A Single Arm, Open Label, Multi-centre, Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO4, a CAR T-cell Treatment Targeting TRBC1, in Patients With Relapsed or Refractory TRBC1 Positive Selected T Cell Non-Hodgkin Lymphoma
Phase: PHASE1
Conditions: T Cell Non-Hodgkin Lymphoma, Peripheral T-Cell Lymphoma, Not Otherwise Specified, Angioimmunoblastic T-cell Lymphoma, Anaplastic Large Cell Lymphoma
Sponsor: Autolus Limited

AUTOLUS LIMITED 
 
AUTO4-TL1 
Version 6.0, 30 June 2022 
 
Clinical Study Protocol 
 
CONFIDENTIAL 
 
PAGE 1 OF 141 
 
CLINICAL STUDY PROTOCOL 
 
A SINGLE ARM, OPEN-LABEL, MULTI-CENTRE, PHASE I/II STUDY 
EVALUATING THE SAFETY AND CLINICAL ACTIVITY OF AUTO4, A CAR T 
CELL TREATMENT TARGETING TRBC1, IN PATIENTS WITH RELAPSED 
OR REFRACTORY TRBC1 POSITIVE SELECTED T CELL NON-HODGKIN 
LYMPHOMA 
 
Short study title: 
Phase I/II study evaluating AUTO4 in patients with TRBC1 
positive T Cell Lymphoma 
Protocol Number: 
AUTO4-TL1 
Study Product: 
AUTO4 for i.v. infusion 
Development Phase: 
I/II 
Sponsor: 
Autolus Limited 
The MediaWorks 
191 Wood LaneWhite City 
London, W12 7FP 
United Kingdom (UK) 
Protocol Version: 
Version 6.0 
EudraCT Number: 
2017-001965-26 
Protocol Date: 
30 June 2022  
Previous Version(s) 
and Dates  
Version 1.0 – 09 September 2017 
Version 2.0 – 09 October 2017 
Version 3.0 – 22 November 2017 
Version 4.0 – 18 July 2019 
Version 5.0 – 07 July 2021 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Conference 
for 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: Autolus Limited 
The MediaWorks 
191 Wood Lane  
White City 
London, W12 7FP 
United Kingdom (UK) 
Tel: +44 (0)20 3829 6230 
European Union Legal Representative: 
 
Autolus GmbH 
Luise-Ullrich-Straße 20 
c/o Design Offices Arnulfpark 
80636 Munich, Germany 
Contact List 
The List of Service Providers for the study will be maintained separately by Autolus Limited 
and kept in the Trial Master File. 
 
Sponsor’s Medical Monitor: 
 
 
 
 
 
Notification of SAEs: 
SAE Fax number: +44 (0) 1189 195 200 
 
Email: Autolus@tmcpharma.com 
24-hour Safety Hotline: 
TMC Pharma 
Hartley Wintney 
Hampshire 
RG27 8AS, UK 
Telephone: +44 (0)1252 842255 
 

AUTOLUS LIMITED 
 
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Clinical Study Protocol 
 
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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 AUTO4, a CAR T Cell Treatment Targeting 
TRBC1, in Patients with Relapsed or Refractory TRBC1 Positive Selected T 
Cell Non-Hodgkin Lymphoma. 
 
 
Short Study Title: 
Phase I/II study evaluating AUTO4 in patients with TRBC1 positive 
T Cell Lymphoma 
Protocol Number: 
AUTO4-TL1 
Version Number:  
Version 6.0 
EudraCT No.:  
2017-001965-26 
Version Date: 
30 June 2022 
I have read the protocol AUTO4-TL1 titled “A Single Arm, Open-Label, Multi-Centre, 
Phase I/II Study Evaluating the Safety and Clinical Activity of AUTO4, a CAR T Cell 
Treatment Targeting TRBC1, in Patients with Relapsed or Refractory TRBC1 Positive 
Selected T Cell Non-Hodgkin 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 
 VP – Head of Clinical 
Development   
 
 
Date 
(DD MMM YYYY) 

AUTOLUS LIMITED 
 
AUTO4-TL1 
Version 6.0, 30 June 2022 
 
Clinical Study Protocol 
 
CONFIDENTIAL 
 
PAGE 4 OF 141 
INVESTIGATOR SIGNATURE PAGE 
Study Title: A Single Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety 
and Clinical Activity of AUTO4, a CAR T Cell Treatment Targeting TRBC1, in Patients with 
Relapsed or Refractory TRBC1 Positive Selected T Cell Non-Hodgkin Lymphoma. 
 
 
Short study title: 
Phase I/II study evaluating AUTO4 in patients with TRBC1 Positive 
T Cell Lymphoma 
Protocol Number: 
AUTO4-TL1 
EudraCT No.: 
2017-001965-26 
Version Number: 
Version 6.0 
Version Date: 
30 June 2022  
I have read the protocol AUTO4-TL1 titled “A Single Arm, Open-Label, Multi-Centre, Phase 
I/II Study Evaluating the Safety and Clinical Activity of AUTO4, a CAR T Cell Treatment 
Targeting TRBC1, in Patients with Relapsed or Refractory TRBC1 Positive Selected T Cell 
Non-Hodgkin 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 (2013), the 
standards of Good Clinical Practice (as defined by the International Conference for 
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) 
 
 
 

AUTOLUS LIMITED 
 
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CONFIDENTIAL 
 
PAGE 5 OF 141 
PROTOCOL SYNOPSIS 
Title 
A Single Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety 
and Clinical Activity of AUTO4, a CAR T Cell Treatment Targeting TRBC1, in 
Patients with Relapsed or Refractory TRBC1 Positive Selected T Cell 
Non-Hodgkin Lymphoma. 
Protocol 
Number 
AUTO4-TL1 
EudraCT No.: 
2017-001965-26 
Sponsor 
Autolus Limited 
Phase 
I/II 
Study Product 
AUTO4 is an autologous, cell and gene therapy investigational medicinal product 
that is manufactured by genetic modification of the patient’s own T cells by ex 
vivo transduction with a murine leukaemia virus-derived retroviral vector that has 
been engineered to stably deliver the RQR8 and anti- T cell receptor beta constant 
(TRBC1)-chimeric antigen receptor (CAR) (aTRBC1-CAR) genes. The active 
substance is the genetically modified (RQR8/aTRBC1-CAR positive) T cells.  
Study 
Population 
Patients with confirmed diagnosis of TRBC1 positive selected T cell 
non -Hodgkin lymphoma (T-NHL) who have relapsed or become refractory after 
exposure to ≥1 line of therapy. 
Study Duration 
The study will take approximately 7 years. The end of the trial will be 24 months 
after the last patient has received an AUTO4 infusion or the last patient last visit 
if this occurs earlier due to patient death or premature withdrawal before 24 
months. 
Overview 
A single arm, open-label, multi-centre, Phase I/II dose escalation and expansion 
study to determine the safety and clinical activity of RQR8/aTRBC1-CAR 
positive T cells administered intravenously (i.v.) in patients with TRBC1 positive 
selected T-NHL. 
During T cell development, each T cell generates a unique T cell receptor (TCR) 
by rearrangement of the alpha and beta chains. Each beta chain also includes a 
constant domain, which is not involved in antigen recognition. A facet of TCR 
gene-rearrangement is that the coding sequence for the T cell receptor beta 
Constant (TRBC) region is duplicated (TRBC1 and TRBC2). Hence, a mature T 
cell, and any subsequent clonal malignancy, is highly likely to express either 
TRBC1 or TRBC2. Normal T cells (including T cell subsets) comprise a mixture 
of T cells (approximately 40%, 60% mix) individually expressing either TRBC1 
or TRBC2. Natural immunity including antiviral immunity is also distributed 
across the two populations. T cell lymphomas on the other hand are clonal tumours 
and are either entirely TRBC1 or TRBC2 positive. 
In this study, Autolus plans to recruit patients with TRBC1 positive selected T cell 
lymphomas. Patients will receive autologous CAR T cells directed against 
TRBC1. These CAR T cells will target the lymphoma in its entirety as well as a 
proportion of normal T cells (i.e., those which are TRBC1 T cells) with the aim of 
maintaining immunity due to the preservation of TRBC2 positive cells.  

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This first-in-human (FIH) study will assess the safety of AUTO4, determine the 
appropriate dose for Phase II and evaluate the efficacy of the AUTO4 in patients 
with selected relapsed or refractory T-NHL. 
Primary 
Objective(s) and 
Endpoints 
The primary objectives of the study are as follows:  
Objectives 
Endpoints 
Phase I 
To assess the safety and tolerability of 
AUTO4 administration. 
Incidence of Grade 3 to 5 toxicity 
occurring within 60 days of AUTO4 
infusion. 
To identify the recommended Phase II 
dose (RP2D) and maximum tolerated 
dose (MTD), if an MTD exists, of 
AUTO4. 
Frequency of dose limiting toxicity 
(DLT) of AUTO4 within 28 days of 
AUTO4 infusion. 
Phase II 
To assess the clinical activity of AUTO4 
when administered at the RP2D.  
Primary endpoint: 
Overall response (CR+PR) rate post 
AUTO4 infusion.  
Study Design 
This is a Phase I/II, open-label, multi-centre study to characterise the safety and 
clinical activity of RQR8/aTRBC1-CAR T cells when administered to patients 
with relapsed or refractory TRBC1 positive selected T-NHL. The study will 
consist of two phases, a Phase I dose escalation, followed by a Phase II dose 
expansion. Both phases of the study will involve patients going through the 
following five sequential stages: screening (including TRBC assessment), 
leukapheresis, pre-conditioning, treatment with AUTO4 and follow-up.  
Phase I (Dose Escalation): To identify the recommended Phase II dose (RP2D) 
based on safety, tolerability and anti-tumour activity of AUTO4 using a rolling six 
design. Up to five cohorts and a maximum of 25 patients with TRBC1 positive T-
NHL will be dosed. The following dose levels are intended to be evaluated but are 
subject to emerging safety data: 25 x 106, 75 x 106*, 225 x 106* 450 and 900 x 106 
RQR8/aTRBC1-CAR positive T cells.  
Phase I (Dose Escalation) with Process B: To enable a greater number of less 
differentiated CAR-positive T cells to be achieved at an earlier harvest timepoint 
compared to the current process, an optimized manufacturing process (Process B) 
will be used to support this Phase I Dose Escalation. 
To identify the recommended Phase II dose (RP2D) based on safety, tolerability 
and anti-tumour activity of AUTO4, 3 cohorts in a rolling six design with 
TRBC1-positive T NHL will be dosed. The following dose levels are intended to 
be evaluated but are subject to emerging safety data: 225 x 106*, 450 x 106 and 
900 x 106 RQR8/aTRBC1-CAR-positive T cells.  
* Cohort 2 (75 x 106) and 3/3b (225 x 106) should have at least 1 patient for the dose escalation 
decision. In this case, any potential single patient cohort would be expanded to n=3-6 (per rolling 
six study design), if at least 1 patient experiences any level of CAR T-cell expansion (above the limit 
of detection) or Grade ≥ 1 CRS/Neurotoxicity or ≥ Grade 2 AUTO4-related AE in the first 28 days 
after AUTO4 infusion (see Section 3). 
Phase II (Dose Expansion): To further characterise the safety and assess the 
efficacy of AUTO4 Process B product at the recommended dose identified in 
Phase I, up to 30 patients will be treated in Phase II, following a Simon’s two-
stage optimal design (Simon 1989).  

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Biomarkers relating to the CAR T cells and tumour will be evaluated in all 
patients. All patients treated in Phase I and II of the study will attend clinic visits 
until End of Study (defined as 24 months post AUTO4 infusion of the last patient 
treated, or less in the event of early withdrawal) for study-specific assessments 
including adverse event (AE) assessments, ECOG, physical examinations, disease 
assessment and laboratory and immunology tests. 
All AUTO4 treated patients will be followed until death, study closure or study 
consent withdrawl (whichever occurs first). After the End of Study patients treated 
with AUTO4 will be invited to enrol on a long-term follow-up study protocol and 
will be followed for long-term safety and disease assessment (if applicable) until 
death or withdrawal of consent for up to 15 years from treatment administration. 
 
Number of 
Patients 
Approximately 200 patients in total are expected to be screened for eligibility. 
This assumes that approximately 35% of patients will be identified as TRBC1 
positive (and assumes that a small number of patients will not provide sufficient 
evaluable tissue). Of those that are identified as TRBC1 positive, it is assumed 
that approximately 20% will fail the AUTO4 manufacture and/or will not continue 
to meet the inclusion and exclusion entry criteria. Up to 73 patients in total are 
anticipated to be treated with AUTO4 therapy. 
• 
Phase I (Escalation): up to 5 dose cohorts and up to 25 patients in total 
(3 to 6 patients per cohort) following a rolling six dose escalation design.  
• 
Phase I (Escalation) with Process B: up to 3 dose cohorts and up to 18 
patients with TRBC1 positive T NHLin a rolling six design.  
• 
Phase II (Expansion): Up to 30 evaluable patients in total treated with 
AUTO4 Process B product, using Simon’s two-stage optimal design.  
Simon's two-stage design trial will be used (Simon 1989). The null hypothesis that 
the true response rate is 10% will be tested against a onesided alternative. In the 
first stage, 10 evaluable patients will be accrued (12 weeks post treatment of tenth 
evaluable patient). If there are one or fewer responses in these 10 patients, the 
study will be stopped. Otherwise, 19 additional evaluable patients will be accrued 
for a total of 29. The null hypothesis will be rejected if six or more responses are 
observed in 29 patients. This design yields a type I error rate of 5% and 80% power 
when the true response rate is 30%. 
Criteria for 
Eligibility 
Only patients with confirmed TRBC1 positive selected T-NHL, and whose 
leukapheresis sample has been successful in generating AUTO4 in adequate 
quantity 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 be screened for TRBC1 
positive T-NHL and to enter the main study. 
3 
Confirmed diagnosis of selected T-NHL, including: 
a Peripheral T cell lymphoma NOS, or 
b Angioimmunoblastic T cell lymphoma, or 
c Anaplastic large cell lymphoma 
4 
Confirmed TRBC1 positive tumour.  
5 
Relapsed or refractory disease and have had ≥1 prior lines of therapy. 

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6 
FDG-avid measurable disease on PET/CT per Lugano classification at 
Screening. 
7 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. 
8 
Adequate bone marrow function without the requirement for ongoing blood 
products and meets the following criteria: 
a Absolute neutrophil count ≥1.0 x 109/L 
b Absolute lymphocyte count ≥0.5 x 109/L (at entry and prior to 
leukapheresis). 
c Haemoglobin ≥80 g/L 
d Platelets ≥75 x 109/L 
9 
Adequate renal, hepatic, pulmonary, and cardiac function defined as: 
a Creatinine clearance (as estimated by Cockcroft Gault) ≥60 cc/min. 
b Serum alanine aminotransferase/aspartate aminotransferase ≤2.5 x upper 
limit of normal (ULN). 
c Total bilirubin ≤25 µmol/L (1.5 mg/dL), except in patients with Gilbert’s 
syndrome. 
d Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram 
(ECHO) or multiple gated acquisition (MUGA) cardiac scan, unless the 
institutional lower limit of normal is lower.  
e Baseline oxygen saturation ≥92% on room air and ≤Grade 1 dyspnoea.  
10 For females of childbearing potential (defined as <2 years 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), a highly 
effective method of contraception together with a barrier method must be 
used from the start of the pre-conditioning stage and for at least 12 months 
after the last dose of AUTO4 (the 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). 
11 For males, it must be agreed that two acceptable methods of contraception 
are used from the start of the pre-conditioning stage and for at least 12 months 
after the last dose of AUTO4 (one by the patient – usually a barrier method, 
and one by the patient’s partner - refer to Appendix 3). Also, that sperm will 
not be donated during the treatment period and for at least 12 months after 
the last dose of study treatment.  
12 No contra-indications for leukapheresis, or the pre-conditioning regimen. 
 
Exclusion Criteria: Patients meeting any of the following exclusion criteria must 
not be enrolled into the study: 
1 
Patients with T cell leukaemia. 
2 
Females who are pregnant or lactating. 
3 
Prior treatment with investigational gene therapy or approved gene therapy 
or genetically engineered cell therapy product or allogeneic stem cell 
transplant. 
4 
Known history or presence of clinically relevant central nervous system 
(CNS) pathology, such as epilepsy, paresis, aphasia, stroke within the prior 

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3 months, severe brain injuries, dementia, Parkinson’s disease, cerebellar 
disease, organic brain syndrome, uncontrolled mental illness, or psychosis. 
Patients with a known history or prior diagnosis of optic neuritis or other 
immunologic or inflammatory disease affecting the CNS. 
5 
Current or history of CNS involvement by malignancy.  
6 
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. 
a Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial 
fibrillation are not excluded). 
b Evidence of pericardial effusion. 
7 
Patients with evidence of uncontrolled hypertension or with a history of 
hypertension crisis or hypertensive encephalopathy. 
8 
Patients with a history (within 3 months) or evidence of deep vein thrombosis 
or pulmonary embolism requiring ongoing therapeutic anticoagulation at the 
time of pre-conditioning. 
9 
Patients with active gastrointestinal (GI) bleeding. 
10 Patients with any major surgical intervention in the last 3 months. 
11 Active infectious bacterial, viral disease or fungal disease (hepatitis B virus, 
hepatitis C virus, human immunodeficiency virus [HIV], human T cell 
lymphotropic virus [HTLV] or syphilis) requiring treatment. 
12 Active autoimmune disease requiring immunosuppression. 
13 History of other neoplasms unless disease free for at least 2 years (adequately 
treated carcinoma in situ, curatively treated non-melanoma skin cancer, 
breast or prostate cancer on hormonal therapy are allowed). 
14 Prior treatment with programmed cell death protein 1 (PD1), programmed 
death-ligand 1 (PD-L1), or cytotoxic T lymphocyte-associated protein 4 
(CTLA-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 AUTO4 infusion.  
15 The following medications are excluded: 
a Steroids: Therapeutic doses of prednisone/equivalent of more than 20 mg 
per day are prohibited within 7 days prior to leukapheresis or pre-
conditioning chemotherapy administration. However, physiological 
replacement, topical, and inhaled steroids are permitted.  
b Cytotoxic chemotherapies within 2 weeks prior to leukapheresis or 
AUTO4 infusion. 
c Antibody therapy use within 2 weeks prior to AUTO4 infusion, or five 
half-lives of the respective antibody, whichever is longer. 
d Live vaccine within 4 weeks prior to enrolment. 
16 Research participants receiving any other investigational agents, or 
concurrent biological, chemotherapy, or radiation therapy. 
17 Use of rituximab (or rituximab biosimilar) within the last 6 months prior to 
AUTO4 infusion. 

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18 Patients, who in the opinion of the Investigator, may not be able to understand 
or comply with the safety monitoring requirements of the study. 
For pre-conditioning chemotherapy and AUTO4 Infusion: Patients meeting 
any of the following exclusion criteria must not be treated with pre-conditioning 
chemotherapy or AUTO4 - and should have treatment delayed until they no longer 
meet these criteria:  
1 
Severe intercurrent infection at the time of pre-conditioning chemotherapy or 
the scheduled AUTO4 infusion.  
2 
Requirement for supplementary oxygen or active pulmonary infiltrates or 
significant deterioration of organ function at the time of pre-conditioning 
chemotherapy or scheduled AUTO4 infusion. 
3 
Significant clinical deterioration of organ functions from screening, as 
determined by the investigator. 

