be tabulated, 
where “treatment-emergent” is defined as any AE that occurs during or after administration of 
AUTO3 up to 75 days after the last infusion, any event that is considered drug-related 
regardless of the start date of the event, or any event that is present at baseline and continues 
after the first dose of study treatment but worsens in intensity. Events that are considered related 
to treatment (possibly, probably, or definitely related) will also be tabulated. Adverse events 
by the NCI CTCAE toxicity grade will also be summarised. Deaths and SAEs will be tabulated 
in data listings including additional relevant information on the patient. 
Laboratory toxicity grades will be calculated for the appropriate laboratory parameters 
according to NCI CTCAE Version 5.0. 
Adverse events of special interest will be analysed in greater depth, including the time to onset 
and time to resolution where appropriate. 
14.3.1.2 
Phase I: RP2D(s) and MTD 
At the end of the Phase I dose escalation phase, the RP2D(s) will be identified based on the 
safety data and evaluation of the activity data collected in the dose escalation phase. 
14.3.1.3 
Phase II: Anti-tumour Effect 
The primary endpoints for Phase II (Cohort 1) will be assessed as follows: 
Proportion of patients in Cohort 1 achieving objective response (CR, PR) per Lugano criteria, 
post AUTO3 infusion, based on independent central radiology review. 
14.3.2 
Secondary Endpoints 
14.3.2.1 
Safety of AUTO3 
Reporting of AEs will be based on the latest MedDRA version at the time of database lock and 
NCI CTCAE Version 5.0. The reporting of CRS and ICANS will be based on the ASTCT 
consensus grading (Lee et al. 2019). Other AEs that are not defined by the CTCAE should be 
evaluated for severity per Table 29.   
Frequency and severity of treatment-emergent AEs and SAEs will be summarised by time of 
onset. A patient with multiple occurrences of an AE will be counted only once in the respective 
AE category. A patient with multiple toxicity grades for the same preferred term (PT) will be 

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summarised under the maximum toxicity grade recorded for the event. Adverse events with 
missing toxicity grade will be included in the all grades column of the summary tables. 
Fatal AEs and SAEs will be listed by patient and summarised by system organ class (SOC) and 
PT. In addition, AEs occurred prior to AUTO3 infusion will be summarised by SOC and PT in 
the Enrolled Set. 
For laboratory tests covered by the CTCAE, the grades will be derived based on the laboratory 
values. Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. Shift tables using CTCAE grades to compare baseline to the worst 
post-AUTO3 value will be presented. For laboratory tests where grades are not defined by 
CTCAE, results will be graded by the low/normal/high classifications based on laboratory 
normal ranges. Shift tables using low/normal/high to compare baseline to the worst post-
AUTO3 value will be presented. 
Special safety topics including CRS, neurotoxicity, severe hypogammaglobulinaemia etc will 
be summarised. Details of analyses will be outlined in the statistical analysis plan (SAP). 
14.3.2.2 
Feasibility of AUTO3 Manufacture in this Patient Population (All Patients) 
Feasibility of product generation will be examined by assessing the number of AUTO3 
successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all 
patients registered).  
14.3.2.3 
Clinical Efficacy of AUTO3  
Efficacy will be evaluated in Cohort 1 and Cohort 2 of Phase 2 separately.  
Duration of Response: DOR is defined as the time from the first documented disease response 
(CR or PR) to progression or death due to underlying cancer. 
If a patient does not have an event prior to data cut-off, DOR will be censored at the date of 
the last adequate assessment by default.  
Patients who proceed to HSCT after AUTO3 infusion will be censored at the time of HSCT in 
the main analysis. In addition, a supportive analysis will be performed without censoring 
HSCT.  
Patients who receive new anticancer therapies other than HSCT will be censored at the date of 
last adequate assessment in the main analysis. In addition, a supportive analysis will be 
performed without censoring new anticancer therapies. 
DOR will be assessed in patients with a BOR of CR or PR in the EAS. Supportive analyses 
will be performed in the Infused Set and the Enrolled Set. DOR will be summarized by BOR 
(CR, PR, stable disease/PD) too. The distribution function of DOR will be estimated using the 
KM method. The median DOR along with 95% CIs will be presented if appropriate. 
Progression free survival: PFS is defined as the time from the date of first AUTO3 infusion 
to the date of first documented progression or death due to any cause. 
If a patient does not have an event prior to data cut off, PFS will be censored at the date of the 
last adequate assessment by default. 