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Study Product 
Dose, Dosing 
Regimen, and 
Administration  
The AUTO4 product consists of enriched autologous genetically modified T cells 
(RQR8/aTRBC1-CAR positive T cells), that express RQR8 and the TRBC1 CAR 
on the cell surface, and non-genetically modified T cells. The dose is expressed as 
the number of RQR8/aTRBC1-CAR positive T cells. AUTO4 also contains non-
transduced autologous lymphocytes as a product-related impurity. Eligible 
patients will receive a single dose i.v. infusion of AUTO4 following pre-
conditioning treatment.  
Up to five dose levels are planned to be explored.  
Phase I Dose Escalation intends to start with 25 x 106 RQR8/aTRBC1-CAR 
positive T cells administered as a single dose. The other planned doses are 
75 x 106, 225 x 106, 450 x 106 and 900 x 106 RQR8/aTRBC1-CAR positive T 
cells.  
Phase I Dose Escalation with Process B will be starting with 225 x 106 
RQR8/aTRBC1-CAR positive T cells, followed by 450 x 106 and 900 x 106 
RQR8/aTRBC1-CAR positive T cells. 
All patients will be admitted to the hospital for at least 14 days for monitoring 
after receiving AUTO4. 
Pre-conditioning 
Treatment 
All patients will receive a pre-conditioning regimen using fludarabine (FLU) 
30 mg/m2 i.v. immediately followed by cyclophosphamide (CY) 500 mg/m2 i.v. 
on Days -6 and -5, and FLU 30 mg/m2 i.v. and on Days -4, -3 (-1 day) before 
AUTO4 infusion. 
Safety 
Evaluation 
Safety will be assessed by physical examinations, ECOG status, vital signs, 
laboratory tests, electrocardiograms, AE and serious AE monitoring, 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), with the exception of neurotoxicity, which will be assessed 
according to the ASBMT Immune Effector Cell-associated Neurotoxicity 
Syndrome (ICANS) grading criteria.  
Efficacy 
Evaluation 
Efficacy will be evaluated as per Lugano Classification. 
Response evaluations will be assessed by PET scans, computed tomography 
(CT) scans, magnetic resonance imaging (MRI), physical examination, and bone 
marrow biopsy (if needed). 
Biomarker 
Evaluation 
Post AUTO4 infusion biomarker evaluation will include the following: 
• 
Expansion and persistence of RQR8/aTRBC1-CAR positive T cells as 
determined by polymerase chain reaction (PCR) and/or flow cytometry. 
• 
Depletion of TRBC1 positive T cell compartment as determined by flow 
cytometry on peripheral blood. 
Special Study 
Procedures 
A separate tumour tissue consent will be sought from all patients who are entering 
the selection process for this trial for the provision of an archival lymph node 
tumour tissue or a newly acquired tumour tissue for evaluation of TRBC1 
expression. If a patient cannot provide sufficient archival tumour tissue for the 
evaluation of TRBC1 expression, newly acquired tumour tissue can be obtained 
by core needle biopsy or excisional biopsy. If a core needle is used, an absolute 
minimum of two cores are required for the determination of TRBC1 status. Timing 
of screening biopsy should be discussed with Sponsor to ensure the result (TRBC1 
positive or not) is known prior to the planned leukapheresis. 

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Only patients identified as TRBC1 positive will be invited to consent to the main 
study. These patients will undergo an unstimulated leukapheresis for AUTO4 
generation. Where feasible, a fraction of leukapheresate will be stored as backup 
(rescue treatment) for immune reconstitution. This can be collected at the same 
time or at a second unstimulated leukapheresis prior to pre-conditioning.  
Statistical 
Analysis 
The data will be summarised using descriptive statistics. Continuous variables will 
be summarised using the number of observations, mean, standard deviation, 
median, and range as appropriate. Categorical values will be summarised using 
the number of observations, percentages and confidence intervals as appropriate. 
Time-to-event endpoints will be estimated using Kaplan-Meier methodology.  
The Phase II part of the study will treat up to 30 evaluable patients. Overall 
response rate with two-sided 95% confidence interval will be estimated based on 
evaluable patients. The definition of an evaluable patient (for efficacy) is one that 
has received an AUTO4 dose (either partial or complete),and has measurable 
disease before starting the pre-conditioning therapy (and after receiving any 
bridging therapies). 
Data from all treated patients (safety analysis set) will be used for safety analyses 
and will be summarised by dose level.  
Interim Analyses 
In Phase II of the study, an interim analysis will be performed after 10 evaluable 
patients are treated and had the opportunity to be followed for at least 12 weeks. 
The study will be stopped at this first stage if no more than one response has been 
observed. 
 
 

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SCHEDULE OF ASSESSMENTS 1 (Safety and Efficacy Follow-up) 
 
SCREE
N 
TRBC 
SCREEN 
1$ 
LEUKA-
PHERESI
S@ 
SCREEN 
2 # 
PRE-
CONDITIONING 
CHEMO-
THERAPY 
TREATMENT STAGE† 
FOLLOW-UP 
STAGE 
END OF 
STUDY 
** 
 
Day -84 to 
Day -35 
Before 
Day -35 
Day -35 
to -7 
Day -7 
(-1d) 
Day  
-6, -5,  
-4, -3  
(-1 d) 
Day 
0 
Day 1, then 
q.a.d. 
Hospitalisatio
n ≥14 d 
Weekly 
after 
discharge 
(±2 d) 
End of DLT 
period* 
Day 28  
(±3 d) 
Month 2, 3,
4, 5, 6, 9, 
12, 15, 18 
& 24  
(±7 d) 
Every 6 
months 
until 
EoS** 
(±4 wk) 
 
Informed Consent 
Part A 
Part B 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data[1] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria[2] 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Medical/ Lymphoma 
History[3] 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Examinations/Investigations 
ECOG Performance 
Status 
X 
X 
 
 
X 
 
 
 
 
X 
X  
 
X 
Physical 
Examination[4] 
 
X 
 
 
X 
 
X 
XD7, D14 
X 
X 
X 
 
X 
Weight 
 
X 
X 
 
X 
 
 
 
 
X 
X  
 
X 
Vital Signs[5] 
 
X 
 
 
X 
 
X[5] 
XD7, D14 
X 
X 
X 
 
X 
12-lead ECG[6] 
 
X 
 
 
X[6] 
 
 
 
 
 
 
 
 
ECHO or MUGA[7] 
 
X 
 
 
 
 
 
 
 
 
 
 
 

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2 # 
PRE-
CONDITIONING 
CHEMO-
THERAPY 
TREATMENT STAGE† 
FOLLOW-UP 
STAGE 
END OF 
STUDY 
** 
 
Day -84 to 
Day -35 
Before 
Day -35 
Day -35 
to -7 
Day -7 
(-1d) 
Day  
-6, -5,  
-4, -3  
(-1 d) 
Day 
0 
Day 1, then 
q.a.d. 
Hospitalisatio
n ≥14 d 
Weekly 
after 
discharge 
(±2 d) 
End of DLT 
period* 
Day 28  
(±3 d) 
Month 2, 3,
4, 5, 6, 9, 
12, 15, 18 
& 24  
(±7 d) 
Every 6 
months 
until 
EoS** 
(±4 wk) 
 
 
 
Tumour Tissues Assessment 
Tumour Tissue 
Sample (TRBC1 
status) [8] 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumour Tissue 
Sample (CAR T-cell 
persistence/TRBC1 
expression)[9] 
 
 
 
 
 
 
 
X between D7-D21 [9] 
 
Xprog 
 
 
Bone Marrow Biopsy 
(if applicable) [10] 
 
 
 
X 
 
 
 
 
X10 
 
 
 
 
Disease Evaluations 
CT Imaging (neck, 
chest, abdomen and 
pelvis)[11] 
 
 
 
X 
 
 
 
 
 
X 
XM3, M6, 
M9, M12, 
M15, M18, 
M24 
X 
[11] 
18-FDG-PET Scan 
(skull base to the 
proximal femur)[11] 
 
 
 
X 
 
 
 
 
 
X 
XM3, M6, 
M9, M12, 
M15, M18, 
M24 
X 
[11] 
Tissue biopsy 
 
 
 
 
 
 
 
 
 
 
[11] 
[11] 
 
 
 
Safety Labs 

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PRE-
CONDITIONING 
CHEMO-
THERAPY 
TREATMENT STAGE† 
FOLLOW-UP 
STAGE 
END OF 
STUDY 
** 
 
Day -84 to 
Day -35 
Before 
Day -35 
Day -35 
to -7 
Day -7 
(-1d) 
Day  
-6, -5,  
-4, -3  
(-1 d) 
Day 
0 
Day 1, then 
q.a.d. 
Hospitalisatio
n ≥14 d 
Weekly 
after 
discharge 
(±2 d) 
End of DLT 
period* 
Day 28  
(±3 d) 
Month 2, 3,
4, 5, 6, 9, 
12, 15, 18 
& 24  
(±7 d) 
Every 6 
months 
until 
EoS** 
(±4 wk) 
 
Haematology[12] 
 
X 
X 
 
X 
 
X 
XD1, D7, D14 
X 
X 
X 
 
 
Biochemistry [13] 
 
X 
X 
 
X 
 
X 
XD1, D7, D14 
X 
X 
X 
 
 
Ferritin, C reactive 
protein[14] 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Coagulation[15]  
 
X 
X 
 
X 
 
X 
XD7, D14 
 
 
 
 
 
Infectious Disease 
Screen[16]  
 
X 
X[16] 
 
 
 
 
 
 
 
 
 
 
Monitoring for 
infections[17]   
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Pregnancy Test[18] 
 
X 
 
 
X 
 
X 
 
 
X 
XM3, M6, 
M12 
 
 

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PRE-
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CHEMO-
THERAPY 
TREATMENT STAGE† 
FOLLOW-UP 
STAGE 
END OF 
STUDY 
** 
 
Day -84 to 
Day -35 
Before 
Day -35 
Day -35 
to -7 
Day -7 
(-1d) 
Day  
-6, -5,  
-4, -3  
(-1 d) 
Day 
0 
Day 1, then 
q.a.d. 
Hospitalisatio
n ≥14 d 
Weekly 
after 
discharge 
(±2 d) 
End of DLT 
period* 
Day 28  
(±3 d) 
Month 2, 3,
4, 5, 6, 9, 
12, 15, 18 
& 24  
(±7 d) 
Every 6 
months 
until 
EoS** 
(±4 wk) 
 
 
 
Pharmacokinetics, Pharmacodynamic and Biomarker Assays 
Serum for 
cytokines[19] 
 
 
 
X 
X 
XD-6 
Xp 
X 
X 
X 
XM2, M3  
 
 
Central Assessment- 
Blood for Tcell 
Subset (TRBC1+, 
TRBC1-, 
CD3+CD4+, CD3+ 
CD8+) Analysis [20] 
 
X 
 
 
X 
 
X 
XD14 only 
 
X 
XM2, M3, 
M4, M5, M6, 
M9, M12, 
M15, M18, 
M24 
 
 
Local Assessment- 
Blood for Tcell 
Subset (CD3+CD4+, 
CD3+CD8+) 
Analysis [20] 
 
X 
 
 
X 
 
X 
XD14 only 
 
X 
XM2, M3, 
M4, M5, M6, 
M9, M12, 
M15, M18, 
M24 
X 
 
Blood for CAR 
T Cells persistance, 
PCR [21] 
 
 
 
 
X 
 
Xp[21] 
X [21] 
X 
X 
XM2, M3, 
M4, M5, M6, 
M9, M12, 
M15, M18, 
M24 
X 
 

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PRE-
CONDITIONING 
CHEMO-
THERAPY 
TREATMENT STAGE† 
FOLLOW-UP 
STAGE 
END OF 
STUDY 
** 
 
Day -84 to 
Day -35 
Before 
Day -35 
Day -35 
to -7 
Day -7 
(-1d) 
Day  
-6, -5,  
-4, -3  
(-1 d) 
Day 
0 
Day 1, then 
q.a.d. 
Hospitalisatio
n ≥14 d 
Weekly 
after 
discharge 
(±2 d) 
End of DLT 
period* 
Day 28  
(±3 d) 
Month 2, 3,
4, 5, 6, 9, 
12, 15, 18 
& 24  
(±7 d) 
Every 6 
months 
until 
EoS** 
(±4 wk) 
 
Blood for CAR T 
Cells, Flow [21] 
 
 
 
 
X 
 
Xp 
X 
X 
X 
XM2, M3, 
M4, M5, M6, 
M9, M12, 
M15, M18, 
M24 
X 
 
Blood for RCR 
Testing & Insertional 
Mutagenesis 
 
 
 
 
X 
 
 
 
 
X 
XM3, M6, 
M12, M18, 
M24   
X 
 
Immunological / 
genomic profiling[22] 
 
 
 
 
X 
 
Xp 
XD7, D14 
X 
X 
XM3, M6, 
M9, M12, 
M15, M18, 
M24 
 
 
 
 
Treatments 
CY and FLU 
 
 
 
 
 
X 
 
 
 
 
 
 
 
AUTO4 Infusion 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Adverse events 
Adverse Events[23] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication[24] 
 
 
 
 
X 
X 
X 
 
 
X 
XM2 
X 
 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CAR = chimeric antigen receptor; CMV= Cytomegalovirus; 
CPK = creatine phosphokinase; CR = complete response; CRS = cytokine release syndrome; CT = computed tomography; CY = cyclophosphamide; D,d = day; DLT = dose 

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limiting toxicity; EBV = Epstein Barr Virus; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiogram; 
EDTA = ethylenediaminetetraacetic acid; FDG = fluorodeoxyglucose; FFPE = formalin fixed paraffin embedded; FLU = fludarabine; JCV=John Cunningham Virus; HHV6= 
Human herpesvirus 6; M = month (where each month is approximately 4.2 weeks, with 12 months per year); MRI = magnetic resonance imaging; MUGA = multigated 
acquisition (cardiac scan); PET = positron emission tomography; q.a.d. = quaque altera die (every other day); RCR = replication competent retrovirus; SAE = serious adverse 
event; TRBC = T cell receptor beta constant. 
*: 
End of DLT period set as 28 days after the dose of AUTO4. 
**: 
End of Study visit is to be performed upon completion of all other study visits or in case of premature withdrawal. The end of the study (EoS) 
is defined as the LPLV expected to be 24 months after the last treated patient with AUTO4 or earlier in the event of patient death or 
consent withdrawal. Of Note:  The patients who experienced disease progression post AUTO4 infusion will continue to be followed 
under this study protocol until death, study closure or consent withdrawal, whichever occurs earlier (see Section 8.5.2, Schedule of 
Assessments).  
Note:  
Additionally, blood samples for CAR T persistence and RCR may also be collected.  
$: 
All tests must be undertaken (and results known) before leukapheresis. 
@:  
Leukapheresis occurs after a patient is confirmed as TRBC1 positive. 
XDx:  
Test to be performed on a particular day or month of the schedule rather than systematically at every visit. Please refer to the number to 
determine the day or month of assessment. 
Xp: 
Sample to be taken prior to infusion. 
Xprog: 
Test to be performed at disease progression. 
#  
Enrolment confirmed once all inclusion and exclusion criteria have been fulfilled and leukapheresate has been accepted for manufacturing. 
Schedule of Assessment Footnotes: 
1. 
Demographic data: race and ethnicity, height, age (month and year) and gender. 
2. 
Eligibility criteria: Performance, disease characteristics and organ and bone marrow function to be assessed before a new node biopsy (if patient will undergo 
a node biopsy). ECHO may be done after node biopsy. Eligibility criteria to be re-assessed on Day -7 (-1 day) prior to pre-conditioning when the patient 
should continue to meet renal, hepatic, pulmonary function and performance status requirements. On Day 0, before infusion, it will be assessed whether the 
patient meets the AUTO4 infusion criteria. 
3. 
Medical/lymphoma history: to include all current and prior clinically significant diseases, surgeries, cancer history (including prior T-cell lymphoma therapies 
or any other cancer therapies and procedures) and prior relevant medications). Obtain histological confirmation of disease diagnosis (pathology report) and 
the presence of T-cell lymphoma in the archived node tissue (if archived tissue is used for the TRBC1 status assessment). Record disease status at Screen 2 
after leukapheresis has been completed.  
4. 
Physical examination: a complete physical examination and complete neurological examination to be performed at Screen 1, Day -7 (-1 day) and Day 0; then 
focused and/or symptom related examination as appropriate at following visits. 
5. 
Vital signs: temperature, systolic and diastolic blood pressure, pulse/heart rate, oxygen saturation and respiratory rate will be performed while the patient is 
in a seated position or supine. On Day 0 of any treatment stage, record vital signs immediately prior to AUTO4 infusion and every 30 minutes (± 10 min) 
for the next 4 hours post AUTO4 infusion, and thereafter monitored as per hospital policy but no less than 3 times a day whilst the patient is in hospital. 
Record weight as per Schedule of Assessments above. 
6. 
12-lead ECG: Repeat as clinically necessary and when patient experiences CRS.  
7. 
ECHO or MUGA cardiac scan: to be performed at Screen 1 and to be repeated if clinically indicated. Same method should be used throughout the study. 

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8. 
Newly acquired tumour tissue sample may be required to determine TRBC1 status unless sufficient archival tumour biopsy material can be obtained – either 
by core needle biopsy or excisional biopsy (archived tissue must not be >5 years old and subtype of T-NHL unchanged from time of archived tissue to current 
status). If a core needle is used, an absolute minimum of two cores are required for the evaluation of TRBC1 expression on T cells using the 
 
. However, additional two cores are requested (if medically feasible) for the further development of a TRBC companion diagnostic assay 
and/or biomarker assessment on FFPE tissue.  
9. 
Lymph node Tumour Tissue Sample for CAR T-cell persistence/TRBC1 expression. If there is a suitable lesion in an accessible location which would not 
put the patient at any safety risk per treating physician judgment. Biopsy samples should be taken once within the first 10 days since CAR T cell infusion 
and at the time of progression. The tumour samples will be analysed by flow cytometry or immunohistochemistry.  
10. Bone Marrow Biopsy. If the Investigator suspects there is lymphoma infiltration in the bone marrow, a bone marrow biopsy should be performed at 
screening (if patient receives bridging therapy it should be done after any bridging therapy). If a bone marrow biopsy is performed and shows lymphoma 
infiltration, a bone marrow biopsy should be repeated at the time of first complete response. 
11. Imaging and scans: For those patients receiving a bridging chemotherapy regimen, the baseline PET/CT (CT portion needs to have diagnostic quality, 
otherwise a separate CT is needed to be taken in the same week of PET) scans must be done after completion of bridging therapy and before start of the 
preconditioning and AUTO4 infusion. 18-FDG-PET Scan: If at 6 months the patient has a CMR on PET scan, CT scans alone may be used for future 
assessment timepoints, 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 together with tissue biopsy (if needed).MRI 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. If progression is suspected from scan(s), but the patient is otherwise not showing clinical progression/deterioration, the disease progression must 
be confirmed not less than 28 days after initial finding to rule out a pseudo-progression. In cases of starting new treatment during response, an efficacy 
assessment is required prior to new treatment. 
12. Haematology: haemoglobin, red blood cell count, platelet count, white blood cell count with differential (neutrophils, eosinophils, lymphocytes, monocytes, 
and basophils). Test to be performed prior to chemotherapy on pre-conditioning days and prior to AUTO4 infusion on Day 0 of any treatment stage. 
13. Biochemistry: Whole panel: sodium, phosphate, potassium, magnesium, chloride, bicarbonate, ALT, AST, urea or blood urea nitrogen, creatinine, serum 
CPK, lactate dehydrogenase, glucose, total bilirubin, calcium (albumin adjusted), total protein, albumin. Serum uric acid to be measured only on Day 0, 1, 
and 7 of any AUTO4 treatment stage. All tests must be performed prior to AUTO4 infusion on Day 0 of any AUTO4 treatment stage. Glomerular filtration 
rate should be calculated at screening as per institutional preferred method. 
14. Ferritin, C reactive protein: May be done more frequently as clinically necessary and during CRS if necessary. 
15. Coagulation: prothrombin time, international normalised ratio, activated partial thromboplastin time, fibrinogen. Day 7, after AUTO4 infusion. 
16. Infectious disease screen: must be performed at screening for the eligibility criteria and within 30 days prior to leukapheresis and must be negative.  It must 
be repeated on the day of leukapheresis (or within 7 days after). HIV-1 and 2, Hep B virus, Hep C virus, HTLV-1, HTLV-2, Syphilis.  
17. Monitoring for infections: CMV, HHV6, EBV & adenovirus monitoring as per schedule in table.  Additonal monitoring for opportunistic infections, such as 
JCV, toxoplasmosis and fungal infections as per institutional guidelines (e.g institutional guidelines used for bone marrow transplant patients) or as clinically 
indicated. Monitoring beyond 3 months should be done if there is low levels of CD4+ T-cells or if clinically indicated. 
18. Pregnancy test: serum (β-human chorionic gonadotropin) or urine pregnancy testing for women of childbearing potential.  
19. Serum for cytokines and biomarkers: During hospital stay, sample collection to be performed every other day (± 1 day). If patient experiences ≥Grade 2 CRS 
then additional samples should be collected daily until CRS resolves or clinically indicated 

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20. Blood for analysis of T cell Subsets will be done both locally and via a Central Lab. Samples are to be collected at the following timepoints: Screening, Day 
-7, Day 0 (predose), Day 14, Day 28, Month 2, 3, 4, 5, 6, 9, 12, 15, 18, 24, and as clinically indicated e.g. in case of opportunistic infections 
21. Blood for CAR T cells persistance: one sample to be taken on Day-7, Day 0 prior to AUTO4 infusion. During hospital stay, sample collection to be performed 
10 min and 1h after completion of CAR T cell infusion, on Day 1 and every other day (± 1 day) and ideally on a Monday to Friday. Following hospital 
discharge (Day 14), blood samples for CAR- T cells (by flow and PCR) are to be collected at the following timepoints: Day 21, Day 28, Month 2, 3, 4, 5, 6, 
9, 12, 15, 18 and 24.  Additional samples should be collected if clinically indicated; an additional sample should be collected at the time of disease progression.  
22. Blood for Immunological / genomic profiling: During hospital stay, sample collection to be performed on Day 7 and Day 14 (± 1 day) and ideally on a 
Monday to Friday 
23. Adverse Events: Only AEs/SAEs related to study procedures should be collected until admission for lymphodepletion chemotherapy (Day -6 [-1 day]). AEs 
related to intervening/bridging non-study related anti-cancer therapy administered prior to pre-conditioning or AEs associated with disease progression 
during the same period will not be reported as AEs. These events will be recorded as an update to the patient’s medical history. After Day 60, only collect: 
All SAES and AUTO4 treatment-related non-serious AEs; All AEs of special interest and AEs related to a study procedure. Please refer to Section 12 for 
specifics about the AE reporting periods. 
24. Concomitant medications: Collect as described in the Schedule of Assessments. Before Day -7 (-1 day) and after 2 months, collect only concomitant 
medications relevant to AUTO4 treatment-related Grade 3 to 4 AEs and treatment-related SAEs; AEs of special interest or AEs related to a study procedure. 
 