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Patients who proceed to HSCT after AUTO3 infusion will be censored at the time of HSCT in 
the main analysis. In addition, a supportive analysis will be performed without censoring 
HSCT.   
Patients who receive new anticancer therapies other than HSCT will be censored at the date of 
their last adequate assessment in the main analysis. In addition, a supportive analysis will be 
performed without censoring new anticancer therapies.  
PFS will be assessed in all patients in the EAS. Supportive analyses will be performed in the 
Infused Set and Enrolled Set. The distribution function of PFS will be estimated using the 
Kaplan-Meier method. The median PFS along with 95% CIs will be presented if appropriate. 
Overall survival will be calculated from the date of AUTO3 infusion to the date of death. 
Patients who have not died will be censored at the date of last contact (clinic visit or telephone 
contact). OS will be assessed in all patients in the EAS. Supportive analyses will be performed 
in the Infused Set and Enrolled Set. The distribution function of OS will be estimated using the 
KM method. The median OS along with 95% confidence intervals will be presented if 
appropriate.  
Overall Response Rate (ORR) per Lugano criteria and RECIL criteria as assessed by the 
Investigator will be summarised descriptively with 95% CI. 
Incidence of CD19-negative relapse, defined as the proportion of responders who have 
relapsed and with CD19 being negative at the time of relapse. This will be assessed in all 
responders in EAS.  
14.3.2.4 
Expansion and Persistence of AUTO3 
Expansion and persistence of CD19/CD22 CAR-positive T cells as determined by PCR will be 
summarised using the appropriate statistical methods.  
• 
Expansion is defined as the maximum level of CD19/CD22 CAR expression by PCR 
(copies/µg genomic DNA) assay during follow-up  
• 
Persistence is defined as the duration of detectability, from infusion to the time of last 
observed detectable concentration. 
The kinetics of CD19/CD22 CAR-positive T cells will be documented over time for each 
patient with AUC calculated, then summarised for all patients descriptively. 
Duration of B cell aplasia as determined by flow cytometry in the peripheral blood. 
14.3.3 
Exploratory 
Humoral and cellular immunogenicity against AUTO3 will be evaluated pre- and post AUTO3 
treatment.  
All analyses for exploratory endpoints outlined in Section 2.3 will be descriptive only. Details 
will be provided in the SAP. 
14.3.4 
Interim Analysis 
An end of the Phase I analysis will be performed when at least 12 patients have been treated at 
the RP2D/dose range. Patients treated during the Phase I portion will be pooled for analysis 
according to the dose received. The overall response rate will be calculated. If the upper limit 

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of the 95% confidence interval is less than 30% for patients treated at the RP2D(s), the study 
will be stopped. If the upper limit of the 95% confidence interval is over 30%, the study will 
continue to the Phase II part of the study. 
In Phase II of the study, an interim analysis on response rates will be performed after 27 patients 
are treated in Cohort 1 and considered evaluable (12 weeks post-treatment of 27th evaluable 
patient). The study will be stopped in this first stage if fewer than nine responses have been 
observed. If the response rate has exceeded interim analysis stopping criteria prior to 
27 evaluable patients having been treated, then the study will continue to full recruitment 
without stopping. A formal interim analysis will still be performed based on the first 
27 evaluable patients. 

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15 
STUDY COMPLETION, DISCONTINUATION AND WITHDRAWAL 
OF PATIENTS 
15.1 
COMPLETION 
Patients enrolled will be considered to have completed the study when they have completed 
assessments until the EOS visit.  
15.2 
WITHDRAWAL FROM THE STUDY 
A patient should be withdrawn before the end of the study if:  
• 
Lost to follow-up 
• 
Withdrawal of consent 
• 
Non-compliance with study procedures 
• 
The Sponsor terminates the study 
• 
Death 
The date of withdrawal will be recorded as the EoS visit or the last recorded visit. The reason 
for discontinuation/withdrawal is to be documented in the eCRF and in the source document. 
If a patient is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the patient and to contact the patient’s family doctor/general practitioner to obtain 
information on the patient’s status to determine the reason for withdrawal. The measures taken 
to follow-up must be documented in the source documents and include steps taken to contact 
the patient, e.g. dates of telephone calls, registered letters, etc. Any patient who had completed 
their end of study visit may be invited to re-enrol in the main AUTO3-DB1 study for long-term 
safety and survival follow-up until the End of Study (36 months after last patient dosed) 
(Schedule of Assessments Table 4). 
For patients who withdraw consent for the study or who are lost to follow-up, the Investigator 
may consult public records, in order to document survival status in the eCRF.  
15.2.1 
Procedures for Handling Withdrawals 
A patient may voluntarily withdraw their consent at any time during the course of the study 
without any resulting detriment. All data collected up to the point of withdrawal will be 
maintained in the study database and included in subsequent analyses, as appropriate. Where a 
patient is withdrawn from the trial at their own request, or based on a decision of the 
Investigator, the follow-up should be maintained for safety review, subject to the continuing 
consent of the patient. The Investigator will discuss the arrangements for withdrawing from 
any further study interventions and continuing to be followed for safety purposes under the 
long-term follow-up study. 
If a patient is lost to follow-up at a site, every effort should be made to contact the patient’s 
family doctor/general practitioner to obtain information on the patient’s status 
 

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15.3 
REPLACEMENT POLICY 
Patients that have disease progression prior to completion of the DLT evaluation period or who 
are withdrawn from the study for reasons other than toxicity may be replaced, unless the SEC 
concludes that the patient is evaluable for dose escalation decision making. 

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16 END OF TRIAL/TERMINATION 
The end of the study is defined as 36 months after the last patient has received their first 
AUTO3 dose or earlier in the event of patient death or consent withdrawal. The study may also 
be terminated at any time at the discretion of the Sponsor. If the study is terminated due to 
safety reasons, the Health Authority will be notified per applicable guidelines. Study 
termination due to business reasons including but not limited to lack of recruitment, will not 
be considered an early termination requiring immediate notification to the Healthy Authority. 
For clinical trials conducted in the EU, a declaration of the end of the clinical trial and early 
termination, as applicable, will be made according to the procedures outlined in Directive 
2001/20/EC, Article 10(c) and for those countries outside the EU, local regulations will be 
followed. In the US, where applicable, the Investigator will notify the IRB in writing of the 
study’s completion or early termination and send a copy of the notification to the Sponsor. A 
final Clinical Study Report will be provided to the relevant authorities within 12 months after 
the end of the study. 

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17 ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 
ETHICS COMMITTEE REVIEW AND APPROVAL 
The final study protocol, including the final version of the written PIS, ICF and any other 
relevant patient facing material, must be approved, or given a favourable opinion in writing by 
an IEC/IRB as appropriate. 
If it is necessary to amend the protocol or the PIS/ICF during the study, an IEC/IRB approval 
of the amended protocol and/or PIS/ICF must be obtained prior to implementation of the 
amended procedures and before new patients are consented to participate in the study using the 
amended version of the PIS/ICF. 
17.2 
REGULATORY AUTHORITY REVIEW AND APPROVAL 
The study will not commence before approval from the regulatory authority has been granted 
according to local requirements. The Sponsor (or designee) will be responsible for the 
preparation, submission, and confirmation of receipt of any regulatory authority approvals 
required prior to release of study treatment for shipment to the study site. 
During the study, the Sponsor (or designee) is also responsible for submitting subsequent 
amendments and notifications to the regulatory authority according to local requirements.  
17.3 
INVESTIGATOR RESPONSIBILITIES 
17.3.1 
Overall Responsibilities 
The Investigator is responsible for conducting the study in full accordance with the clinical 
study protocol, the latest revision of the Declaration of Helsinki, the GCP: Consolidated 
Guideline, and all applicable national and local laws and regulations for clinical research. 
Information regarding any investigational sites participating in this study that cannot comply 
with these standards will be documented and appropriate actions taken. For studies conducted 
in the EU/European Economic Area countries, the Investigator will ensure compliance with the 
EU Clinical Trial Directive [2001/20/EC]. For studies conducted in the United States or under 
a United States Investigational New Drug, the Investigator will additionally ensure adherence 
to the basic principles of “Good Clinical Practice” as outlined in the current version of 21 Code 
of Federal Regulations, subchapter D, part 312, “Responsibilities of Sponsor and 
Investigators”, part 50, “Protection of Human Subjects”, and part 56, “Institutional Review 
Boards”. 
17.3.2 
Site Review 
Prior to the study start, the Investigator is required to sign a Protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all the 
instructions and procedures found in this Protocol, and to give access to all relevant data and 
records to Clinical Research Associates, auditors and regulatory authorities as required. 
Investigators ascertain that they will apply due diligence to avoid protocol deviations. 
The Investigator will make appropriate reports on the progress of this study to the Sponsor or 
its designee in accordance with applicable government regulations and their agreement with 
the Sponsor/Contract Research Organisation. 