Note: The total estimated volume of blood collected for safety, biomarkers and immunological assessments (with the exception of the leukapheresis procedure) across any one 
year will not normally exceed 850 mL (this is expected volume for females with serum pregnancy test). The maximum volume of blood collected on any day will 
unlikely exceed 80mL. No more than 470mL of blood will be collected in any 28-day period.  
 

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SCHEDULE OF ASSESSMENTS 2 (Safety and Survival Follow-up) 
Applies to all patients who fail to respond to treatment or who respond but subsequently experienced disease progression. Please refer to the 
relevant abbreviations and footnotes in SCHEDULE OF ASSESSMENTS 1 (Safety and Efficacy Follow-up) table above and to Section 8.5.2 for 
further details.  
                  
Visits 
 
         Assessments 
SAFETY AND SURVIVAL FOLLOW-UP 
END OF 
STUDY 
M2 
±7d 
M3  
±7d 
M6  
±7d 
M9 
±7d 
M12  
±7d 
M24  
±7d 
Every 6 months  
until EoS** # 
±4wk 
EoS**/Early 
Withdrawal 
PATIENT INFORMATION 
 
Subsequent anti-T-cell 
lymphoma therapy and disease 
response 
X 
Survival Status 
X 
Selected Concomitant 
Medication [23] 
X 
EXAMINATIONS, INVESTIGATIONS AND SAFETY EVALUATIONS 
 
Pregnancy test [17] 
 
X 
X 
 
 
X 
 
 
Adverse events [22]  
X 
Physical Exam 
X yearly 
BIOMARKERS 
 
PERIPHERAL BLOOD 
 

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Visits 
 
         Assessments 
SAFETY AND SURVIVAL FOLLOW-UP 
END OF 
STUDY 
M2 
±7d 
M3  
±7d 
M6  
±7d 
M9 
±7d 
M12  
±7d 
M24  
±7d 
Every 6 months  
until EoS** # 
±4wk 
EoS**/Early 
Withdrawal 
Local Assessment- Blood for 
Tcell Subset (CD3+CD4+, 
CD3+CD8+) Analysis [20] 
X every 6 months  
Blood for CAR T Cells 
persistance, PCR [21] 
X as clinically indicated 
RCR  
 
X 
X 
 
X 
X 
X yearly 
X 
Insertional Mutagenesis  
 
X 
X 
 
X 
X 
X 
X 
d = days; EoS = end of study; M = month; RCR = replication competent retrovirus; wk = weeks. 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................... 5 
SCHEDULE OF ASSESSMENTS 1 (SAFETY AND EFFICACY FOLLOW-
UP) ........................................................................................................... 13 
SCHEDULE OF ASSESSMENTS 2 (SAFETY AND SURVIVAL FOLLOW-
UP) ........................................................................................................... 21 
TABLE OF CONTENTS ......................................................................................... 23 
LIST OF APPENDICES .......................................................................................... 29 
LIST OF TABLES .................................................................................................... 29 
LIST OF FIGURES .................................................................................................. 30 
1. 
INTRODUCTION ................................................................................... 35 
1.1. 
T CELL LYMPHOMAS ......................................................................... 35 
1.2. 
T CELL RECEPTOR BETA CONSTANT 1 AS A TARGET FOR 
THERAPY ............................................................................................... 36 
1.3. 
CLINICAL EXPERIENCE WITH CAR T THERAPIES IN T CELL 
LYMPHOMA .......................................................................................... 36 
1.4. 
DESCRIPTION OF AUTO4 – RQR8/ANTI-TRBC1 CAR POSITIVE 
T CELLS .................................................................................................. 37 
1.5. 
SUMMARY OF NONCLINICAL STUDIES ......................................... 38 
1.5.1. 
Estimating Safety Concerns of Targeting T Cells ................................... 39 
1.6. 
SUMMARY OF CLINICAL STUDIES WITH AUTO4 ........................ 40 
1.7. 
OVERALL RATIONALE FOR THE STUDY ....................................... 40 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................... 40 
2.1. 
PRIMARY OBJECTIVES AND ENDPOINTS ...................................... 40 
2.2. 
SECONDARY OBJECTIVES AND ENDPOINTS ............................... 41 
2.3. 
EXPLORATORY OBJECTIVES ........................................................... 41 
3. 
STUDY DESIGN .................................................................................... 41 
3.1. 
STUDY OVERVIEW .............................................................................. 41 
3.2. 
PHASE I DOSE ESCALATION RULES AND ROLLING SIX DESIGN
 ................................................................................................................. 44 
3.3. 
PLANNED DOSE LEVELS ................................................................... 45 
3.4. 
PHASE II DOSE EXPANSION .............................................................. 47 
3.5. 
DOSE LIMITING TOXICITY ................................................................ 47 
3.6. 
SAFETY STOPPING CRITERIA FOR THE CLINICAL TRIAL ......... 48 
3.7. 
STUDY DURATION .............................................................................. 49 
3.8. 
NUMBER OF PATIENTS ...................................................................... 49 

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4. 
SCIENTIFIC RATIONALE FOR STUDY ............................................. 50 
4.1. 
DESIGN RATIONALE ........................................................................... 50 
4.2. 
POPULATION RATIONALE ................................................................ 50 
4.2.1. 
Current Therapeutical Options for this Population and Rationale for 
Inclusion .................................................................................................. 51 
4.3. 
STARTING DOSE RATIONALE .......................................................... 52 
4.4. 
RATIONALE FOR MAXIMUM ADMINISTERED DOSE (MAD) ..... 53 
4.5. 
RATIONALE FOR DOSING SCHEDULE ............................................ 54 
4.6. 
FLUDARABINE AND CYCLOPHOSPHAMIDE PRE-
CONDITIONING RATIONALE ............................................................ 54 
4.7. 
BIOMARKER COLLECTION AND ASSESSMENT RATIONALE ... 55 
5. 
RISKS AND MITIGATION STRATEGY ............................................. 55 
5.1. 
TUMOUR TISSUE BIOPSY .................................................................. 55 
5.2. 
LEUKAPHERESIS ................................................................................. 55 
5.3. 
PRE-CONDITIONING CHEMOTHERAPY ......................................... 56 
5.4. 
AUTO4 INFUSION ................................................................................. 56 
5.5. 
UNKNOWN LONG-TERM RISKS OF GENE THERAPY .................. 59 
6. 
PATIENT POPULATION ....................................................................... 59 
6.1. 
INCLUSION CRITERIA ........................................................................ 60 
6.2. 
EXCLUSION CRITERIA ....................................................................... 61 
7. 
ADVANCED THERAPY INVESTIGATIONAL MEDICINAL 
PRODUCT: AUTO4 ............................................................................... 62 
7.1. 
AUTO4 DESCRIPTION ......................................................................... 62 
7.2. 
AUTO4 MANUFACTURING ................................................................ 63 
7.3. 
PACKAGING AND LABELLING ......................................................... 63 
7.4. 
SUPPLY AND STORAGE ..................................................................... 64 
7.5. 
ACCOUNTABILITY AND DESTRUCTION........................................ 64 
8. 
STUDY PROCEDURES AND TREATMENT ...................................... 65 
8.1. 
CONSENT, SCREENING, TISSUE BIOPSY AND REGISTRATION 65 
8.1.1. 
Consent processes .................................................................................... 65 
8.1.2. 
Patient Registration .................................................................................. 65 
8.1.3. 
Patient Screening for TRBC1 Positive T-NHL ....................................... 66 
8.1.4. 
Tumour Tissue Provision ......................................................................... 66 
8.1.5. 
NGS Assay Used to Select TRBC1 Positive Patients for Entry .............. 66 
8.1.6. 
Patient Screening to the Main Study ....................................................... 67 
8.1.7. 
Infectious Disease Screening ................................................................... 68 

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8.2. 
LEUKAPHERESIS FOR AUTO4 MANUFACTURING ...................... 68 
8.2.1. 
Leukapheresis for Immune Reconstitution (Rescue Treatment Storage) 69 
8.3. 
PRE-CONDITIONING CHEMOTHERAPY ......................................... 69 
8.3.1. 
Pre-conditioning Chemotherapy Dose and Regimen .............................. 69 
8.3.2. 
Supply of Fludarabine and Cyclophosphamide ....................................... 70 
8.3.3. 
Accountability of Fludarabine and Cyclophosphamide .......................... 70 
8.4. 
AUTO4 TREATMENT AND PATIENT MONITORING ..................... 70 
8.4.1. 
Assessment Prior to AUTO4 Infusion ..................................................... 70 
8.4.2. 
AUTO4 Administration ........................................................................... 71 
8.4.3. 
Monitoring During and After Drug Administration ................................ 72 
8.4.4. 
Monitoring for Infections ........................................................................ 72 
8.4.5. 
Dose Delay of Pre-conditioning and AUTO4 Treatment ........................ 72 
8.4.6. 
Interruption of Infusion ............................................................................ 73 
8.4.7. 
Duration of Treatment ............................................................................. 73 
8.4.8. 
Re-treatment of Patients .......................................................................... 73 
8.5. 
FOLLOW-UP PHASE............................................................................. 74 
8.5.1. 
Efficacy and Safety Follow-up ................................................................ 74 
8.5.2. 
Safety and Survival Follow-up ................................................................ 75 
8.6. 
LONG-TERM FOLLOW-UP .................................................................. 75 
9. 
STUDY ASSESSMENTS ....................................................................... 76 
9.1. 
DEMOGRAPHIC AND BASELINE ASSESSMENTS ......................... 76 
9.1.1. 
Demographic Data and Baseline Variables (Screen 1) ............................ 76 
9.1.2. 
Tumour Tissue Biopsy and TRBC1 Status at Baseline (During Screen 1)
 ................................................................................................................. 76 
9.1.3. 
T-cells subsets analysis ............................................................................ 76 
9.1.4. 
Efficacy Scans ......................................................................................... 77 
9.2. 
SAFETY EVALUATIONS ..................................................................... 77 
9.2.1. 
Adverse Events and Toxicity ................................................................... 77 
9.2.2. 
Clinical Laboratory Tests ........................................................................ 77 
9.2.3. 
12-lead Electrocardiogram ....................................................................... 78 
9.2.4. 
Echocardiogram or Multiple Gated Acquisition Cardiac Scan ............... 79 
9.2.5. 
Vital Signs ............................................................................................... 79 
9.2.6. 
Physical Examination .............................................................................. 79 
9.2.7. 
Concomitant Medications ........................................................................ 79 
9.2.8. 
ECOG Performance Status ...................................................................... 79 

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9.3. 
PHARMACOKINETICS, PHARMACODYNAMICS AND 
BIOMARKER EVALUATION .............................................................. 79 
9.3.1. 
Evaluation of AUTO4 Persistence in Peripheral Blood .......................... 79 
9.3.2. 
Evaluation of AUTO4 Persistence and TRBC1 Expression in Lymph 
Node Tumour ........................................................................................... 80 
9.3.3. 
Evaluation of RCR in Peripheral Blood .................................................. 80 
9.3.4. 
TRBC1 Positive T Cell Aplasia ............................................................... 80 
9.3.5. 
Insertional Mutagenesis ........................................................................... 80 
9.3.6. 
Exploratory Biomarker Assessments ....................................................... 80 
9.3.7. 
Immunogenicity Analysis ........................................................................ 81 
9.4. 
EFFICACY EVALUATION ................................................................... 81 
9.4.1. 
Radiographic Image Assessments (CT/MRI) .......................................... 81 
9.4.2. 
Positron Emission Tomography Scan ...................................................... 82 
9.4.3. 
Tissue Biopsy........................................................................................... 82 
9.4.4. 
Efficacy Criteria ....................................................................................... 82 
9.5. 
BLOOD VOLUME COLLECTIONS ..................................................... 83 
10. 
GUIDELINES FOR PREVENTION, MONITORING, AND 
MANAGEMENT OF ADVERSE EVENTS ........................................... 84 
10.1. 
GENERAL SUPPORTIVE CARE GUIDELINES FOR PATIENTS 
RECEIVING CAR T CELL THERAPY ................................................. 84 
10.2. 
PRE- AND POST-INFUSION SUPPORTIVE THERAPY.................... 85 
10.3. 
MANAGEMENT OF INFUSION-RELATED REACTIONS ................ 86 
10.4. 
GRADING AND MANAGEMENT OF CYTOKINE RELEASE 
SYNDROME (CRS) ................................................................................ 88 
10.5. 
MANAGEMENT OF MACROPHAGE ACTIVATION SYNDROME 
(MAS) ...................................................................................................... 95 
10.6. 
GRADING AND MANAGEMENT OF NEUROTOXICITY (ICANS) 95 
10.7. 
MANAGEMENT OF TUMOUR LYSIS SYNDROME ...................... 100 
10.8. 
T CEL APLASIA .................................................................................. 101 
10.9. 
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS DUE 
TO ON-TARGET BUT OFF-TUMOUR TOXICITY .......................... 101 
11. 
CONCOMITANT MEDICATIONS AND THERAPIES ..................... 101 
11.1. 
BRIDGING THERAPY ........................................................................ 102 
11.2. 
ALLOWED CONCOMITTANT MEDICATIONS/THERAPIES ....... 102 
11.3. 
PROHIBITED AND CAUTIONARY THERAPIES ............................ 102 
11.4. 
OVERDOSAGE .................................................................................... 103 
11.5. 
DIETARY AND LIFESTYLE RESTRICTIONS ................................. 103 

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12. 
SAFETY AND PHARMACOVIGILANCE ......................................... 104 
12.1. 
DEFINITIONS ...................................................................................... 104 
12.1.1. 
Definition of an Adverse Reaction ........................................................ 104 
12.1.2. 
Definition of a Serious Adverse Event .................................................. 104 
12.1.3. 
Adverse Events of Special Interest ........................................................ 105 
12.1.4. 
Disease Progression ............................................................................... 105 
12.2. 
ASSESSMENT OF ADVERSE EVENTS ............................................ 106 
12.2.1. 
Severity of Adverse Events ................................................................... 106 
12.2.2. 
Relationship of Adverse Events to Treatment ....................................... 106 
12.3. 
REPORTING PROCEDURES .............................................................. 107 
12.3.1. 
All Adverse Events ................................................................................ 107 
12.3.2. 
Adverse Events Associated with Laboratory Values ............................. 108 
12.3.3. 
Adverse Events Associated with Cytokine Release Syndrome (CRS) .. 109 
12.3.4. 
Adverse Events Associated with CAR-T Neurotoxicity (ICANS) ........ 109 
12.3.5. 
Serious Adverse Events Reporting ........................................................ 109 
12.3.6. 
Adverse Events of Special Interest Reporting ....................................... 111 
12.3.7. 
Pregnancy Reporting and Management ................................................. 111 
12.3.8. 
Overdose Reporting and Dosing Errors ................................................. 112 
13. 
OVERSIGHT COMMITTEES .............................................................. 113 
13.1. 
SAFETY EVALUATION COMMITTEE ............................................ 113 
13.2. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ...... 113 
14. 
STATISTICS ......................................................................................... 114 
14.1. 
SAMPLE SIZE ESTIMATION ............................................................. 114 
14.2. 
DESCRIPTION OF ANALYSIS DATASETS ..................................... 115 
14.2.1. 
Enrolled Set ........................................................................................... 115 
14.2.2. 
Infused Set ............................................................................................. 115 
14.2.3. 
Safety Set ............................................................................................... 115 
14.2.4. 
Efficacy Analysis Set ............................................................................. 115 
14.3. 
STATISTICAL ANALYSES AND METHODS .................................. 115 
14.3.1. 
Primary Endpoints ................................................................................. 115 
14.3.2. 
Secondary Endpoints ............................................................................. 117 
14.3.3. 
Exploratory Objectives .......................................................................... 118 
14.3.4. 
Immunogenicity Data ............................................................................ 118 
14.3.5. 
Other Analyses ....................................................................................... 118 
14.3.6. 
Interim Analyses .................................................................................... 118 

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14.3.7. 
Final Analysis ........................................................................................ 119 
15. 
STUDY COMPLETION, PREMATURE DISCONTINUATION AND 
WITHDRAWAL FROM AUTO4-TL1 ................................................. 119 
15.1. 
COMPLETION OF STUDY ................................................................. 119 
15.2. 
PATIENT WITHDRAWAL FROM AUTO4-TL1 ............................... 119 
15.2.1. 
Procedures for Handling Premature Withdrawal from the Study .......... 120 
15.3. 
REPLACEMENT POLICY ................................................................... 120 
16. 
END OF TRIAL/TERMINATION BY SPONSOR .............................. 120 
17. 
ETHICAL AND REGULATORY CONSIDERATIONS ..................... 121 
17.1. 
ETHICS COMMITTEE REVIEW AND APPROVAL ........................ 121 
17.2. 
REGULATORY AUTHORITY REVIEW AND APPROVAL............ 121 
17.3. 
INVESTIGATOR RESPONSIBILITIES .............................................. 121 
17.3.1. 
Overall Responsibilities ......................................................................... 121 
17.3.2. 
Site Review ............................................................................................ 121 
17.3.3. 
Informed Consent .................................................................................. 122 
17.3.4. 
Delegation of Investigator Duties .......................................................... 122 
17.3.5. 
Communication with Independent Ethics Committee/Institutional 
Review Board ........................................................................................ 122 
17.3.6. 
Confidentiality of Trial Documents and Patient Records ...................... 123 
17.4. 
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL 
FUTURE RESEARCH .......................................................................... 123 
18. 
ADMINISTRATIVE REQUIREMENTS ............................................. 124 
18.1. 
DATA QUALITY CONTROL AND ASSURANCE ........................... 124 
18.1.1. 
Compliance with the Protocol and Protocol Revisions ......................... 124 
18.1.2. 
Protocol Violations and Deviations ....................................................... 124 
18.1.3. 
Monitoring ............................................................................................. 125 
18.1.4. 
Audits and Site Inspections ................................................................... 125 
18.2. 
DATA HANDLING AND RECORD KEEPING ................................. 125 
18.2.1. 
Data Management .................................................................................. 125 
18.2.2. 
Study Documentation and Retention of Records ................................... 126 
18.3. 
CLINICAL TRIAL AGREEMENT, FINANCE, AND INSURANCE 126 
19. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS .............................................................................................. 127 
20. 
REFERENCES ...................................................................................... 128 
21. 
APPENDICES ....................................................................................... 135 
 