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17.3.3 
Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from patients prior 
to conducting any study-related procedures. All consent documentation must be in accordance 
with applicable regulations and International Council on Harmonisation (ICH) GCP. Each 
patient is requested to sign and date the ICF after she/he has received and read the PIS and 
received an explanation of what the study involves, including but not limited to: the objectives, 
potential benefits and risk, inconveniences and the patient’s rights and responsibilities. Patients 
will be given adequate time to evaluate the information given to them before signing and dating 
the ICF. It will also be explained to the patients that they are free to refuse entry into the study 
or withdraw at any time and without prejudice to future treatment. The ICF must also be signed 
and dated by the person obtaining consent. The original signed ICF for each patient will be 
retained on file by the Investigator, a copy will be given to the patient, and a copy will be kept 
in the patient’s hospital notes. 
Informed consent forms must be retained for all screened patients and must be available for 
verification by the Study Monitor at any time.  
In the event of changes to the ICF during the study, the Investigator must always use the most 
current IEC/IRB approved form for documenting written informed consent. 
17.3.4 
Delegation of Investigator Duties 
The Investigator should ensure that all persons involved in the clinical study are adequately 
qualified, informed about the protocol, any amendment to the protocol, the study treatments, 
and their study related duties and functions before any involvement takes place. Delegation of 
any study related duties and documentation of training performed will be recorded in the 
signature and delegation log. 
17.3.5 
Communication with IEC/IRB 
A list of IEC/IRB members should be obtained by the Investigator or qualified designee and 
provided to the Sponsor/ representative. 
The Sponsor or its designee is responsible for assisting the Investigator with applicable 
documentation for communication with IECs/IRBs. Before initiating a trial, the 
Investigator/institution should have written and dated approval of the study protocol, the patient 
ICF, any written information to the patients, patient recruitment procedures (e.g. advertisement 
if applicable), the IB, Investigational Medicinal Product labelling (if applicable) and the 
coordinating Investigator’s curriculum vitae to the relevant IEC/IRB for evaluation before the 
study start. The IEC/IRB’s unconditional approval statement will be transmitted by the 
Investigator to the Sponsor or a designee prior to shipment of AUTO3 to the site. This approval 
must refer to the study by exact protocol title and number, and should identify the documents 
reviewed and the date of review. 
During the trial, the Investigator or designee is responsible for forwarding the applicable 
documents (including protocol deviations, protocol amendments, ICF changes or revisions of 
other documents originally submitted for review; serious and/or unexpected adverse 
experiences occurring during the study; new information that may affect adversely the safety 
of the patients or the conduct of the study; annual updates and/or request for re-approval) for 
approval and/or review and when the study has been completed. The Investigator or designee 
will follow national and local requirements.  

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The Investigator must supply the Sponsor with a copy of the list of members of the IEC/IRB 
and the letter(s) of approval(s) defining the version of each document approved. 
17.3.6 
Confidentiality of Trial Documents and Patient Records 
The Investigator must ensure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorised parties. The Sponsor will maintain confidentiality 
standards by assigning a unique coded ID number to each patient included in the study. Patient 
names will never be included in data sets that are transmitted to the Sponsor or their 
representatives, or to third parties as permitted by the ICF.  
On eCRFs or other documents submitted to the Sponsor, patients will not be identified by their 
names, but by an identification code. The Investigator will keep a patient enrolment log relating 
codes to the names of patients. The Investigator will maintain documents not for submission to 
the Sponsor, e.g. patients’ written consent forms, in strict confidence. Records will not be 
destroyed without giving the Sponsor prior written notice and the opportunity to further store 
such records, at the Sponsor’s cost and expense. 
After obtaining a patient’s consent, the Investigator will permit the study monitor, independent 
auditor, or regulatory agency personnel to review the portion of the patient’s medical record 
directly related to the study. This shall include all study relevant documentation (e.g. patient 
medical history to verify eligibility, laboratory test results, admission/discharge summaries for 
hospital admissions occurring while the patient is enrolled in the study, and autopsy reports for 
deaths occurring during the study). 
Patient medical information obtained by this study is confidential and may only be disclosed 
to third parties as permitted by the ICF signed by the patient, unless permitted or required by 
law. 
17.4 
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL 
FUTURE RESEARCH 
Samples collected in this study may be stored by the Sponsor for up to 15 years (or according 
to local regulations) for additional research. Samples will only be used to further understand 
AUTO3, to understand advanced cancers, to understand differential drug responders, and to 
develop tests/assays related to AUTO3 and advanced cancer. The research may begin at any 
time during the study or the post-study storage period. 
Stored clinical samples will be coded throughout the sample storage and analysis process and 
will not be labelled with personal identifiers. GMP AUTO3-derived samples will be stored 
according to local GMP rules and procedures. 

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18 ADMINISTRATIVE REQUIREMENTS 
18.1 
DATA QUALITY CONTROL AND ASSURANCE 
18.1.1 
Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in the approved protocol. All revisions to the 
protocol must be discussed with and be prepared by the Sponsor. The Investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favourable opinion from the IEC/IRB of an amendment, except where necessary to 
eliminate an immediate hazard(s) to the study patients. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IEC/IRB approval/favourable opinion. The deviation or change will be submitted 
as soon as possible to: 
• 
The IEC/IRB for review and approval/favourable opinion. 
• 
The Sponsor. 
• 
Regulatory authority(ies) if required by local regulations. 
Documentation of approval signed by the chairperson or designee of the IEC(s)/IRB(s) must 
be sent to the Sponsor. 
If an amendment substantially alters the study design or increases the potential risk to the 
patient (1) the ICF must be revised and submitted to the IEC(s)/IRB(s) for review and 
approval/favourable opinion; (2) the revised ICF must be used to obtain consent from patients 
currently enrolled in the study if they are affected by the amendment; and (3) the new ICF must 
be used to obtain consent from new patients prior to enrolment. 
If the revision is an administrative letter, Investigators must inform their IEC(s)/IRB(s). 
18.1.2 
Protocol Violations and Deviations 
All patients who are enrolled into the study, irrespective of whether or not they receive any 
treatment, will be followed according to the protocol regardless of the number of treatments 
received, unless consent for follow-up is withdrawn. Minor protocol deviations that do not 
result in harm to the study patients or significantly affect the scientific value of the reported 
results of the study will be recorded. In case of a major protocol deviation occurring (i.e. a 
deviation that could have a significant effect on the patient’s safety, rights, welfare and/or on 
the integrity of the study data), the Investigator must notify the Sponsor and the appropriate 
IEC/IRB as soon as possible or as per local requirements. Major protocol deviations that meet 
the criteria for a serious breach of GCP (e.g. a protocol violation, or non-reporting of critical 
safety information potentially jeopardising patient safety) should be reported within 24 hours 
to the Sponsor. The Sponsor is required to report a serious GCP breach within 7 days to the 
applicable Health Authorities. Protocol deviations will be recorded on the source documents 
with an explanation for the deviation. No deviation from the inclusion/exclusion criteria will 
be permitted. 

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18.1.3 
Monitoring 
Before the trial can be initiated at a site, the prerequisites for conducting the trial must be 
clarified and approved by the Sponsor.  
Representatives of the Sponsor (or designee) must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity according to EU directives, ICH GCP, 
and the FDA regulations. On-site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the Investigator and verify that 
the facilities remain acceptable. With prior agreement from the study site, remote monitoring 
may also be performed.  
Electronic Case Report Form completion and accuracy will be checked by performing source 
data verification that is a direct comparison of the entries made against the appropriate source 
documentation. Any resulting discrepancies will be reviewed with the Investigator(s) and/or 
his/her site staff and resolved. Monitoring procedures require that patients’ informed consents, 
adherence to the inclusion/exclusion criteria and SAE documentation be verified. Additional 
monitoring activities including requirements for remote monitoring will be outlined in the 
study specific monitoring plan. The Sponsor may request adequately redacted source 
documents and hospital records for review by the medical monitor (e.g. pathology reports, 
imaging reports, cancer treatment history), which may help to better understand the patient’s 
general condition, emerging safety issues, and the activity of AUTO3 efficacy. 
The Sponsor must be informed immediately of any change in the personnel involved in the 
conduct of the trial. 
18.1.4 
Audits and Site Inspections 
Authorised personnel from domestic and foreign regulatory authorities and the Sponsor Quality 
Assurance (or designee) may carry out inspections and audits respectively. The purpose of an 
audit/inspection is to ensure that ethical, regulatory and quality requirements are fulfilled in the 
Sponsor studies. 
The Investigator will permit international, national, and local Health Authorities, the Sponsor 
monitors, representatives, and collaborators, and the IECs/IRBs to inspect facilities and records 
relevant to this study. The Investigator should promptly notify the Sponsor or their authorised 
representative of any inspections scheduled by any regulatory authorities and promptly forward 
copies of any audit reports received to the Sponsor or their authorised representative. 
18.2 
DATA HANDLING AND RECORD KEEPING 
18.2.1 
Data Management 
Data for each patient will be entered into the (Sponsor-approved) clinical database via 
electronic data capture [EDC]) in a timely manner. The EDC application uses system controls 
to ensure that unauthorised users cannot access or modify data. All users must have 
successfully undergone EDC application training prior to entering data into the EDC system. 
Electronic Cases Report Forms should be reviewed and electronically signed and dated by the 
Investigator or a designee. The eCRF system will be compliant with FDA Code of Federal 
Regulations 21 Part 11 and EU Clinical Trial Directive (EC) No. 2001/20/EC. 