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LIST OF APPENDICES 
Appendix 1: Patients with T-NHL will be Evaluated Using Response Criteria for 
Non-Hodgkin Lymphoma for Documenting Disease Response ........... 135 
Appendix 2: Eastern Cooperative Oncology Group Performance Status Score .... 138 
Appendix 3: Highly Effective and Acceptable Methods of Birth Control ............. 139 
LIST OF TABLES 
Table 1: 
Primary Objectives and Endpoints for Phase I ........................................ 40 
Table 2: 
Primary Objectives and Endpoints for Phase II ....................................... 40 
Table 3: 
Secondary Objectives and Endpoints for Phase I and II .......................... 41 
Table 4: 
Dose Escalation Decision Rules .............................................................. 45 
Table 5: 
Phase I Planned Dose Levels and Treatment Cohorts ............................. 46 
Table 6: 
Phase I (with Process B) Planned Dose Levels and Treatment Cohorts . 46 
Table 7: 
Leukapheresis – Risks and Mitigation Strategy ...................................... 55 
Table 8: 
Pre-conditioning Chemotherapy – Risks and Mitigation Strategy .......... 56 
Table 9: 
AUTO4 Infusion – Risks and Mitigation Strategy .................................. 57 
Table 10: Distribution of TRBJ and TRBC in Tonsil TCR-β Transcripts ............... 67 
Table 11: Infectious Disease Screening ................................................................... 68 
Table 12: Clinical Laboratory Tests ........................................................................ 78 
Table 13: General Supportive Care Guidelines for Patients Receiving CAR T Cell 
Therapy .................................................................................................... 84 
Table 14: Pre- and Post-infusion Medications ......................................................... 86 
Table 15: Guidelines for the Management of Infusion-related Reactions ............... 87 
Table 16: Severity Grading of Cytokine Release Syndrome (ASTCT/ASBMT CRS 
Consensus Grading and CTCAE Version 5.0) (Lee et al. 2019) ............ 89 
Table 17: Management of Cytokine Release Syndrome .......................................... 90 
Table 18:  Pharmacologic Management of CRS and ICANS ................................... 92 
Table 19:  Assessment & Grading of ICANS ........................................................... 97 
Table 20:  Immune Effector Cell-associated Encephalopathy (ICE) Scale .............. 97 
Table 21:  Management of ICANS ........................................................................... 98 
Table 22:  Recommendations for the Management of Status Epilepticus After CAR 
T Cell Therapy ......................................................................................... 99 
Table 23:  Recommendation for Management of Raised Intracranial Pressure (ICP) 
After CAR T Cell Therapy .................................................................... 100 
Table 24: Severity Grading of AEs Not Listed on the NCI CTCAE Grading System
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Table 25: Reporting Period for All AEs ................................................................ 108 
 
LIST OF FIGURES 
Figure 1: 
Transgenic Proteins Expressed on Autologous T Cells (AUTO4) .......... 38 
Figure 2: 
Proposed Dose Escalation and Dose Expansion Phases .......................... 42 
Figure 3: 
Overview of the Stages of the Study ....................................................... 43 
Figure 4: 
Cytokine Release Syndrome Management Overview ............................. 91 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event  
AESI 
Adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALL 
Acute lymphoblastic leukaemia 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
ASBMT 
American Society for Blood and Marrow Transplantation 
AST 
Aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
ATIMP 
Advanced therapy investigational medicinal product 
aTRBC 
Anti-T cell receptor beta constant 
aTRBC -CAR 
Anti-T cell receptor beta constant 1 chimeric antigen receptor 
BCMA 
B cell maturation antigen 
B-NHL 
B cell non-Hodgkin lymphoma 
CAR 
Chimeric antigen receptor 
CD3, 19, 20, 28, 68, 134 
Cluster of differentiation 3, 19, 20, 28, 68 134 
CHIM 
Cell handling instruction manual 
CHOP 
Cyclophosphamide, Hydroxydoxorubicin, Oncovin, Prednisone 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CR 
Complete response 
Cru 
Complete response unconfirmed 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA 
Cytotoxic T lymphocyte-associated protein 
CY 
Cyclophosphamide 
DFS 
Disease-free survival 
DHAP 
Dexamethasone, High-dose Ara-C, Platinum 
DIC 
Disseminated Intravascular Coagulation 
DLBCL 
Diffuse Large B Cell Lymphoma 
DLT 
Dose limiting toxicity 
DMSO 
Dimethyl sulphoxide 

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Abbreviation 
Definition 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
EBV 
Epstein Barr Virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EFS 
Event free survival 
ESHAP 
Etoposide, Methylprednisolone, Ara-C, Platinum 
EU 
European Union 
EudraCT 
European Clinical Trials Database  
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin fixed paraffin embedded 
FIH 
First-in-human 
FLU 
Fludarabine 
FLU-CY 
Fludarabine and cyclophosphamide 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GI 
Gastrointestinal 
GM CSF 
Granulocyte-Macrophage Colony-Stimulating Factors 
GMP 
Good Manufacturing Practice 
HDAC 
Histone deacetylase 
HIV 
Human immunodeficiency virus 
HHV6 
Human herpesvirus 6 
HLH 
Haemophagocytic lymphohistiocytosis  
HSCT 
Hematopoietic stem cell transplantation 
HTLV 
Human T cell lymphotropic virus 
IB 
Investigator’s Brochure 
ICANS 
Immune Effector Cell-associated Neurotoxicity Syndrome 
ICE 
Ifosfamide, Carboplatin, Etoposide 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 

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Abbreviation 
Definition 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMPD 
Investigational Medicinal Product Dossier 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
i.v. 
Intravenous(ly) 
JCV 
John Cunningham Virus 
JOVI-1 
JOVI-1 assay 
LDH 
Lactate dehydrogenase 
Ldi 
Longest transverse diameter of a lesion 
LVEF 
Left ventricular ejection fraction 
MAD 
Maximum administered dose 
MAS 
Macrophage activation syndrome 
MLV 
Murine Leukaemia Virus 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multiple gated acquisition 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
NGS 
Next-Generation Sequencing 
NOS 
Not otherwise specified 
NSAID 
Non-steroidal anti-inflammatory drugs 
OR 
Overall response 
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 
PD1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Prescribing information 

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Abbreviation 
Definition 
PIS 
Patient Information Sheet 
PPD 
Perpendicular diameter (cross product of the LDi and perpendicular 
diameter) 
PR 
Partial response 
PTCL 
Peripheral T cell lymphoma 
PTT 
Partial thromboplastin time 
q.a.d 
Quaque altera die (every other day) 
QP 
Qualified Person 
RCR 
Replication competent retrovirus 
RP2D 
Recommended Phase II dose 
RQR8 
Ritux-QBEND/10-Ritux-CD8 sort-suicide gene generated as a 
marker/suicide gene for T cells  
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
scFv 
Single chain variable fragment 
SCT 
Stem cell transplant/transplantation 
SEC 
Safety Evaluation Committee 
SmPC 
Summary of Product Characteristics 
SPD 
Sum of the product of the perpendicular diameters for multiple lesions 
SUSAR 
Suspected unexpected serious adverse reaction 
TBD 
To be determined 
TCR 
T cell Receptor 
TLS 
Tumour lysis syndrome 
TNF 
Tumour necrosis factor 
TRBC 
T cell receptor beta constant 
T-NHL 
T cell non-Hodgkin Lymphoma 
ULN 
Upper limit of normal 
US 
United States 
 
 

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1. 
INTRODUCTION 
AUTO4 is an autologous, cell and gene therapy investigational medicinal product that is 
manufactured by genetic modification of the patient’s own T cells by ex vivo transduction with 
a murine leukaemia virus (MLV)-derived retroviral vector that has been engineered to stably 
deliver the RQR8 and aTRBC1-CAR genes. The active substance is the genetically modified 
(RQR8/aTRBC1-CAR positive) T cells. RQR8 is a Ritux-QBEnd/10-Ritux-cluster of 
differentiation 8 (CD8) sort-suicide gene generated as a marker/suicide gene for T cells 
combining target epitopes from both CD34 and CD20 antigens. 
T cell receptor (TCR) beta constant region (TRBC) 1 and 2 are isoforms of the TCR and all 
T cells, normal and malignant, express either TRBC1 or TRBC2. Malignant T cells are clonal 
and the majority express exclusively either entirely TRBC1 or TRBC2. Normal T cells consist 
of a mixture of T cells individually expressing either TRBC1 or TRBC2. In this study, Autolus 
Limited (Autolus) plans to recruit patients with TRBC1 positive T cell lymphomas. Patients 
will receive autologous CAR T cells directed against TRBC1. These CAR T cells will target 
the lymphoma in its entirety as well as a proportion of normal T cells (i.e. those which are 
TRBC1 T cells) with the aim of maintaining immunity due to preservation of TRBC2 positive 
cells. 
The objectives of this Phase I/II first-in-human (FIH) study (AUTO4-TL1) are to: (1) evaluate 
the safety profile, (2) establish a recommended Phase II dose (RP2D), and (3) in Phase II 
determine the anti-lymphoma activity of AUTO4 in patients with relapsed or refractory T cell 
non-Hodgkin Lymphoma (T-NHL). AUTO4 will be administered following lymphodepletion 
with fludarabine (FLU) and cyclophosphamide (CY). 
A summary of the nonclinical characteristics of AUTO4 are described below in Section 1.5. 
For the most comprehensive nonclinical information, refer to the Investigator's Brochure (IB). 
Details regarding AUTO4 administration and laboratory procedures are provided in the cell 
handling manual (CHM) and laboratory manual, respectively. 
1.1. 
T CELL LYMPHOMAS 
T cell lymphoma is a rare and heterogeneous form of NHL with low incidence rates in Europe 
and the United States (Bellei et al. 2012). T cell lymphomas represent approximately 3% to 4% 
of all haematological malignancies and 10% to 20% of non-Hodgkin lymphomas (NHL) 
(Ascani et al. 1997) and (Anderson et al. 1998). While T cell lymphoma is the smaller subset 
of all lymphomas (e.g., compared to B cell lymphomas), this is an aggressive disease with a 
very poor prognosis for T cell lymphoma patients. In the United Kingdom, there are about 650 
T cell lymphoma cases expected per annum and the incidence rates have shown modest 
increases in the past decades (NICE 2016). The first line treatment for the more common T cell 
lymphoma subtypes, i.e. peripheral T cell lymphoma, peripheral T cell lymphoma not 
otherwise specified (NOS) and angioimmunoblastic T cell lymphoma, consists of combination 
chemotherapy, such as cyclophosphamide, doxorubicin, vincristine and prednisolone, but is 
not without toxicity concerns. Little is understood in terms of treatment guidance for the lesser 
T cell subtypes and they remain without clear treatment guidelines. A large proportion of T 
cell lymphoma patients are refractory to or relapse following standard therapies and there 
remains a requirement to develop an effective therapy for this unmet need. 
Unlike B cell lymphomas, patients with T cell lymphomas have not benefited from advances 
in immunotherapeutic approaches such as BiTE or CAR T cell therapies. This is mainly due to 
the lack of therapeutic development in T cell lymphomas to identify a suitable target antigen(s) 
to discriminate malignant T cells from normal T cells. While a similar problem exists with B 

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cell lymphomas, targeting a pan B cell antigen is an acceptable strategy, as the concomitant 
depletion of the normal B cell compartment is well tolerated and certain targeted approaches 
may be ameliorated via the i.v. administration of immunoglobulin. In contrast, targeting a pan 
T cell antigen would result in severe immunosuppression, where there is currently no available 
rescue medication. Autolus has developed an innovative ATIMP, AUTO4, which uses a novel 
targeting approach to attempt to address this issue. 
1.2. 
T CELL RECEPTOR BETA CONSTANT 1 AS A TARGET FOR 
THERAPY 
During T cell development, each T cell generates a unique T cell receptor by rearrangement of 
the alpha and beta chains. Each beta chain also includes a constant domain which is not 
involved in antigen recognition. A facet of TCR gene-rearrangement is that the coding 
sequence for the T cell receptor beta constant region is duplicated (TRBC1 and TRBC2) 
(Maciocia et al. 2016). Hence, in a manner analogous to antibody light chain selection, a mature 
T cell is highly likely to express either TRBC1 or TRBC2. Normal T cells (including T cell 
subsets) comprise a mixture of T cells (approximately 40%, 60% mix) individually expressing 
either TRBC1 or TRBC2. Natural immunity including antiviral immunity is also distributed 
across the 2 populations. T cell lymphomas on the other hand are clonal tumours and are either 
entirely TRBC1 or TRBC2 positive. 
With this present study, Autolus plans to recruit patients with the most common T cell 
lymphomas that are also TRBC1 positive. 
Patients will receive autologous CAR T cells directed to TRBC1. These CAR T cells will target 
the lymphoma in its entirety as well as a proportion of normal T cells (i.e. those which are 
TRBC1 T cells). It is hypothesised untargeted (TRBC2) normal T cells will constitute sufficient 
immunity to protect the patient from opportunistic infections. 
1.3. 
CLINICAL EXPERIENCE WITH CAR T THERAPIES IN T 
CELL LYMPHOMA 
To date, clinical experience with CAR-T therapy in NHL has mainly been limited to B cell 
lymphomas and there is little clinical experience with CAR T therapies in T cell lymphomas. 
One recent Phase 1 study with preliminary data demonstrated a tolerable safety profile and 
promising clinical efficacy with a first-in-class autologous CD7-CAR-T cell product in 
relapsed and refractory T-Lymphoblastic Leukemia/Lymphoma (Zhang et al 2020). In B cell 
lymphomas, several clinical trials have been initiated targeting CD19 demonstrating efficacy 
with overall response rate (ORR) ranging from 50% to 86% (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. The major toxicities observed after CD19 
CAR positive T cell transfusion are B cell depletion, cytokine release syndrome (CRS) and 
neurotoxicity. Management of CRS has significantly improved with the use of guidelines and 
early use of tocilizumab. Neurotoxicity is the most challenging clinical problem. Close 
monitoring, use of steroids and other immunosuppressants have improved the management of 
neurotoxicity; however, further improvements are still needed (Brudno and Kochenderfer 
2016). 

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CAR T immunotherapy for B cell malignancies typically targets pan B cell antigens, resulting 
in B cell aplasia. However, similar approaches of targeting pan T cell antigens resulting in 
elimination of malignant and non-malignant T cells is challenging as T cell aplasia will result 
in significant morbidity and mortality, necessitating an allogenic stem cell transplantation. 
Considering the significant unmet need in these patients and in the absence of truly 
tumour-specific targets applicable to a high proportion of patients, the alternate approach of 
targeting an antigen expressed in normal T cells followed by allogenic stem cell transplantation 
is considered a viable option. Pre-clinical studies using an anti-CD5 CAR have shown select 
killing of CD5+ T cell targets both in vitro and in vivo (Mamonkin et al. 2015). A clinical trial 
using anti-CD5 CAR T cells is listed on clinicaltrials.gov, but to date has yet to start recruitment 
(NCT03081910). As expected, this study only recruits patients suitable for consideration for 
allogeneic hematopoietic stem cell transplantation (HSCT) with an identified donor, contingent 
on entering remission. 
An alternate approach is using CAR T cells to target CD4, which is expressed on approximately 
40% of cases of peripheral T cell lymphoma (PTCL) or T cell acute lymphoblastic leukemia 
(T-ALL) as well the majority of peripheral T cells. Whilst pre-clinical studies have 
demonstrated CD4 CAR T mediated killing of CD4+ tumour (Pinz et al. 2016), this approach 
will also lead to aplasia of the entire CD4+ compartment likely compromising normal T cell 
immunity necessitating an allogeneic HSCT. Another approach targets the pan-T cell antigen 
CD3 with chimeric antigen receptors (Chen et al. 2016), but utilises natural killer cells as the 
effector population. Efficacy was shown in vitro and in vivo against cell lines and primary 
tumour cells187 but again the disadvantage of this approach would be complete T cell aplasia, 
necessitating rescue transplant. 
The proposed approach with AUTO4 would not necessitate a rescue transplant as it would only 
result in partial depletion of the normal T cell compartment and preservation of natural 
immunity (Brudno and Kochenderfer 2016) 
1.4. 
DESCRIPTION OF AUTO4 – RQR8/ANTI-TRBC1 CAR 
POSITIVE T CELLS 
The AUTO4 therapeutic comprises of enriched autologous T cells retrovirally transduced to 
express an anti-TRBC1 specific CAR, as well as the safety switch RQR8. The active substance, 
which consists of the genetically modified T cells, will be referred to as RQR8/aTRBC1-CAR 
positive T cells. AUTO4 also contains non-transduced autologous lymphocytes. This is a 
second-generation CAR which has a 41BB-CD3ζ endodomain. The retroviral cassette co-
expresses the RQR8 safety switch with the CAR. RQR8 expression renders the T cells 
susceptible to rituximab-mediated depletion of AUTO4. A schematic representation of the 
transgenic expression of AUTO4 is provided in Figure 1. 

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1.5. 
SUMMARY OF NONCLINICAL STUDIES 
Further details regarding AUTO4 nonclinical studies can be found in the IB. A package of 
nonclinical work has been completed that demonstrates the in vitro and in vivo specificity and 
potency of AUTO4 to target TRBC1-expressing cells. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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The in vivo function of the RQR8 safety switch has previously been demonstrated using a 
mouse model (Bellei et al. 2012). Additionally, the functionality of RQR8 combined with the 
TRBC1-CAR has been demonstrated in vitro. 
In summary, it has been demonstrated both in vitro and in vivo that AUTO4 aTRBC1-CAR 
positive T cells can effectively eliminate TRBC1-expressing tumour cells. Nonclinical studies 
suggest that no off-target toxicity is anticipated. 
1.5.1. 
Estimating Safety Concerns of Targeting T Cells 
Comparing the cellular distribution and frequency of B cells and T cells may help estimate the 
relative potential for on-target off-tumour toxicities due to cytolysis of the normal cell 
population. The distribution of T cells and B cells within human organs is generally similar. 
The major distribution of both T and B cells is located within most lymphoid organs (lymph 
nodes, spleen, tonsils, thymus, bone marrow and lymphoid-associated tissue). T and B cells are 
also abundant in the blood, as well as part of the cellular infiltrate of multiple organs such as 
heart, lung, liver, various glandular tissue, and reproductive tissues. 
The tissue cross reactivity studies have noted T cell, but not B cell, distribution in the cerebral 
cortex of the brain, blood vessels, kidney, pituitary gland, placenta, skeletal muscle, skin, testes 
and thyroid. Neither B nor T cells were found in the cerebellum of the brain, spinal cord, eye 
and nerve. A comparison of the relative numbers of T and B cells from normal tissues has been 
made (Sathaliyawala et al. 2013). The frequency of B and T cells from blood and eight different 
healthy tissues, including multiple lymphoid tissues (spleen, inguinal, mesenteric and 
bronchial/lung-draining lymph nodes) and mucosal tissues including the lung, small intestine 
regions (jejunum, ileum) and colon tissues (blood, spleen, inguinal lymph node) was compared. 
The frequency of T cells outnumbered B cells in all sites except the spleen - by 2 to 4-fold in 
blood and LNs, 5 to 8-fold in ileum and colon and >15 to 20-fold in the lung and jejunum. A 
similar number of B and T cells were found in the spleen. In summary, whilst there is a slightly 
higher cellular distribution of T cells across major organs, the frequency of T cells distribution 
within some organs and blood are significantly higher compared to B cells. Whilst targeting 
TRBC1 cells will only ablate approximately one-third of normal T cells, there is likely to be 
more cytolysis of normal T cells within the lung and jejunum compared to targeting B cells. 
However, a significant number of these cells would have been depleted by the pre-conditioning 
chemotherapy. 
An additional observations is the target antigen density on normal cells, the antigen density of 
TCR is about 100,000 copies per T cell, (Schodin BA et al., 1996) which is 5 times higher than 
the antigen density of CD19 on B cells. However, the CAR T cell response against target cell 
as well as the production of interleukin 2 (IL-2), interferon-g (IFN-) and granzyme-b follows 
a sigmoid curve, and higher antigen density is likely to generate a saturated response (Nguyen 
S et al., 2016). 
Considering the current experience with CD19 CARs in acute lymphoblastic leukaemia (ALL), 
diffuse large B-cell lymphoma and chronic lymphocytic leukaemia involving patients with 
significant amounts of antigen-positive disease in various organs, including brain, the acute 
toxicity is unlikely to be significantly worse than that observed with CD19 CARs and, most 
probably manageable with current safety management guidelines. In addition, starting at a low 
CAR T cell dose is likely to add to the safety. 