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It is the responsibility of the Investigator to ensure that the data included in the eCRF is 
accurate, complete, and electronically signed where appropriate.  
The data will be electronically verified through use of on-line checks during data entry and 
through programmed edit checks specified by the clinical team. Discrepancies in the data will 
be brought to the attention of the investigational site personnel. Data entered into the eCRF 
will be validated as defined in the data validation specifications. All updates to queried data 
will be made by authorised study site personnel only, and all modifications to the database will 
be recorded in an audit trail. Once all the queries have been resolved, eCRFs will be locked by 
password protection. Any changes to locked eCRFs will be approved by the Investigator. Once 
the full set of eCRFs have been completed and locked, the Sponsor will authorise a database 
lock and all electronic data will be sent to the designated statistician for analysis. Subsequent 
changes to the database will then only be made with written agreement of the Sponsor. 
Adverse events and medical/cancer history terms will be coded from the verbatim description 
(Investigator term) using the Medical Dictionary for Regulatory Activities. Prior and 
concomitant medications and therapies will be coded according to the World Health 
Organisation drug dictionary. Coding review will be performed by the Sponsor (or designee) 
prior to database lock. 
At the end of the study, the clinical data will be transferred to the Sponsor and the investigative 
site will receive patient data for their site in a readable format that must be kept with the study 
records. 
18.2.2 
Study Documentation and Retention of Records 
The Investigator must maintain records of all study documents and supporting information 
relating to the conduct of the study. This documentation should include but is not limited to, 
protocols, eCRF data, SAE reports, patient source data, correspondence with Health 
Authorities and IEC/IRBs, ICFs, Investigator(s) and study team members’ curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory directors’ curricula vitae (essential documentation listed in ICH 
GCP [CPMP/ICH/135/95]). Patient files and other source data must be kept for the maximum 
period of time required by applicable regulations and guidelines or institution procedures or 
for the period specified by the Sponsor, whichever is longer. The Sponsor must be consulted if 
the Investigator(s) wishes to assign the study files to someone else, remove them to another 
location or is unable to retain them for the specified period. 
The patient medical records must contain the product name/code, the trial reference code, trial 
patient code and administration dates and dose in order to ensure that a link can be made back 
to the identity of the product and further traceability records of the Investigator and Sponsor. 
18.3 
CLINICAL TRIAL AGREEMENT, FINANCE, AND INSURANCE 
This study will be conducted under a Clinical Trial Agreement between Autolus Limited 
(“Sponsor”) and the institution(s) representing the investigational study site(s) (“Investigator”). 
Financial support to the investigational site(s) will be detailed in the Clinical Trial Agreement. 
The Clinical Trial Agreement must be signed before the commencement of the study and will 
clearly delineate the responsibilities and obligations of the Investigator and the Sponsor, and 
will form the contractual basis under which the clinical study will be conducted.  

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A Certificate of Clinical Trials Insurance will be provided to the study centres by the Sponsor, 
where required. Details of the Sponsor’s arrangement for clinical study insurance to provide 
for compensation to patients for any claim for bodily injury or death arising from participation 
in the clinical study are provided in the PIS. 