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1.6. 
SUMMARY OF CLINICAL STUDIES WITH AUTO4 
The current study is a first-in-human (FIH) study of the ATIMP, AUTO4, in patients with T 
cell non-Hodgkin lymphoma (T-NHL). Therefore, no clinical experience is available at the 
time of the initial application. 
1.7. 
OVERALL RATIONALE FOR THE STUDY 
Outcomes for patients with T cell lymphoma are generally poor. The patients relapsing after 
one line of therapy or those with refractory disease have worse outcome and the disease remains 
incurable with the currently established therapy modalities. A considerable number of T cell 
lymphoma 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 T cell lymphoma. CD19 
CAR positive T cells in clinical development for the treatment of B cell lymphoma have 
demonstrated significant efficacy in clinical trials. Similar approaches of pan T cell depletion 
are not possible for T cell malignancies, as survival without T cells is likely to be poor. 
Selective depletion of only TRBC1 positive T cells offers a unique way to address this issue 
without making the patient T cell aplastic or compromising patients’ T cell immunity. AUTO4 
offers the potential to provide a therapeutic option for patients with different T cell lymphomas 
that are TRBC1 positive. 
Further, AUTO4 has also been engineered to be effective and safe with the incorporation of 
both 41BB-ζ co-stimulatory signals and incorporation of a RQR8 safety switch, which would 
allow for selective depletion of AUTO4 if necessary. Additionally, the storage of unprocessed 
apheresate (where possible at the site) as backup, to be used for immune re-constitution if 
necessary also adds to the safety of the current trial. This FIH, Phase I/II study will assess the 
safety and efficacy of AUTO4, in patients with relapsed or refractory select T cell lymphoma. 
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 1 
and Table 2, respectively. 
Table 1: 
Primary Objectives and Endpoints for Phase I 
Objectives 
Endpoints 
To assess the safety and tolerability of AUTO4 
administration.  
Incidence of Grade 3 to 5 toxicity occurring within 
60 days of AUTO4 infusion. 
To identify the RP2D and MTD, if an MTD exists, 
of AUTO4. 
Frequency of DLT of AUTO4 within 28 days of 
AUTO4 infusion. 
DLT = dose limiting toxicity; MTD = maximum tolerated dose; RP2D = recommended Phase II dose 
Table 2: 
Primary Objectives and Endpoints for Phase II 
Objectives 
Endpoints 
To assess the clinical activity of AUTO4 when 
administered at the RP2D 
Overall response (CR+PR) rate post AUTO4 
infusion  
CR = complete response; PR = partial response 

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2.2. 
SECONDARY OBJECTIVES AND ENDPOINTS 
Secondary objectives and endpoints are presented in Table 3. 
Table 3: 
Secondary Objectives and Endpoints for Phase I and II 
Objectives 
Endpoints 
To assess the overall safety and tolerability of 
AUTO4.  
Frequency and severity of all AEs and SAEs  
Incidence and severity of opportunistic infections 
following AUTO4 infusion. 
To evaluate the feasibility of generating the 
ATIMP, AUTO4. 
Proportion of patients (who are TRBC1 positive and 
undergo leukapheresis), for whom an AUTO4 product can 
be generated (feasibility). 
To evaluate the overall clinical efficacy of 
AUTO4. 
Determine the CR rate following treatment with AUTO4. 
Evaluate clinical outcomes including DOR, DFS, PFS, 
OS, time to response (CR or PR) and time to CR. 
To determine the expansion and persistence of 
AUTO4 following infusion. 
 
Duration of TRBC1 positive T cell aplasia. 
RQR8/aTRBC1-CAR positive T cells as determined by 
PCR and/or flow cytometry at a range of time points in the 
peripheral blood.  
Enumeration of circulating TRBC1 positive T 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; DFS = disease 
free survival; DOR = duration of response; PCR = polymerase chain reaction: OS = overall survival; PFS = progression free 
survival; PR = partial response; SAE = serious adverse event; TRBC = T cell receptor beta constant. 
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 assess the duration of depletion of circulating TRBC1 positive T 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 AUTO4. 
• To characterise the relationship between the CAR T cell phenotype/genomics and 
persistence. 
• To investigate if there is a relationship between parameters of activity, percent TRBC1 
positive T cells, level of TRBC1 expression on tumour cells and CAR T cell phenotype. 
• To investigate if there is a relationship between incidence and severity of CRS, 
neurotoxicity or other toxicity, and tumour burden, percent TRBC1 positive T cells, 
level of TRBC1 expression on tumour cells pre-treatment and CAR T cell phenotype. 
3. 
STUDY DESIGN 
3.1. 
STUDY OVERVIEW 
This multi-centre, single-arm study will consist of two parts, a Phase I/dose escalation phase 
and a Phase II/dose expansion phase: 

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• Phase I: Dose escalation, using a rolling six design to identify the RP2D (optimal) dose 
of AUTO4. The following doses are intended to be evaluated, but are subject to 
emerging safety data: 25 x 106, 75 x 106*, 225 x 106*, 450 x 106 and 900 x 106 
RQR8/aTRBC1-CAR positive T cells, administered as a single dose.  
• Phase I: Dose escalation with Process B, using a rolling six design to identify the 
RP2D (optimal) dose of AUTO4. The following doses are intended to be evaluated, but 
are subject to emerging safety data: 225 x 106*, 450 x 106 and 900 x 106 
RQR8/aTRBC1-CAR positive T cells, administered as a single dose. Drug product 
manufactured using an optimized process that can consistently meet the required dose 
(Process B) will be used to support these cohorts. A summary of proposed changes is 
provided in Section 7.2.  
*Cohort 2 (75 x 106) and 3/3b (225 x 106) should have at least 1 patient for the dose escalation decision. In this case, 
any potential single patient cohort would be expanded to n=3-6 (per rolling six study design), if at least 1 patient 
experiences any level of CAR T-cell expansion (above the limit of detection) or Grade ≥ 1 CRS/Neurotoxicity or ≥ 
Grade 2 AUTO4-related AE in the first 28 days after AUTO4 infusion. The inter-patient interval between patients 
in 2 different dose level cohorts can not be less than 28 days from AUTO4 infusion of the previous patients to the 
start of the lymphodepletion of the next patient (the Safety Evaluation Committee (SEC) will meet after the first 
patient in every cohort completes 28 days). 
• Phase II: Dose expansion to assess anti-lymphoma activity and safety at the RP2D 
using AUTO4 Process B product. 
An overview of the study design is presented in Figure 2 below. 
Figure 2: 
Proposed Dose Escalation and Dose Expansion Phases 
 
 
**At least 3 patients must be treated per cohort from Cohort 4 onwards (per rolling six study design),  Subsequent dose 
increase/dose level (Cohort 5) to be determined based on the available safety-, pharmacokinetic-, pharmacodynamic-data and 
manufacturing feasibility. 

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CAR = chimeric antigen receptor; CY = cyclophosphamide; DLT = dose-limiting toxicity; FLU = fludarabine; MTD = 
Maximum Tolerated Dose; RQR8/aTRBC1 = Ritux QBEnd/10-Ritux-cluster of differentiation 8 sort-suicide gene/anti-T cell 
receptor beta 1; tbd = to be determined. 
The study consists of two phases – Phase I (dose escalation and RP2D), followed by Phase II 
(dose expansion, efficacy and safety). Each patient (irrespective of phase) will go through the 
following five stages: 
• Screening stage: There are two separate Informed Consent Forms (ICFs) during the 
screening stage – ICF Part A and ICF Part B. After providing written informed consent 
(ICF Part A) to enter the screening process to determine the TRBC1 status, patients will 
be screened for preliminary study eligibility, demographic details, and the provision of 
an archival tumour tissue sample or a newly acquired tumour tissue sample. 
• Once a patient is confirmed as TRBC1 positive, the patient will be asked to consent to 
the main study (ICF Part B). All the remaining screening activities, including the 
baseline disease assessment, will occur at Screen 1 and Screen 2 – see the Schedule of 
Assessments for details. Only patients who are identified as TRBC1 positive, and 
otherwise eligible, will proceed to leukapheresis. 
• Leukapheresis: Eligible patients that are TRBC1 positive will undergo leukapheresis 
to facilitate manufacture of the ATIMP, AUTO4.  
• Pre-conditioning: If sufficient AUTO4 is successfully manufactured and released, and 
the patient continues to meet eligibility requirements for the study, the patient will 
proceed to receive a lymphodepleting pre-conditioning treatment with FLU for 4 days 
and CY for 2 days, to end 3 days (-1 day) before AUTO4 infusion. 
• Treatment stage: AUTO4 will be administered i.v. as a single infusion on Day 0. 
• Follow-up stage: The follow-up stage will begin after AUTO4 administration and end 
24 months (104 weeks) after the infusion of the last patient with AUTO4 or at their 
disease progression or withdrawal of consent, which ever happens first. For patients 
who experienced disease progression post AUTO4 infusion before the End of Study 
and those still in CR 24-months post infusion please see the Schedule of Assessments 
and Section 8.5.2 for their follow-up schedule. An End of Study visit will be conducted 
for all patients. 
An overview of the five study stages is presented in Figure 3. 
Figure 3: 
Overview of the Stages of the Study 
 
 
From signing of informed consent (ICF Part A) until the End of Study visit, information 
relating to adverse events (AEs), laboratory abnormalities, disease response and biomarker 
changes will be collected according to the Schedule of Assessments. 
All AUTO4-treated patients will be eligible for enrolment into a long-term follow-up protocol 
(AUTO-LT1) at the end of the study (see Section 15). The patients will be followed for safety 

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evaluation and survival for 15 years from the AUTO4 infusion or until death or withdrawal of 
consent, whichever happens first.  
3.2. 
PHASE I DOSE ESCALATION RULES AND ROLLING SIX 
DESIGN 
Phase I is designed to determine the RP2D of AUTO4 in patients with selected T-NHL. Each 
dose level may treat up to six patients and is based on total RQR8/aTRBC1-CAR positive 
T cells. Escalation to the next dose level requires the evaluation of a dose level with at least 
three patients treated at the planned dose level and completing the 28-day DLT evaluation 
period. The dose escalation decision rules are outlined in Table 4. 
Patient entry at a given dose level will follow a rolling six design which will enable patients to 
continue to be enrolled at a given dose level up to a maximum of six patients.  
The trial is intended to consist of five dose levels (Figure 2); however, the dose levels may be 
adjusted depending on emerging safety data. Eligible patients will be assigned to dose groups 
sequentially. The inter-patient dosing interval for AUTO4 in Phase I will be 4 weeks between 
the first and second patient and 2 weeks between subsequent patients (measured from infusion 
of AUTO4 in one patient to start of pre-conditioning in the next patient), to allow for 
assessment of possible toxicity, until a dose level is declared safe.  
Patients will be admitted to hospital for at least 14 days (or longer) for monitoring after 
receiving AUTO4 or until all AUTO4-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 the dose of AUTO4. 
The Safety Evaluation Committee (SEC) will meet after the first patient in every cohort 
completes 28 days, to confirm continuation of enrolment to that cohort and thereafter meet 
again after the third and or sixth patient in a cohort has completed the DLT assessment period. 
For Cohorts 2 (75 x 106 cells) and 3/3b (225 x 106 cells) if there is no CAR-T expansion (eg no 
expansion is observed above the assay limit of detection threshold) in any of the patients treated 
(with at least one patient treated at that dose), together with no Grade ≥ 1 CRS/Neurotoxicity 
or ≥ Grade 2 AUTO4-related adverse events in the DLT period (first 28 days after AUTO4 
infusion) SEC may then meet to determine if that dose level can be declared safe and to escalate 
to the next level. If any CAR-T expansion level is seen in the potential single patient cohorts 
(Cohort 2 and 3) the cohort must be expanded and have a minimum of 3 patients treated to be 
considered complete (per rolling six study design). From cohort 4 (450 x 106 cells) onwards, 
the standard rolling six design will apply with a minimum of 3 patients treated per cohort.  
Only after a cohort is declared safe by the SEC can the next higher dose level be opened. 
Enrolment to a cohort (maximum n=6 evaluable patients/cohort) that has already been declared 
safe may be undertaken in parallel to the ongoing enrolment of a higher dose level, to enable 
the treatment of a patient who would not otherwise be treated (for example, a patient with 
manufactured product who is unable to wait until a slot is available in the higher dose cohort 
due to rapid disease progression). In this situation, a minimum dosing interval of 7 days will 
be maintained between patients - even if they are enrolled to a cohort that is declared safe in 
the Phase I part of the study. 
The starting dose level will be 25 x 106 RQR8/aTRBC1-CAR positive T cells (Table 4) and if 
this dose is declared safe then the second cohort will receive 75 x 106 RQR8/aTRBC1-CAR 
positive T cells. Dose escalation may continue until the planned maximum administered dose 
(MAD) of 900 x 106 RQR8/aTRBC1-CAR positive T cells is reached. A dose lower than 

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planned MAD (or 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 the 75 x 106 RQR8/aTRBC1-CAR positive T cell dose is declared as RP2D then Phase II 
can be opened and in parallel further evaluation of Phase I dose escalation may be continued 
to determine a second (higher) RP2D dose and or schedule. Should there be a need to assess 
more than one RP2D in Phase II then this will be undertaken only after a protocol amendment.    
If patients are treated below the planned dose due to AUTO4 manufacturing limitations 
(outside the ± 20% window) 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 x 106 RQR8/aTRBC1-CAR positive 
T cells. All patients will be evaluated for efficacy. 
Table 4: 
Dose Escalation Decision Rules 
Number of Patients with DLT at a Given Dose 
Level 
Escalation Decision Rule 
Zero out of three (where all three patients have been 
followed for the 28-day DLT period) 
For Cohorts with less than 3 patients (specifically 
Cohort 2 and 3):    
• 
zero treated have a DLT   
• 
zero Grade ≥ 1 CRS/Neurotoxicity or ≥ 
Grade 2 AUTO4-related adverse events in 
the first 28 days after AUTO4 infusion 
Escalate to the next dose level. Or per sponsor 
decision enrol three additional patients at the current 
dose level for a total of six patients to further 
explore safety and efficacy. 
For Cohorts with less than 3 patients (specifically 
Cohort 2 and 3):    
Escalate to the next dose level. Or per sponsor 
decision, enrol two additional patients (to have a 
total of 3) at the current dose level or a total of six 
patients to further explore safety and efficacy. 
One out of three (irrespective of whether all three 
patients have completed the 28-day DLT period)  
Continue to enrol three additional patients at the 
current dose level for a total of six patients. 
One out of six (where all six patients have 
completed the 28-day DLT period) 
Escalate to the next dose level or an intermediate 
dose level. 
Two or more patients in a dosing cohort (up to 
six patients)  
The MTD has been exceeded. Either:  
• 
Evaluate a dose lower than the current dose 
(following a substantial protocol amendment).  
• 
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. 
3.3. 
PLANNED DOSE LEVELS 
The planned  dose levels are presented in Table 5 and Table 6. These dose levels were selected 
as they provide an optimum range for assessing safety, CAR T cell persistence and anti-tumour 
activity. This range is within the dose levels assessed in other CAR T studies. Based on 
emerging data, intermediate or additional dose levels may also be explored as described above.  
The Phase I dose escalation phase was intended to consist of five dose levels (Table 5) before 
the change in the manufacturing process. After the change to Process B, considering the 
preliminary safety results of tested lower doses with the initial manufacturing process, the two 

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lowest dose levels (Level 1 and 2) are skipped and three dose levels are planned in this amended 
Phase I study with Process B: Level 3b (225 x 106 cells), Level 4b (450 x 106 cells) and Level 
5b (900 x106 cells) (Table 6).  
Table 5: 
Phase I Planned Dose Levels and Treatment Cohorts 
Dose Levels  
Treatment 
Cohorts 
Pre-conditioning (Flu 
& CY; Days -6, -5, -4, 
-3 [-1 day]) 
Total RQR8/aTRBC1-
CAR Positive T Cells  
(Day 0) 
Number of Patients  
Dose Level 1 
Cohort 1 
Yes 
25 x 10
6 
3 treated 
Dose Level 2 
Cohort 2 
Yes 
75 x 10
6 
1-6* 
Dose Level 3 
Cohort 3 
Yes 
225 x 10
6 
1-6* 
Dose Level 4 
Cohort 4  
Yes 
450 x 10
6 
3-6 ** 
Dose Level 5 
Cohort 5  
Yes 
900 x 10
6 
3-6** 
CAR = chimeric antigen receptor; FLU-CY = fludarabine and cyclophosphamide; RQR8/aTRBC1 = Ritux QBEnd/10-
Ritux-cluster of differentiation 8 sort-suicide gene/anti-T cell receptor beta 1.  
* For Cohorts 2 (75 x 106 cells) and 3 (225 x 106 cells) if there is no CAR-T expansion in any of the patients treated (with at 
least one patient treated at that dose) together with no Grade ≥ 1 CRS/Neurotoxicity or ≥ Grade 2 AUTO4-related adverse 
events in the first 28 days after AUTO4 infusion, SEC may approve escalation to next level. If any CAR-T expansion (above 
the assay limit of detection) is seen the cohort must have a minimum of 3 patients treated to be considered complete (per 
rolling six study design)  
** From Cohort 4 (450 x 106 cells) onwards, standard rolling six design will apply with a minimum of 3 patients treated per 
cohort. Cohort is expanded from 3 to 6 patients when 1 patient has a DLT. 
Table 6: 
Phase I (with Process B) Planned Dose Levels and Treatment Cohorts 
Dose Levels  
Treatment 
Cohorts 
Pre-conditioning (Flu 
& CY; Days -6, -5, -4, 
-3 [-1 day]) 
Total RQR8/aTRBC1-
CAR Positive T Cells  
(Day 0) 
Number of Patients  
Dose Level 3 
Cohort 3b 
Yes 
225 x 10
6 
1-6* 
Dose Level 4 
Cohort 4b  
Yes 
450 x 10
6 
3-6 ** 
Dose Level 5 
Cohort 5b  
Yes 
900 x 10
6 
3-6 ** 
 
* For Cohort 3b (225 x 106 cells) if there is no CAR-T expansion in any of the patients treated (with at least one patient 
treated at that dose) together with no Grade ≥ 1 CRS/Neurotoxicity or ≥ Grade 2 AUTO4-related adverse events in the first 
28 days after AUTO4 infusion, the SEC may approve escalation to the next level. If any CAR-T expansion (above the assay 
limit of detection) is seen, the cohort must have a minimum of 3 patients treated to be considered complete (per rolling six 
study design)  
** For Cohort 4b (450 x 106 cells), the standard rolling six design will apply with a minimum of 3 patients treated per 
cohort. The cohort is expanded from 3 to 6 patients when 1 patient has a DLT. 
 