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19 PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
Both the EU Data Protection Regulations and the FDA Amendments Act mandates the 
registration with ClinicalTrials.gov of certain clinical trials of drugs (including biological 
products) and medical devices subject to FDA regulations for any disease or condition. The 
International Committee of Medical Journal Editors requires study registration as a condition 
for publication of research results generated by a clinical study (http://www.icmje.org). 
All information supplied by the Sponsor in connection with this study and not previously 
published to the public, is considered confidential information (“Confidential Information”). 
This confidential information includes, but is not limited to, the IB, clinical protocol, eCRFs 
and other scientific data. Any data collected during the study are also considered confidential 
information. This confidential information shall remain the sole and exclusive property of the 
Sponsor, shall not be disclosed to others without prior written consent of the Sponsor, and shall 
not be used except in the performance of this study.  
The information developed during the conduct of this study is also considered confidential 
information, and will be used by the Sponsor in connection with the development of the 
ATIMP. The confidential information may be disclosed as deemed necessary by the Sponsor. 
To allow the use of the confidential information derived from this study, the Investigator is 
obliged to provide the Sponsor with complete test results and all data developed in this study. 
The Sponsor has full ownership of the original eCRFs completed as part of the study. 
By signing the Clinical Study Protocol, the Investigator agrees that the results of the study may 
be used for the purposes of national and international registration, publication, and information 
for medical and pharmaceutical professionals. The authorities will be notified of the 
Investigator’s name, address, qualifications, and extent of involvement.  
It is agreed that, consistent with scientific standards, publication of the results of the study shall 
be made only as part of a publication of the results obtained by all sites performing the protocol.  
Should the Investigator wish to publish the results of this study, the Investigator agrees to 
provide the Sponsor with a manuscript for review 60 days prior to submission for publication. 
The Sponsor retains the right to delete from the manuscript, information that is confidential or 
proprietary and to object suggested publication and/or its timing (at the Sponsor’s discretion). 
In addition, if requested by the Sponsor, the Investigator shall withhold publication an 
additional 6 months to allow for filing a patent application or taking such other measures as the 
Sponsor deems appropriate to establish and preserve its proprietary rights. 
In the event that the Sponsor chooses to publish the data from this study, a copy will be 
provided to the Investigator at least 30 days prior to the expected date of submission to the 
intended publisher (Fitzgerald et al. 2016). 

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Zhang, X, Lu X, Yang J, Fanyong LV, Xiong M, Zhang J, et al (2018). Efficacy and Safety of 
CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for B-Cell Acute Lymphocytic 
Leukemia (B-cell ALL) in a Large Cohort Including Patients with Extramedullary Disease 
(EMD), High Leukemia Burden, BCR-ABL (+) Mutation, TP53 Mutation, and Post Transplant 
Relapse. Blood 132(1):280. 

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Response  
Site  
PET-CT-Based Response  
CT-Based Response  
 
New lesions  
New FDG-avid foci consistent with lymphoma rather 
than another aetiology (e.g. infection, inflammation). If 
uncertain regarding aetiology of new lesions, biopsy or 
interval scan may be considered  
Regrowth of previously resolved lesions  
A new node >1.5 cm in any axis  
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any axis, its 
presence must be unequivocal and must be attributable to lymphoma  
Assessable disease of any size unequivocally attributable to 
lymphoma  
 
Bone marrow  
New or recurrent FDG-avid foci  
New or recurrent involvement  
5PS=5-point scale; CT=computed tomography; FDG=fluorodeoxyglucose; IHC=immunohistochemistry; LDi=longest transverse diameter of a lesion; MRI=magnetic resonance imaging; 
PET=positron emission tomography; PPD=cross product of the LDi and perpendicular diameter; SDi=shortest axis perpendicular to the LDi; SPD=sum of the product of the perpendicular 
diameters for multiple lesions.  
a 
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where de-escalation is 
investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid under-treatment). Measured dominant lesions: Up to 6 of the largest dominant nodes, nodal 
masses, and extranodal lesions selected to be clearly measurable in 2 diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g. liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. 
Non-measured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal 
masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability, but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (e.g. GI tract, liver, bone marrow), fluorodeoxyglucose 
uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g. with marrow activation as a 
result of chemotherapy or myeloid growth factors).  
b 
PET 5PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake >mediastinum but ≤liver; 4, uptake moderately >liver; 5, uptake markedly higher than liver and/or new 
lesions; X, new areas of uptake unlikely to be related to lymphoma 
 

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Appendix 2: Eastern Cooperative Oncology Group Performance Status Score 
Grade  
Eastern Cooperative Oncology Group Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g. light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair (Oken et al. 1982). 

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Appendix 3:  Highly Effective Methods of Birth Control 
For females of childbearing potential (defined as <24 months after last menstruation or not 
surgically sterile), a negative serum or urine pregnancy test must be documented at screening, 
prior to conditioning and confirmed before receiving the first dose of study treatment 
(AUTO3). Pregnancy testing will also occur during the follow-up period (Day 28, Day 56, 
Month 3, Month 6, Month 12, Month 18 and Month 24), as outlined in the Schedule of 
Assessments. (Note: If patient discontinues study due to disease progression pregnancy testing 
will stop at Month 12). 
For females who are not postmenopausal (<24 months of amenorrhea) or who are not surgically 
sterile (absence of ovaries and/or uterus), two methods of contraception comprising of one 
highly effective method of contraception together with a barrier method must be used during 
the treatment period and for at least 12 months after the last dose of study treatment. They must 
agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the 
study and for 12 months after receiving the last dose of study drug.  
For males, it must be agreed that two acceptable methods of contraception are used (one by the 
patient – usually a barrier method, and one highly effective method by the patient’s partner as 
defined below) during the treatment period and for at least 12 months after the last dose of 
study treatment and that sperm will not be donated during the treatment period and for at least 
12 months after the last dose of study treatment.  
Highly effective methods of birth control: 
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly are considered as highly effective birth control 
methods. Such methods include: 
• 
Combined (oestrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1:  
o 
Oral  
o 
Intravaginal  
o 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 1: 
o 
Oral 
o 
Injectable 
o 
Implantable2  
• 
Intrauterine device 2  
• 
Intrauterine hormone-releasing system 2  
• 
Bilateral tubal occlusion 2  
• 
Vasectomised partner 2, 3  
• 
Sexual abstinence 4 
1 
Hormonal contraception may be susceptible to interaction with the AUTO3, which may reduce the 
efficacy of the contraception method.  

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2 
Contraception methods that in the context of this guidance are considered to have low user 
dependency.  
3 
Vasectomised partner is a highly effective birth control method provided that the vasectomised 
partner is the sole sexual partner of the women of child bearing potential trial participant and that 
the vasectomised partner has received medical assessment of the surgical success.  
4 
In the context of this guidance, sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk associated with 
the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Birth control methods that may NOT be considered as highly effective  
Acceptable birth control methods that result in a failure rate of more than 1% per year include:  
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action  
• 
Male or female condom with or without spermicide 5  
• 
Cap, diaphragm or sponge with spermicide 5  
5 
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) are also considered acceptable, but NOT highly effective, birth control methods. 
Birth control methods that are considered UNACCEPTABLE in clinical trials 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus) 
• 
Spermicides only 
• 
Lactational amenorrhoea method are not acceptable methods of contraception.  
• 
Female condom and male condom should not be used together. 
Birth control methods that are considered ACCEPTABLE in clinical trials 
• 
Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are NOT acceptable methods of contraception. 
• 
Female sterilisation (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow-up hormone level assessment. 
• 
Male sterilisation (at least 6 months prior to screening). For female patients on the study 
the vasectomised male partner should be the sole partner for that patient. 
• 
BOTH of the following forms of contraception must be utilised: 
a. 
Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception. 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 

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• 
Use of IUDs are excluded due to increased risks of infection and bleeding in this 
population. 
• 
In case of use of oral contraception, women must be stable on the same pill for a minimum 
of 3 months before taking study treatment. 
Women who are not of reproductive potential (defined as either <11 years of age, Tanner 
Stage 1, post-menopausal for at least 24 consecutive months or have undergone hysterectomy, 
salpingectomy, and/or bilateral oophorectomy) are eligible without requiring the use of 
contraception. Acceptable documentation includes written or oral documentation 
communicated by clinician or clinician's staff of one of the following: 
• 
Demographics show age <11. 
• 
Physical examination indicates Tanner Stage 1. 
• 
Physician report/letter. 
• 
Operative report or other source documentation in the patient record. 
• 
Discharge summary. 
• 
Follicle stimulating hormone measurement elevated into the menopausal range.