Note: The dose determination is based solely upon the genetically modified cells 
(i.e. RQR8/aTRBC1-CAR positive T cells). A patient may be evaluable for a planned dose 
level if the dose is within ±20% of the prescribed RQR8/aTRBC1-CAR positive T cells dose. 
• On occasion, AUTO4 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 x 106 
(approximately 
0.2 x 106/kg 
RQR8/aTRBC1-CAR positive T cells), then the patient will not be treated on the study. 
Only patients treated at the planned dose level will be evaluable for dose escalation 

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decision making and primary efficacy analysis. Additional patients will be treated to 
meet the minimum number of patients needed to make the dose escalation decision. 
• If emerging data suggest that escalation to an intermediate dose which is a lower than 
the planned dose is appropriate, then such an intermediate dose escalation can be 
undertaken. The total number of patients in 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 x 106 RQR8/aTRBC1-CAR T cells will not be undertaken 
without a protocol amendment.  
3.4. 
PHASE II DOSE EXPANSION 
Once the RP2D is determined, the Phase II dose expansion part of the study will open. This 
part will recruit and treat up to 30 patients with AUTO4 Process B product at the RP2D. There 
is no mandated inter-patient dosing interval in this phase. 
3.5. 
DOSE LIMITING TOXICITY 
Toxicities will be graded for severity according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0, with the exception of 
neurotoxicity, which will be assessed according to the American Society for Transplantation 
and Cellular Therapy (ASTCT)/American Society for Blood and Marrow Transplantation 
(ASBMT) Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) grading 
criteria. The DLT criteria take into consideration the single dose nature of AUTO4 treatment 
(unlike repeat dose treatments of usual anti-cancer agents), the potential for differential 
expansion of CARs post infusion in different patients and the inclusion of consolidation 
therapy. As well as features inherent to CAR therapy, transient fever due to low grade CRS, 
and in the setting of pre-conditioning, induced cytopenias/neutropenia are seen in most 
patients. These are not necessarily classical neutropenic fevers resulting from infection. 
The DLT evaluation period will be 28 days after the infusion of AUTO4. 
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 AUTO4 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. 
• Any other fatal adverse reaction (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. Efforts should be made to perform an autopsy in case 
of a fatal event where the aetiology is unclear. 
• Any reason for activation of the safety switch after receiving AUTO4. 
• Any event that in the opinion of treating investigators and/or Medical Monitor puts the 
patient at undue risk may also be considered a DLT 

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Reporting Requirements for DLT 
All DLTs must be reported to the Sponsor as 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 the 
Independent Data Monitoring Committee (IDMC).  
Maximum Tolerated Dose: The MTD is defined as the highest dose level of AUTO4 at which 
≤one patient out of six patients experiences 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 x 106 
RQR8/aTRBC1-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 is the optimal dose and will be either identical to 
the MTD or MAD (or a lower dose), selected on the basis of a cumulative review of safety, 
persistence of the CAR T cells and clinical activity. The RP2D dose level may be expanded to 
up to six patients to further characterise safety. 
3.6. 
SAFETY STOPPING CRITERIA FOR THE CLINICAL TRIAL 
Phase I 
The Phase I portion of the study may be paused after review and recommendation from the 
SEC or the IDMC if any of the following SAEs, not related to disease progression, occur 
within 28 days post-AUTO4 infusion: 
• Unexpected and related SAEs that exposed patients participating in the study to 
unacceptable risk of harm (class-related toxicities such as CRS and neurotoxicities will 
not automatically result in stopping unless patients are exposed to risk above what is 
generally seen with similar therapies). 
• Uncontrolled SAEs related to identified risks (see Section 5). 
• The occurrence of Grade 4 toxicity in three patients related to AUTO4 that is 
unmanageable (i.e., lasting more than 7 days despite the implementation of appropriate 
management).  
The Phase I portion of the study may be paused after review and recommendation from the 
SEC or the IDMC in the event of:  
• Death of a patient at any time after therapy that is at least possibly related to CAR T 
cell therapy. 
• The occurrence of a second malignancy at any point after therapy that is at least possibly 
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 relevant regulatory 
authorities and ethics committees. 

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Phase II 
As part of its continuous oversight, the SEC and/or the IDMC may pause study enrolment after 
15 patients treated in the Phase II portion of the study are followed for at least 28 days after 
AUTO4 infusion. Enrolment may be paused after IDMC recommendation if any of the 
following SAEs, not related to disease progression, occur within 28 days following AUTO4 
infusion: 
• Life-threatening (Grade 4) non-hematological toxicity related to AUTO4 therapy 
observed in ≥ 5 of 15 patients and that is either unexpected (i.e., toxicities not 
commonly recognized as CAR T-related) or  
• unmanageable (i.e., lasting more than 7 days despite the implementation of appropriate 
management).  
3.7. 
STUDY DURATION 
The total study duration is estimated to be 7 years from first patient enrolled to the last patient 
last visit (24month visit). The end of the study (EoS) is defined as LPLV and is expected to be 
24 months after the last patient has received AUTO4 infusion (or earlier in the event of patient 
death, study closure by the Sponsor or consent withdrawal). 
In the event of disease progression prior to the EoS, patients will continue to be monitored for 
safety and survival under this study protocol in order to collect health authority requested data 
(e.g. delayed AEs) until the end of the study. The survival follow-up can be conducted via 
telephone contact if necessary. At Study Closure/End of the Study, all patients who have 
received AUTO4 will be eligible to enrol in a separate long-term follow-up study protocol 
(separate informed consent will be provided for this protocol; Section 8.5). All patients will 
undergo semi-annual and annual evaluations for up to 15 years following AUTO4 infusion as 
recommended by health authority guidance for patients treated with such gene therapies. 
3.8. 
NUMBER OF PATIENTS 
Approximately 200 patients in total are expected to be screened for eligibility for entry to this 
study. This assumes that approximately 35% of patients are identified as TRBC1 positive (and 
assumes that a small number of patients will not provide sufficient evaluable tissue). Of those 
that are identified as TRBC1 positive, it is assumed that a further approximate 20% will fail 
the AUTO4 manufacture and/or will not continue to meet the inclusion and exclusion entry 
criteria. Up to 73 patients in total are anticipated to be treated with AUTO4 therapy.  
• Phase I: Dose escalation involving up to a total of 25 patients (up to six patients per 
dose cohort and five cohorts). 
• Phase I: Dose escalation with Process B involving up to a total of 18 patients. 
• Phase II: Dose expansion involving up to a total of 30 patients using AUTO4 Process 
B product.  
The sample size for Phase II of the study will follow Simon’s two-stage optimal design as 
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4. 
SCIENTIFIC RATIONALE FOR STUDY 
4.1. 
DESIGN RATIONALE 
This single-arm, multi-centre, open-label, dose-escalation Phase I/II study is designed to assess 
safety, tolerability, and RP2D and MTD, if a MTD exists, for AUTO4. A cautious dose 
escalation design encompassing three dose levels is considered appropriate. As these patients 
are expected to be relatively uncommon and may have rapid disease progression, a rolling six 
dose escalation design in Phase I of the study has been chosen. This will enable continued 
enrolment of patients even if not all the previously dosed patients (usually three) at the current 
dose level have been followed for the 28-day DLT period. 
A dose escalation with ≤half log increase over the previous dose is appropriate considering the 
in vivo expansion of the CAR T cells. CAR T studies in B cell lymphoma have used half-
log/300% (Brudno and Kochenderfer 2016) to a log/1000% (Turtle et al. 2016) increase in 
dose. The proposed dose levels between 25x 106 and 900 x 106RQR8/aTRBC1-CAR positive 
T cells are conservative and designed to identify a safe and efficacious dose for Phase II of the 
study. The rationales for the starting dose levels and dosing schedule are outlined in detail in 
Sections 4.2.1 and 0.  
During Phase I, a minimum dosing interval of 4 weeks between the first and second patient, 
and thereafter 2 weeks between patients until the dose is declared safe, is incorporated to reduce 
the risk of inducing severe adverse effects in more than one patient. Additionally, 
hospitalisation for at least 14 days after AUTO4 infusion is designed to enable patient 
monitoring for safety. A DLT assessment window of 28 days is incorporated and is appropriate 
as the therapy involves a single dose of AUTO4 and the majority of toxicities with CAR T 
therapy occur within the first few weeks (Davila et al. 2014). Considering the extensive clinical 
experience with these agents, this window is considered adequate.  
The rationale for Simon’s two-stage optimal design for the Phase II part of the study is to allow 
for the termination of the study at interim analysis after 10 patients if the true response rate is 
10% or less. The rationale for dosing up to 30 patients is to detect early signs of efficacy in 
addition to generating additional safety data at the RP2D. 
4.2. 
POPULATION RATIONALE 
Most patients with PTCL will either not achieve remission or will relapse after first line 
therapy. Given the paucity of data and limited therapeutic options, participation in clinical trials 
is recommended (National Comprehensive Cancer Network PTCL Guidelines 2016). Most 
patients with relapsed or refractory PTCL have poor outcomes with short survival. In a study 
of 153 patients (Mak V et al, 2013) with PTCL-NOS, Angioimmunoblastic T cell lymphoma 
and Anaplastic large cell lymphoma (both ALK+ and ALK-); after relapse or progression in 
the absence of hematopoietic stem-cell transplantation, the median time from initial diagnosis 
to relapse or progression after first treatment was only 6.7 months. The median overall survival 
and median progression-free survival after relapse or progression were 5.5 and 3.1 months 
respectively. This was minimally improved in patients who received chemotherapy at relapse 
with median overall survival and median progression-free survival at 6.5 and 3.7 months 
respectively. For subsets like ALK-positive anaplastic large cell lymphoma (ALCL) with 
newer treatment options such as brentuximab, outcomes have shown incremental improvement 
(Pro et al. 2012), but overall the prognosis for most PTCL subtypes in the relapse or refractory 
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The study patient population for this study is TRBC1 positive selected T- cell lymphoma and 
will include the three most common sub-types of PTCL which are typically nodal and present 
with latestage disease and have similar clinical course and poor prognosis in the 
relapsed/refracted setting. These subtypes are:  
• 
Peripheral T cell lymphoma NOS  
• 
Angioimmunoblastic T cell lymphoma 
• 
Anaplastic large cell lymphoma 
4.2.1. 
Current Therapeutical Options for this Population and Rationale for 
Inclusion 
In the frontline setting most patients with PTCL are treated with multi-agent anthracycline 
based chemotherapy regimens such as cyclophosphamide-doxorubicin-oncovin (vincristine)-
prednisone (CHOP). A systematic meta-analysis evaluated CHOP or CHOP-like regimens in 
2815 patients with PTCL. The CR rates associated with anthracycline-based regimens ranged 
from 30% to 76% across studies and subtypes of PTCL. As expected, ALCL showed a higher 
complete response (CR) rate with anthracycline-based chemotherapy than other T cell 
lymphomas; in patients with Angioimmunoblastic T cell lymphoma, a CR rate of 36% to 70% 
was seen and in patients with PTCL-NOS, 44% to 64% was observed. The 5-year overall 
survival (OS) was of 38.5% (Abouyabis et al. 2011). Autologous hematopoietic cell 
transplantation is incorporated into the initial treatment of patients with PTCL as consolidation 
therapy after initial combination chemotherapy. 
Most patients with PTCL will however either not achieve remission or will relapse after first 
line therapy (Dreyling et al. 2013). Given the paucity of data and limited therapeutic options, 
participation in clinical trials is recommended (National Comprehensive Cancer Network 
PTCL Guidelines 2016, ESMO consensus guidelines). Most patients with relapsed or 
refractory PTCL have poor outcomes with short survival. In a study of 153 patients (Mak et al. 
2013) with PTCL-NOS, Angioimmunoblastic T cell lymphoma and Anaplastic large cell 
lymphoma (both ALK+ and ALK-) and in the absence of hematopoietic stem-cell 
transplantation, the median time from initial diagnosis to relapse or progression after first 
treatment was only 6.7 months. The median overall survival and median progression-free 
survival after relapse or progression were 5.5 and 3.1 months respectively. This was minimally 
improved in patients who received chemotherapy at relapse with median overall survival and 
median progression-free survival at 6.5 and 3.7 months respectively. For subsets such as 
ALCL, with newer treatment options such as brentuximab, outcomes have shown incremental 
improvement (Pro et al. 2012), but overall the prognosis for most PTCL subtypes in the relapse 
or refractory setting remains poor. 
Conventional platinum-based regimens such as DHAP, ESHAP or ICE, as used in the larger 
Diffuse Large B Cell lymphoma population, are used in patients with relapsed PTCL especially 
those who are transplant candidates. The efficacy of these regimens in PTCL is not well known 
as no large published study is available in these lymphomas. The Canadian Cancer Trials Group 
LY.12 Phase 3 trial included 59 patients with PTCL. Among these, 81% had advanced stage 
disease, and 41% were refractory to primary therapy. The ORR after two cycles of salvage 
chemotherapy was 36%; no difference was observed between dexamethasone, cytarabine, 
cisplatin (33%), and gemcitabine, cisplatin, dexamethasone (38%) therapy. At one year, event-
free survival (EFS) was 16% and OS was 28% (Skamene et al. 2017). Patients who received 
autologous stem cell transplant (SCT), two-year EFS and OS were 21% and 42%, respectively. 

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Patients with PTCL had inferior OS and outcomes when compared to patients with B cell 
lymphomas. 
Newer agents are being evaluated and have shown some marginal efficacy in patients with 
relapsed PTCL. A single arm Phase 2 PROPEL study of pralatrexate evaluated 115 heavily 
pre-treated patients with the most common types of PTCL. In this study, the ORR was 29% 
with CR/CRu (complete response unconfirmed) of 11%; the median PFS and OS was 3.5 and 
14.5 months respectively. Responses were observed across all histologic subtypes, although 
patients with Angioimmunoblastic T cell lymphoma were less likely to respond than patients 
with other common PTCL subtypes (O'Connor et al. 2011). 
HDAC inhibitors such as belinostat and romidepsin have shown modest efficacy in patients 
with PTCL. In the single arm Phase 2 BELIEF study with belinostat, a total of 129 patients 
were enrolled, with a median of two prior systemic therapies. ORR and CR in the 120 evaluable 
patients was 26%, 11% respectively. Median duration of response was 13.6 months, whilst 
median PFS and OS were 1.6 and 7.9 months respectively (O'Connor et al. 2015). 
Similarly, in the single arm Phase 2 study of romidepsin, 130 patients with histologically 
confirmed PTCL who had relapsed or were refractory to least one prior therapy were treated. 
The ORR was 25% including 15% CR/CRu. The median duration of response was 17 months 
(Coiffier et al. 2012). 
For patients with CD30 positive Anaplastic large cell lymphoma, newer treatment options such 
as anti CD30 antibody drug conjugate brentuximab have shown incremental improvement in 
outcomes (Pro et al. 2012). In this Phase 2 study of 58 patients the ORR was 86% and 57% 
achieved a CR. The median durations of overall response and CR were 12.6 and 13.2 months, 
respectively.  
With exception of brentuximab, these newer agents are only approved by the Food and Drug 
Administration (FDA) and are not readily available elsewhere. 
Relapses in patients with PTCL are common; therefore, SCT as a consolidation and salvage 
strategy may improve therapeutic results. However, the role of SCT especially in relapsed 
PTCL remains to be determined and there is lack of prospective clinical trials. Some limited 
retrospective studies have evaluated the efficacy of autologous and allogeneic transplant in 
relapsed PTCL. For example, a longitudinal study of 241 patients with PTCL NOS, ALCL and 
angioimmunoblastic T cell lymphoma has shown that SCT is better in the earlier disease setting 
with chemo-sensitive disease when used as consolidation therapy at first CR (Smith 2013).  
4.3. 
STARTING DOSE RATIONALE 
A starting dose of 25 x 106 RQR8/aTRBC1-CAR positive T cells (single dose) for Phase I Dose 
Escalation is proposed, which corresponds to a dose of approximately 0.33 x 106 
RQR8/aTRBC1-CAR positive T cells/kg based on an average person’s weight of 75 kg. 
 
 
 
 
 
 
 
 
 
 

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4.4. 
RATIONALE FOR MAXIMUM ADMINISTERED DOSE 
(MAD) 
A MAD of 900x 106 RQR8/aTRBC1-CAR T cells in this study has been chosen based on the 
experience with CD19 CARs in B cell lymphoma. 
 
 
 
 
 
 
 
 
 
 
  
 
 

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4.5. 
RATIONALE FOR DOSING SCHEDULE 
Chimeric antigen receptor 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 41BB-ζ co-stimulatory domain is incorporated into the CAR, persist long-
term in a proportion of patients (Maude et al. 2014). It is anticipated that AUTO4 will have 
similar expansion and persistence in vivo to the CD19 CAR positive T cells with 41BB-ζ 
co-stimulatory domain, such as those utilised in the University of Pennsylvania studies, 
rendering the need for re-dosing unnecessary (Schuster et al. 2016). On rare occasion, a 
re-treatment dose may be given if the patient meets the criteria for re-treatment (Section 8.4.8). 
Patients will receive a single dose of AUTO4. After treatment with AUTO4, safety will be 
monitored closely (both in hospital and as an outpatient), 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. 
4.6. 
FLUDARABINE AND CYCLOPHOSPHAMIDE PRE-
CONDITIONING RATIONALE 
Pre-conditioning strategies that deplete host lymphocytes prior to adoptive transfer of tumour 
specific T-lymphocytes are 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 
(Louis et al. 2011). The FLU-CY combination is well tolerated and is commonly used in the 
treatment of 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-CY (FLU [30 mg/m2 for 4 days] and 
CY [500 mg/m2 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 IB Section 7.2 for further 
background information relating to the pre-conditioning treatment. 
In the current study, we propose pre-conditioning treatment with low dose FLU & CY (FLU 
[30 mg/m2 for 4 days] and CY [500 mg/m2 for 2 days]) followed, (after a 3-day wash out) by 
a low starting dose of 25 x 106 RQR8/aTRBC1-CAR positive T cells and up titrating the CAR 
T dose based on emerging safety data. The 3-day washout period prior to infusion of AUTO4 
is incorporated in consideration of the 20-hour half-life of FLU.  
In summary, given the nature of the patient population, the role of FLU-CY in enhancing the 
clinical efficacy of CAR T cells, the proposed dose and regimen are justified. 

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4.7. 
BIOMARKER COLLECTION AND ASSESSMENT 
RATIONALE 
Current experience with CAR T cell therapies indicates that the safety depends on the disease 
burden (in ALL), 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 
blood cytokine levels, and CAR T levels and persistence at various time points after AUTO4 
infusion. In addition, peripheral blood sampling will be performed to assess functionality (such 
as proliferation) of RQR8/aTRBC1-CAR T positive cells, which would help evaluate surrogate 
efficacy as well as resistance. 
5. 
RISKS AND MITIGATION STRATEGY 
This exploratory study is designed to assess the safety and biological activity of different doses 
of AUTO4 in a limited number of patients. Given the novelty of the treatment, 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. 
TUMOUR TISSUE BIOPSY  
If it is necessary for the patient to provide newly acquired tumour tissue, this can be provided 
from either an excisional biopsy or core needle biopsy. Although an excisional biopsy is 
preferred, the Investigator may choose to provide a core needle biopsy if a lesion is suitable. 
The serious risks from a biopsy include pain, haemorrhage, biopsy site infection and rarely, 
death. The people performing these procedures are well experienced and routinely perform 
such procedures under required anaesthesia (local, regional) and under strict aseptic conditions 
which is likely to minimise the pain/discomfort, bleeding and infection risk. 
5.2. 
LEUKAPHERESIS 
Leukapheresis is a prerequisite for preparing AUTO4. Cell production efficiency of at least 
80% of the anticipated dose is required and is dependent on the quality of the leukapheresate. 
AUTO4 infusion may or may not provide clinical benefit to these patients. Risks of 
leukapheresis are summarised in Table 7. 
Table 7: 
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. 

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5.3. 
PRE-CONDITIONING CHEMOTHERAPY 
Pre-conditioning with CY and FLU will only be undertaken after confirmation of the successful 
production of AUTO4. The risks of pre-conditioning with chemotherapy are summarised in 
Table 8. Please refer to the Summaries of Product Characteristics (SmPCs) for more details on 
these products. 
Table 8: 
Pre-conditioning Chemotherapy – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Myelosuppression resulting in anaemia, 
thrombocytopenia, and lymphopenia, is the most 
common toxicity. 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 than 
general chemotherapy received by patients and will 
be given only once (one cycle, given over 3 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 
5.4. 
AUTO4 INFUSION 
Risks associated with the infusion of AUTO4 are presented in Table 9. 

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Table 9: 
AUTO4 Infusion – Risks and Mitigation Strategy 
Risks  
Mitigation Strategy  
Infusion reactions may occur with the infusion 
of AUTO4. 
The product is autologous and the risk is likely to be 
low. Patients may be pre-medicated with 
diphenhydramine/chlorpheniramine and 
paracetamol/acetaminophen (see 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 DIC. The 
clinical features may overlap with macrophage 
activation syndrome. The absolute level of risk in 
T-NHL is difficult to determine. 
Patients will be monitored for CRS and appropriate 
treatment given in the event of the occurrence (see 
Section 10.4). These have been formulated based on 
prior CAR T cell-gene therapy experience at various 
institutions.  
Neurotoxicity has been seen in patients with 
leukaemia after treatment with CAR T cell 
therapy and is now referred to as ICANS. The 
cause of neurotoxicity 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, and 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; neuroimaging will be performed 
as required. Appropriate treatment, including 
dexamethasone, will be given in the event of severe 
neurotoxicity, including cerebral oedema and seizures 
(See Section 10.6). 
Macrophage activation syndrome (MAS) and 
Haemophagocytic lymphohistiocytosis (HLH) 
may occur in some patients for whom CAR T 
cell-mediated inflammatory responses continue 
to evolve. The clinical syndrome of MAS is 
characterized by high-grade non-remitting fever, 
cytopenias affecting at least two of three 
lineages, and hepatosplenomegaly. 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 activity. Other findings include variable 
levels of transaminases up to signs of acute liver 
failure and coagulopathy with findings consistent 
with DIC. 
Patients will be monitored for MAS/HLH following 
Neelapu et al. 2018 criteria and appropriate treatment 
given in the event of the occurrence (see Section 10.5). 

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Risks  
Mitigation Strategy  
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 RQR8/aTRBC1) 
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.  
Preclinical toxicology indicates the risk to be low as 
TRBC1 expression is limited to the T cell lineage and 
this risk is likely to be low.  
Cardiac toxicity: One cardiac-related fatality 
has been reported with CD19 CAR positive T 
cells, although the causality was unclear. 
The protocol excludes patients with underlying/prior 
cardiac history. Additionally, patients will be required 
to undergo ECHO or MUGA cardiac scans to 
demonstrate normal cardiac functioning prior to study 
enrolment and at the onset of CRS.  
Tumour lysis syndrome may occur on treatment 
with AUTO4 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 and is 
also less likely to happen with AUTO4 in T-
NHL. 
If TLS occurs, all sites have extensive experience in 
managing this complication and supportive care will 
be initiated rapidly as per standard institutional 
protocols. Based on emerging data prophylactic 
therapy with allopurinol and i.v. fluids may be given 
(see Section 10.7). 
T cell aplasia may occur because of depletion of 
normal T cells by AUTO4. Potentially this may 
increase the risk of infections. However, since 
only half of the T cell population is being 
targeted for depletion, and polyclonal nature of 
the immune response this risk is likely to be low. 
The duration of partial T cell aplasia is likely to 
be variable depending on the persistence of CAR 
T cells. 
Patients will be monitored for infections as per the 
Schedule of Assessments for CMV, HHV6, EBV and 
adenovirus. Other infections such as JCV, 
toxoplasmosis and fungal infections will also be 
monitored per institutional guidelines for bone marrow 
transplant patients, or as clinically indicated. In the 
event of active infection, patients will be managed as 
per the institutional standards or as clinically indicated.  
Additionally, where possible, unprocessed 
leukapheresate will be stored. Should a patient develop 
complete T cell aplasia or, severe and/or recurrent 
infections, then the rituximab safety switch can be 
activated to deplete AUTO4. Since stem cells are not 
impacted, normal haematopoiesis should lead to 
recovery of T cell compartment. In addition, the 
unprocessed leukapheresate can be infused to facilitate 
rapid immune re-constitution. Should this be 
unsuccessful then the patient could be rescued with an 
allogenic stem cell transplant. The patients recruited in 
this study are naïve for allogenic stem cell transplant. 
Sepsis: Sepsis leading to death has been noted in 
3 patients treated with very high doses (5 x 108 
CAR T cells) of CD19 CAR in a study done at 
University of Pennsylvania. 
Gradual titration of dose, prophylactic antibiotics and 
antiviral medications as appropriate, close monitoring 
of patients and early intervention is likely to reduce the 
risk. 
Insertional mutagenesis: Disruption of the 
cellular transcriptome by retroviral-mediated 
insertion has, in rare cases and in haematopoietic 
stem cell gene therapy trials only, resulted in 
insertional mutagenesis, and given rise to 
haematopoietic stem cells with elevated 
expression of growth-related genes, which 
subsequently resulted in T cell leukaemia and/or 
lymphoma. 
T cells that have been transduced with a retroviral 
vector have, to date, been proven safe. Unlike 
haematopoietic stem cells, T cells are highly resistant 
to retroviral vector-induced transformation. The 
patients will be monitored for secondary malignancy 
and survival in a long-term follow-up protocol for a 
total of 15 years. 

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Risks  
Mitigation Strategy  
Risk of transducing and re-infusing 
lymphoma cells 
Typically, these patients will have very low circulating 
malignant cells, and hence the absolute number of 
malignant T cells present within the leukapheresate is 
also likely to be low. Additionally, it has been noted 
that TRBC1 positive cells are refractory to 
transduction with 
 (this is postulated to be 
due to receptor interference, as the virions may bind 
the cells via the TCR rather than the RD114 receptor). 
Moreover, any incidental TRBC1 positive lymphoma 
cells will be killed by RQR8/aTRBC1-CAR positive T 
cells during the expansion phase of the manufacturing 
process. 
In addition, a negative sorting step has been 
incorporated during manufacturing to deplete any 
normal or malignant TRBC1 positive cells prior to 
transduction. 
Risks associated with a replication competent 
retrovirus (RCR): There is a risk that a 
recombination event may occur during vector 
production that results in a 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 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. 
Dimethyl sulfoxide, 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; for every patient, the amount of DMSO 
exposure will be kept 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. 
ALL = acute lymphoblastic leukaemia; BCMA= B Cell Maturation Antigen; CAR = chimeric antigen receptor; 
CD19 = cluster of differentiation 19; CD22 = cluster of differentiation 22; DIC = disseminated intravascular 
coagulation; CMV = cytomegalovirus; CRS = cytokine release syndrome; DMSO = dimethyl sulfoxide; 
EBV = Epstein Barr Virus; ECHO = echocardiogram; HHV6 = Human herpesvirus 6; IB = Investigator’s Brochure; 
ICANS = Immune Effector Cell-associated Neurotoxicity Syndrome; JCV = John Cunningham Virus; 
i.v. = intravenous; MUGA = multigated acquisition (cardiac scans); PCR = polymerase chain reaction; 
RCR = replication competent retrovirus; RQR8/aTRBC1 = Ritux QBEnd/10-Ritux-cluster of differentiation 8 sort-
suicide gene/anti-T cell receptor beta 1; TLS = tumour lysis syndrome; T-NHL = T cell non-Hodgkin Lymphoma. 
5.5. 
UNKNOWN LONG-TERM RISKS OF GENE THERAPY 
Following treatment of AUTO4, all patients will be invited to enrol in a long-term follow-up 
study and monitored for up to 15 years for SAEs related to AUTO4, Adverse Events of Special 
Interest (AESIs), new malignancies and survival. 
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 
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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 be screened for TRBC1 positive 
T-NHL and to enter the main study. 
3 
Confirmed diagnosis of selected T-NHL including: 
a 
Peripheral T cell lymphoma NOS, or  
b 
Angioimmunoblastic T cell lymphoma or  
c 
Anaplastic large cell lymphoma.  
4 
Confirmed TRBC1 positive tumour.  
5 
Relapsed or refractory disease and have had ≥1 prior lines of therapy. 
6 
FDG-avid measurable disease on PET / CT per Lugano classification.  
7 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. 
8 
Adequate Bone Marrow Function without the requirement for ongoing blood products and 
meets the following criteria: 
a 
Absolute neutrophil count ≥1.0 x 109/L 
b 
Absolute lymphocyte count ≥0.5 x 109/L (at entry and prior to leukapheresis) 
c 
Haemoglobin ≥80 g/L 
d 
Platelets ≥75 x 109/L 
9 
Adequate renal, hepatic, pulmonary, and cardiac function defined as: 
a Creatinine clearance (as estimated by Cockcroft Gault) ≥60 cc/min. 
b Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x upper limit of 
normal (ULN). 
c Total bilirubin ≤25 µmol/L (1.5 mg/dL), except in patients with Gilbert’s syndrome. 
d Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO) or 
multiple gated acquisition (MUGA) cardiac scan, unless the institutional lower limit of 
normal is lower.  
e Baseline oxygen saturation ≥92% on room air and ≤Grade 1 dyspnoea  
10 For females of childbearing potential (defined as <2 years 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), a highly effective method of 
contraception together with a barrier method must be used from the start of the 
pre-conditioning stage and for at least 12 months after the last dose of AUTO4 (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). 

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11 For males, it must be agreed that two acceptable methods of contraception are used from 
the start of the pre-conditioning stage and for at least 12 months after the last dose of 
AUTO4 (one by the patient – usually a barrier method, and one by the patient’s partner - 
refer to Appendix 3). Also, that sperm will not be donated during the treatment period and 
for at least 12 months after the last dose of study treatment. 
12 No contra-indications for leukapheresis or the pre-conditioning regimen. 
6.2. 
EXCLUSION CRITERIA 
Patients meeting any of the following exclusion criteria must not be enrolled into the study: 
1 
Patients with T cell leukaemia. 
2 
Females who are pregnant or lactating. 
3 
Prior treatment with investigational gene therapy or approved gene therapy or genetically 
engineered cell therapy product or allogeneic stem cell transplant. 
4 
Known history or presence of clinically relevant central nervous system (CNS) pathology 
such as epilepsy, paresis, aphasia, stroke within prior 3 months, severe brain injuries, 
dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, uncontrolled 
mental illness, or psychosis. Patients with a known history or prior diagnosis of optic 
neuritis or other immunologic or inflammatory disease affecting the CNS. 
5 
Current or history of CNS involvement by malignancy. 
6 
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. 
a 
Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are 
not excluded). 
b 
Evidence of pericardial effusion 
7 
Patients with evidence of uncontrolled hypertension or with a history of hypertension crisis 
or hypertensive encephalopathy. 
8 
Patients with a history (within 3 months) or evidence of deep vein thrombosis or 
pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of 
pre-conditioning. 
9 
Patients with active gastrointestinal (GI) bleeding. 
10 Patients with any major surgical intervention in the last 3 months. 
11 Active infectious bacterial, viral or fungal disease (hepatitis B virus, hepatitis C virus, 
human immunodeficiency virus [HIV], human T cell lymphotropic virus [HTLV] or 
syphilis) requiring treatment. 
12 Active autoimmune disease requiring immunosuppression. 
13 History of other neoplasms unless disease free for at least 2 years (adequately treated 
carcinoma in situ, curatively treated non-melanoma skin cancer, breast or prostate cancer 
on hormonal therapy are allowed). 

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14 Prior treatment with programmed cell death protein 1 (PD1), programmed death-ligand 1 
(PD-L1), or cytotoxic T lymphocyte-associated protein 4 targeted therapy (CTLA-4), 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 AUTO4 infusion. 
15 The following medications are excluded: 
a 
Steroids: Therapeutic doses of prednisone/equivalent of more than 20 mg per day are 
prohibited within 7 days prior to leukapheresis or pre-conditioning chemotherapy 
administration. However, physiological replacement, topical, and inhaled steroids are 
permitted. 
b 
Cytotoxic chemotherapies within 2 weeks prior to leukapheresis or AUTO4 infusion. 
c 
Antibody therapy use within 2 weeks prior to AUTO4 infusion, or five half-lives of 
the respective antibody, whichever is longer 
d 
Live vaccine within 4 weeks prior to enrolment. 
16 Research participants receiving any other investigational agents, or concurrent biological, 
chemotherapy, or radiation therapy. 
17 Use of rituximab (or rituximab biosimilar) within the last 6 months prior to AUTO4 
infusion. 
18 Patients, who in the opinion of the Investigator, may not be able to understand or comply 
with the safety monitoring requirements of the study. 
For pre-conditioning chemotherapy and AUTO4 Infusion: Patients meeting any of the 
following exclusion criteria must not be treated with pre-conditioning chemotherapy or 
AUTO4 - and have treatment delayed until they no longer meet these criteria:  
1 
Severe intercurrent infection at the time of pre-conditioning chemotherapy or the 
scheduled AUTO4 infusion.  
2 
Requirement for supplementary oxygen or active pulmonary infiltrates or significant 
deterioration of organ function at the time of pre-conditioning chemotherapy or scheduled 
AUTO4 infusion. 
3 
Significant clinical deterioration of organ functions from screening, as determined by the 
investigator. 
7. 
ADVANCED THERAPY INVESTIGATIONAL MEDICINAL 
PRODUCT: AUTO4 
7.1. 
AUTO4 DESCRIPTION 
AUTO4 is an autologous, cell and gene therapy investigational medicinal product that is 
manufactured by genetic modification of the patient’s own T cells by ex vivo transduction with 
a MLV-derived retroviral vector (
 that has been engineered to stably deliver the 
RQR8 and aTRBC1-CAR genes. The active substance is the genetically modified 
(RQR8/aTRBC1-CAR positive) T cells. AUTO4 also contains non-transduced autologous 
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AUTO4 is presented for i.v. infusion in one or more CryoMACS® bag(s) as a cell dispersion 
in phosphate-buffered saline/EDTA/human albumin solution and a final concentration of 7.5% 
DMSO.  
7.2. 
AUTO4 MANUFACTURING 
The Sponsor is responsible for the manufacturing of the drug product, AUTO4, according to 
Good Manufacturing Practice (GMP) principles and guidelines applicable to ATIMPs. The 
starting material for generation of AUTO4 is the unstimulated leukapheresate taken from the 
patient and 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 AUTO4, where under aseptic GMP conditions, the PBMCs will be transduced 
with a recombinant viral vector to co-express aTRBC1 and RQR8. Further details regarding 
this process can be found in the IB. 
AUTO4 is manufactured by genetic modification of the patient’s T cells by ex vivo transduction 
with a MLV-derived retroviral vector (
 Briefly, T cells will be obtained from the 
leukapheresate taken from each lymphoma patient who has been identified as TRBC1 positive 
during study screening. After a TRBC1 positive cell depletion of the leukapheresate, the T cells 
within the TRBC1 negative cell collected fraction are activated and then transduced with the 
 retroviral vector. Cells are then expanded (drug substance) and then cryopreserved 
(drug product). Drug product from initial AUTO4 process was used to support dosing in 
Phase I Dose Escalation (Table 5). The process was further optimized to enable a greater 
number of less differentiated CAR positive T cells to be achieved at an earlier harvest timepoint 
compared to the current process. Drug product manufactured using this process (Process B) 
will be used to support Phase I Dose Escalation with Process B (Table 6).  
AUTO4 manufacture and release will take approximately 4 weeks from receipt of 
leukapheresate at the manufacturing site. Full release testing will be performed to pre-defined 
specifications.  
AUTO4 will be cryopreserved in one or more CryoMACS® bag(s) and stored in a vapour-phase 
liquid nitrogen environment prior to administration.  
Please refer to the AUTO4 IB and CHIM for further details on the manufacture of AUTO4, 
shipment, storage, and handling. 
7.3. 
PACKAGING AND LABELLING 
AUTO4 is supplied as a cryopreserved cell dispersion in a sealed CryoMACS® bag containing 
the required number of RQR8/aTRBC1-CAR positive T cells for the planned dose level. Each 
AUTO4 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 AUTO4 cells. The 
CryoMACS® freezing bags are comprised of a freezing bag (with access ports) as the primary 

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containment for AUTO4 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 AUTO4. 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). 
7.4. 
SUPPLY AND STORAGE 
Cryopreserved AUTO4 will be supplied to the study sites (authorised to receive genetically 
modified organisms, in accordance with local requirements) by the Sponsor. Transport of 
AUTO4 to the study site will be performed by validated shippers under controlled temperature 
conditions below -150°C. In the case of a temperature excursion occurring during transit, the 
disposition of AUTO4 will be decided following the review of the temperature data. All 
temperature excursions outside the storage conditions specified in the Labels/Trial-Specific 
Procedures for receipt and storage of AUTO4 must be documented and reported to the Sponsor 
via the Clinical Research Associate as per the CHIM. The Sponsor must be informed 
immediately if a patient has been administered AUTO4 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.  
AUTO4 must be stored at below -150°C, under controlled temperature and will be maintained 
in a validated liquid nitrogen shipper and temperature monitored, in a secure storage area with 
restricted access until ready for thawing and preparation as specified in the CHIM. The study 
site will be responsible for the receipt, storage, and issue of AUTO4, and will comply with 
trial-specific procedures and the CHIM.  
AUTO4 supplied for the AUTO4-TL1 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 unique identification number of the patient, the administration date, batch number, expiry 
date and dose of AUTO4 dispensed will be recorded on the appropriate inventory forms.  
The Sponsor may authorise unused AUTO4 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 AUTO4 is destroyed, and AUTO4 destruction must be documented on 
the appropriate form. Further details can be found in the CHIM. 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 AUTO4 received at, dispensed from, returned 
to, and disposed of by the study site should be recorded on the Product Inventory Log. 

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8. 
STUDY PROCEDURES AND TREATMENT  
8.1. 
CONSENT, SCREENING, TISSUE BIOPSY AND 
REGISTRATION 
8.1.1. 
Consent processes 
All patients must sign the relevant informed consent form (ICF) prior to the conduct of any 
study-related procedure. Sites are responsible for assessing a patient’s capacity to give 
informed consent. There are two informed consents for this study: 
i. Consent to be screened for TRBC1 positive T-NHL. Patients will be provided with a 
PIS and ICF (PIS/ICF Part A) before a tumour tissue sample is obtained (i.e. archived 
tissue) or undertaken to determine TRBC1 status. 
ii. Consent to enter the main study will be sought from patients who are identified as 
TRBC1 positive. A separate PIS and ICF (PIS/ICF Part B) will be provided.  
Sites must ensure that all patients have been given the current approved version of the relevant 
PIS, are fully informed about the selection process and the trial, and have confirmed their 
willingness to take part in the selection process by signing the PIS/ICF Part A consent form. 
Separately, patients must confirm their willingness to take part in the main trial by signing the 
PIS/ICF Part B 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 screening process and the trial and all relevant 
treatment options to each patient prior to any trial-specific procedures being conducted. During 
these discussions, the current and relevant approved PIS should be discussed with the patient.  
Sufficient time must be allowed for the patient to consider and discuss participation in the 
selection process for the trial (PIS/ICF Part A). The patient can also receive and review the 
PIS/ICF Part B at the same time, but the patient cannot provide consent to the main study until 
their disease is confirmed as TRBC1 positive. Once the patient is confirmed as having TRBC1 
positive T-NHL, adequate time should be given to the patient to review PIS/ICF Part B; 
however, no minimum time is specified.  
Written informed consent on the current and relevant approved version of the ICF(s) for the 
trial must be obtained before any trial-specific procedures are conducted. The discussion and 
consent process(es) must be documented in the patient notes. 
8.1.2. 
Patient Registration 
Patient registration will be performed after patient consent (PIS/ICF Part A) to enter the 
screening process and prior to commencement of any trial procedure. Registration is completed 
using the Registration Form which must be sent to Autolus Limited after the following have 
been completed: 
• 
Patient written consent to screening (PIS/ICF Part A) for TRBC1 positive T-NHL.  
• 
Provisional confirmation of eligibility of a patient at a site. 
The patient information will be reviewed by the Sponsor’s Medical Monitor. 

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8.1.3. 
Patient Screening for TRBC1 Positive T-NHL 
After providing written informed consent to participate in the screening process, 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 for TRBC1 positive T-NHL begins with the provisional assessment of eligibility 
and obtaining a tumour tissue sample. During this screening process, preliminary eligibility 
criteria will be reviewed, demographic data (age, gender, race, and ethnicity), lymphoma 
disease history and a tumour tissue sample (new or archived) will be obtained. The patient’s 
tumour tissue will be analysed for TRBC1 status and TRBC1 positive disease confirmed before 
written consent is sought and obtained to enter the main study. 
Within PIS/ICF Part A, the patient will be asked to consent to the provision of an archival 
tumour tissue sample or a newly acquired tumour biopsy tissue. 
A screening log must be maintained by the site and filed in the Investigator Site File, and data 
collected during screening will be recorded on the electronic Case Report Form (eCRF). In 
accordance with Table 25, Section 12.3.1, AEs related to a study screening procedure will be 
collected.  
The screening process to determine TRBC1 status is expected to take up to 28 days. 
8.1.4. 
Tumour Tissue Provision 
Following patient consent (PIS/ICF Part A) and registration into the TRBC1 screening process, 
all patients must provide an archival tumour tissue (FFPE block) or, if not available, patients 
must undergo a tumour tissue biopsy to provide a newly acquired tumour tissue sample. 
The new tumour tissue sample could be either from an excisional biopsy or from a core needle 
biopsy. An excisional biopsy sample is preferred. If a core needle biopsy is undertaken, a 
minimum of 2 cores are required for the evaluation of TRBC1 expression on tumour cells using 
the 
 on FFPE tissue (see Section 8.1.5). Additional two cores are 
requested (if medically feasible) for the future development of a TRBC companion diagnostic 
assay. Core needle biopsies should be preferably taken with a needle of gauge 18 or larger. See 
pathology manual for additional details and information regarding fixation, storage and 
shipping.  
If available, additional archival tumour biopsy material should be provided for diagnostic assay 
development and biomarker evaluation (e.g. PD-L1 expression). Archival material can be 
provided as a FFPE block or slides (see the pathology manual). If the patient is identified as 
having TRBC1 positive T-NHL, and subsequently receives AUTO4, further tumour tissue 
biopsies (one between Day 7 and Day 21 after AUTO4 administration and at progression of 
disease) are requested if a suitable lesion is available. These are required for biomarker (such 
as PD-L1 expression) evaluation and for the presence of TRBC1-CAR T cells. If emerging 
safety and efficacy data suggest further investigation is warranted, bone marrow sampling may 
be requested. 
Tumour lesions used for newly acquired biopsies should not be the same lesions used as 
Lugano Classification target lesions, unless there are no other lesions suitable for biopsy. 
8.1.5. 
NGS Assay Used to Select TRBC1 Positive Patients for Entry 
TRBC1 expression on FFPE tumour biopsy tissue will be evaluated 
 
 

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A patient will be identified as having a TRBC1 positive T-NHL if the tumour sample is 
determined to be clonal by the 
 Assay – 
 
.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.6. 
Patient Screening to the Main Study 
Once a patient is identified as having TRBC1 positive T-NHL, the remaining screening 
procedures can be conducted following written informed consent to participate in the main 
study (PIS/ICF Part B). The remaining screening (including the baseline disease assessment) 
and other procedures will be performed and are likely to take at least 8 weeks (56 days). The 
total screening window (from initial consent Part B to AUTO4 administration) is up to 
12 weeks (84 days). 
If an assessment is or has been 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 AUTO4 administration.  
With the exception of re-test for TRBC1 positive status, the re-testing of abnormal screening 
values that lead to exclusion is allowed during the screening phase (to reassess eligibility). On 
Day -7 (-1 day), the patient should continue to meet renal, hepatic, pulmonary function and 

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performance status requirements prior to initiating pre-conditioning chemotherapy. On Day 0, 
before infusion, it will be assessed whether the patient meets the AUTO4 infusion criteria. The 
measurements collected at the time closest to, but prior to, the administration of AUTO4 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. 
8.1.7. 
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; and then, tested again on the day of leukapheresis or within 7 days after 
leukapheresis. Table 11 lists the tests that must be performed as a minimum requirement. 
Table 11: 
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. 
8.2. 
LEUKAPHERESIS FOR AUTO4 MANUFACTURING 
Following completion of all the procedures and assessments required in ‘Screen 1’ (including 
the confirmation that the patient is TRBC1 positive), patients will undergo an unstimulated 
leukapheresis for the generation of AUTO4.   
Leukapheresis must be performed within 30 days of infectious disease testing and will be done 
following the standard institutional processes. Sites may choose to take the blood sample for 
infectious disease screening at the time of the tumour tissue biopsy to ensure the infectious 
disease screen result is known within 30 days before leukapheresis. An additional sample is to 
be taken for a second infectious screen on the day of leukapheresis (or within 7 days after). 
In general, leukapheresis should be performed at least 35 days before the planned AUTO4 
dosing date, as AUTO4 manufacture and release takes approximately 1 month. Based on 
emerging data this window can be changed. If the product is ready early the patient may receive 
the product early. 
The leukapheresate is the starting material for the manufacture of the ATIMP, AUTO4. 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 between 
1 x 109- 5 x 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 research purposes as per the patient informed consent. The 
leukapheresate will be transported to the Sponsor for generation of AUTO4 at a temperature of 

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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 CHIM. 
Bridging chemotherapy may be prescribed to the patient during the AUTO4 manufacturing 
period at the discretion of the Investigator and in accordance with the exclusion criteria and 
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 release of AUTO4 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 AUTO4 product to the participating site. Further details are provided in the 
CHIM. 
However, if a patient is withdrawn after the successful leukapheresis and manufacture of 
AUTO4, but is subsequently re-screened and eligible for treatment, it may not be necessary to 
repeat leukapheresis and manufacture of AUTO4. To be discussed with the Sponsor. 
8.2.1. 
Leukapheresis for Immune Reconstitution (Rescue Treatment Storage) 
Where feasible, a fraction of leukapheresate (minimum 1 x 106 lymphocytes/kg) should be 
stored as a backup (rescue treatment) for immune reconstitution. This apheresate can be 
collected at the same time as the primary leukapheresis described above (in a different bag) or 
at a second unstimulated leukapheresis prior to pre-conditioning. This apheresate should be 
processed, frozen and stored at the local institution using the local standard labelling, freezing 
and storage process. If, and when necessary, these cells should be released for immune re-
constitution following depletion of AUTO4 using Rituximab. These cells will be thawed and 
infused as per the local institutional standards for autologous cells. 
8.3. 
PRE-CONDITIONING CHEMOTHERAPY 
Patients that still meet eligibility requirements for the study and for whom the AUTO4 product 
has been release to specification, will proceed to receive a lymphodepleting pre-conditioning 
treatment with Fludarabine (FLU) and Cyclophosphamide (CY) before AUTO4 infusion. The 
pre-conditioning phase will begin with administration of pre-conditioning chemotherapy and 
will end with the beginning of treatment with AUTO4 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 lymphodepleting pre-conditioning treatment with FLU 
and CY for 4 days (starting Day -6 [-1 day]) and timed to end 3 days (-1 day) before AUTO4 
infusion.  
8.3.1. 
Pre-conditioning Chemotherapy Dose and Regimen 
Patients will receive FLU and CY according to the dosing described below; FLU will be given 
first. 
• 
Day -6: FLU 30 mg/m2 followed by CY 500 mg/m2  
• 
Day -5: FLU 30 mg/m2 followed by CY 500 mg/m2  

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• 
Day -4: FLU 30 mg/m2  
• 
Day -3: FLU 30 mg/m2 
The pre-conditioning chemotherapy should be completed a minimum of 3 days (-1 day) prior 
to AUTO4 infusion. 
Fludarabine will be given by i.v. infusion over 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%). 
Cyclophosphamide will be given by i.v. infusion over 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/L with 6 hours post-hydration.  
Anti-emetic prophylaxis will be given as per standard institutional policy. Prophylaxis for TLS 
with allopurinol and i.v. fluids may be given if clinically necessary  
For additional information, please refer to the FLU and CY SmPCs. 
8.3.2. 
Supply of Fludarabine and Cyclophosphamide 
Fludarabine and CY are non-investigational medicinal products 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 AUTO4 treatment. Both drugs are 
authorised and commercially available in the UK 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 to 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 SmPCs for FLU and CY. 
8.3.3. 
Accountability of Fludarabine and Cyclophosphamide 
Pharmacy records should be kept of the FLU and CY dispensed to trial patients. The expiry 
date, batch number used, and manufacturer should be recorded as well as details of vials 
dispensed and returned.  
8.4. 
AUTO4 TREATMENT AND PATIENT MONITORING 
The treatment phase will involve infusion of AUTO4 on Day 0. The patient will be admitted 
to hospital for at least 14 days for monitoring and management of CRS and other toxicities. 
The actual time in hospital will be clinically determined depending on the patient’s toxicity 
profile. 
8.4.1. 
Assessment Prior to AUTO4 Infusion 
Prior to administration of AUTO4, patients will undergo clinical and laboratory assessments 
and the site Investigator or designee will determine if the patient is eligible to receive AUTO4 
as per protocol Section 6 (See Schedule of Assessments for details). For patients who receive 

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bridging therapy, baseline disease assessment with PET/CT should be done after completion 
of bridging therapy and before preconditioning and AUTO4 infusion. 
If a patient is not eligible to receive infusion of AUTO4 (Section 6.2), the AUTO4 infusion 
will be delayed. Infusion may be performed at a later date, as per dose delay guidelines 
(Section 8.4.5) or cancelled. 
8.4.2. 
AUTO4 Administration 
AUTO4 will be administered as a single rapid infusion on Day 0 in an in-patient setting. Full 
details will be provided in the CHIM. 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 AUTO4 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 along with a second person (e.g., research nurse) 
will verify that the patient details (Unique Patient Number) on the AUTO4 label matches the 
recipient, check the dose of cells, volume, and number of cryobags to be infused and prescribe 
the AUTO4 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. 
AUTO4 will be infused as described in the CHM. In brief: 
• 
AUTO4 will be thawed rapidly in a 37°C water bath under sterile conditions.  
• 
The entire contents of the bag(s) will be given as an i.v. infusion using a syringe or gravity 
aided infusion through a central or large bore peripheral venous access over a few minutes 
(maximum 30 minutes from AUTO4 being thawed to preserve cell viability).  
• 
A leukodepleting filter MUST NOT be used for the infusion of the T cell product. 
• 
A nurse or physician experienced in the administration of cellular blood products as per 
the trial-specific procedure. 
• 
The infusion line and the bag(s) should be flushed as described in the CHM to ensure all 
cells have been administered. 
• 
If there are multiple bags of cell product, one bag should be thawed and safely infused 
before the second one is thawed. 
• 
If the AUTO4 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 AUTO4 is 
administered by a site for the first time), when Sponsor representatives may be present to 
observe the thawing and/or dosing of AUTO4. 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 
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8.4.3. 
Monitoring During and After Drug Administration 
Patients are intended to stay as in-patients for at least 14 days following the cell infusion (longer 
if clinically necessary). All patients will be monitored closely with temperature, pulse/heart 
rate, blood pressure, respiratory rate, and oxygen saturations immediately prior to and every 30 
minutes (±10 minutes) for the next 4 hours after AUTO4 infusion. 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 care, patients will be monitored at a minimum 1 to 2 times daily. The 
patients 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.  
Patients may be discharged from hospital when clinically appropriate or following successful 
management of CRS. 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 8.4.8), patients may 
receive re-treatment (second cycle) of AUTO4. 
After the end of the study, patients will roll over into a separate long-term follow-up protocol 
(AUTO-LT1) if informed consent is provided. 
8.4.4. 
Monitoring for Infections 
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 at least 6 months (or longer if clinically 
indicated) post AUTO4 infusion.  
It is likely that in the first few weeks following pre-conditioning chemotherapy patients will be 
neutropenic and pan lymphopaenic. The patients will be monitored for infections in accordance 
with the Schedule of Assessments; specifically, patients will be monitored for viral infections 
cytomegalovirus (CMV), Human herpesvirus 6 (HHV6), Epstein Barr virus (EBV) and 
adenovirus. Other monitoring, such as John Cunningham virus (JCV), toxoplasmosis and 
fungal infections should be per institutional guidelines used for bone marrow transplant 
patients or as clinically indicated. 
All patients with fevers while neutropenic must have blood cultures drawn and receive 
broad-spectrum antibiotics as per institutional practice. 
8.4.5. 
Dose Delay of Pre-conditioning and AUTO4 Treatment 
If the pre-conditioning regimen is interrupted for intercurrent illness or other reasons, the 
patient may complete or recommence the preparative 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 pre-conditioning regimen.  

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If a patient is unable to be dosed with AUTO4 on the planned day, they may undergo delayed 
dosing after having received the pre-conditioning chemotherapies again (if appropriate – and 
if they continue to meet the study enrolment criteria). 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 AUTO4, they will be discontinued from the 
clinical trial (see Section 15.2) and replaced. Each case will be discussed with the Sponsor. 
8.4.6. 
Interruption of Infusion 
In the event of severe (≥Grade 3) infusion reaction, the FLU-CY or AUTO4 infusion should 
be stopped and the patient treated as clinically indicated. When the patient has recovered, the 
infusion may be restarted. 
Interruption of AUTO4 should not be greater than 30 minutes after thawing of AUTO4. 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. 
8.4.7. 
Duration of Treatment 
In most patients, it is expected that AUTO4 will be given once. However, if a patient has 
sufficient AUTO4 remaining from the original manufacture and meets the re-treatment criteria, 
a second treatment may be given (see re-treatment of patient Section 8.4.8).  
8.4.8. 
Re-treatment of Patients 
It is expected that most patients will receive a single dose of AUTO4, as part of their treatment. 
However, some patients may qualify for a re-treatment upon treating physician request. This 
re-treatment may be for patients in whom there has been no CAR T- cell engraftment ( e.g 
absence or low levels of CAR T-cell expansion), and could use either remaining CAR T-cells 
from the initial manufacturing process (if there is AUTO4 product leftover), or by a new 
AUTO4 manufacturing (e.g repeating the leukapheresis procedure and manufacturing process), 
if the patient clinical status allows (per treating physician decision). Specific criteria for re-
treatment are described below and individual risk-benefit considerations should be taken into 
account upon Sponsor and treating physician discussion. 
Prior to re-treatment, the patient must meet the following criteria: 
1 
Circulating levels of AUTO4 are low (<0.2 x 109/dL AUTO4 cells) or undetectable 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 
AUTO4 infusion (i.e. Stable Disease or better).  
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3 
The patient has evidence of progressive disease in the context of declining levels of 
AUTO4. Circulating levels AUTO4 cells must be low (<0.2 x 109/dL) or undetectable for 
at least 2 weeks prior to the second infusion.  
AND all of the following: 
4 
The patient tolerated the first infusion without dose-limiting or other severe (≥Grade 4) or 
unmanageable toxicity for a follow-up period of at least 28 days.  
5 
The patient still fulfils the trial entry criteria required to tolerate another pre-conditioning 
treatment and AUTO4 infusion.  
Patients undergoing a second AUTO4 infusion should receive the same pre-conditioning 
chemotherapy. The dose of AUTO4 can be at (or up to) the highest dose that has been declared 
safe with at least three patients completing the DLT period (or at least 1 patient in case there is 
any single patient dose cohort) and is considered to be more likely to be more active than the 
patient’s first dose of AUTO4. 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, in that 
they would start evaluation and management as defined in the protocol, starting from the 
pre-conditioning stage. 
8.5. 
FOLLOW-UP PHASE 
Upon completion of the first 28 days following AUTO4 infusion, patients will enter the Follow-
up Phase where they will continue to be followed as per the schedule of assessments for the 
duration of the study (Table 1) or until early withdrawal or death whichever is the latest for the 
assessment of anti-tumour response and or safety evaluation.  
8.5.1. 
Efficacy and Safety Follow-up 
After AUTO4 infusion, all patients will be followed up for efficacy and safety. Patients will 
have periodic monitoring of response based as described in the Schedule of Assessments (Table 
1). Patients who proceed to hematopoietic stem cell transplantation or any other anti-T-cell 
lymphoma 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 the end of the 
study. 
Relapse/Disease Progression evaluation: If at any time during the Efficacy and Safety 
Follow-Up, a patient experiences disease progression a full disease evaluation will be 
completed.  
Any patients in CR who have completed the 24 months follow-up period post first AUTO4 
infusion, will be monitored thereafter every 6 months until the EoS as per the Schedule of 
Assessments 1, including:  
• Survival, limited concomitant medication (e.g. therapeutic doses of steroids, 
inmunossuppressive, medications AE-related, any T-cell Lymphoma treatments), all 
SAEs and AEs considered related to the AUTO4, AEs of special interest and any new 
malignancy.  
• Disease response until the end of the study or until the patient experiences disease 
progression (whichever occurs first).  
• Once a year for AUTO4 vector persistence and RCR. 

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• T-cell Subset Analysis (local) – every 6 months until end of study  
8.5.2. 
Safety and Survival Follow-up 
Patients who fail to respond (within 2 months post AUTO4 treatment) to treatment or who 
respond but subsequently relapse or progress will continue to be monitored for safety and 
survival through to EoS as per the safety and survival Schedule of Assessments 2 (Table 2).  
At the end of the study, the patients will complete an EoS visit and will be invited to participate 
to 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 2.  
During the safety and survival follow-up, patients will come to the site as per the Schedule of 
Assessments. If a patient cannot attend a scheduled visit, the information can be collected 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 response is no longer willing to be followed up for efficacy 
and safety anymore but however 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/disease progression status and whether the patient has started receiving 
additional antineoplastic therapies.  
The efficacy data collected as per the local standard of care may recorded in the clinical 
database until they experience disease progression/relapse or rollover to the long-term follow-
up study.  
Selected AEs and concomitant medications will be recorded, please refer to Section 12.3.  
Patients who are discontinued from the study will complete the EoS visit. The reason for 
discontinuation will be documented. 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. Any patients who progressed 
post AUTO4 infusion and have completed the 24 months follow-up period will be monitored 
every 6 months until the EoS as per the Schedule of Assessments (Table 2). They will be 
followed-up for: 
• Survival, all SAEs and AEs considered related to AUTO4, AEs of special interest and 
any new malignancy  
• Subsequent therapy and response if applicable 
• Once a year for AUTO4 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. 
8.6. 
LONG-TERM FOLLOW-UP 
If a patient signs a new ICF for entry to the long-term follow-up study, they will be enrolled 
into a long-term follow-up study after treatment of AUTO4-TL1 on completion of the study. 
They will be monitored for SAEs considered related to the study treatment, AESIs and new 

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malignancy for a period of up to 15 years following last treatment with AUTO4. See 
Sections 15.1 and 16. 
9. 
STUDY ASSESSMENTS 
9.1. 
DEMOGRAPHIC AND BASELINE ASSESSMENTS 
The following will be collected at Screen 1 and Screen 2 to determine eligibility and baseline 
status of the patient. 
9.1.1. 
Demographic Data and Baseline Variables (Screen 1) 
Demographic data 
• Demographic data will include self-reported race/ethnicity, age, gender, and height at 
screening visit. 
Medical/lymphoma history 
• Medical history includes all current and past clinically significant diseases, surgeries, 
cancer history (including prior cancer therapies and procedures) and medications 
(e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, 
nutritional supplements). Histological confirmation of disease diagnosis will be 
obtained (pathology report). 
Physical examinations and investigations: 
• Physical examination (see Section 9.2.6) 
• Weight, vital signs (see Section 9.2.5) 
• Electrocardiogram (ECG – see Section 9.2.3), ECHO or MUGA (Section 9.2.4) 
• ECOG (see Section 9.2.8) 
• Laboratory (haematology, coagulation and biochemistry – Section 9.2.2) 
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 pre-conditioning treatment, and prior to AUTO4 
infusion. Following AUTO4 infusion, pregnancy testing will be performed at Day 28, 
Month 3, Month 6 and Month 12 as described in the Schedule of Assessments. 
9.1.2. 
Tumour Tissue Biopsy and TRBC1 Status at Baseline (During Screen 1) 
The patient must provide tumour tissue from an archival biopsy or a new biopsy for the 
evaluation of TRBC1 status (see Section 8.1.4). The TRBC1 status of the lymphoma tumour 
tissue will be determined by a central laboratory, and the TRBC1 status must be known prior 
to leukapheresis. 
9.1.3. 
T-cells subsets analysis 
Local assessment of peripheral blood T-cell subsets levels is required according to the SoA 
(Table 1). Documentation of the absolute number of the total lymphoid events in the sample 

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analysed, as well as absolute numbers of CD3+, CD3+CD4+, CD3+CD8+ cells are the 
minimum requirements. 
9.1.4. 
Efficacy Scans  
Both PET and a diagnostic quality CT are required at screening. Both images should be taken 
at a similar time (< 2 weeks apart). Measurable disease on CT needs to be FDG-avid and at 
least 1 lesion to be >= 20mm in its shortest axis. For patients receiving a bridging chemotherapy 
regimen, screening PET/CT scans must be done after completion of bridging therapy and 
before preconditioning and AUTO4 infusion. 
Patients will undergo baseline scan(s) – CT imaging of the neck, chest, abdomen and pelvis. 
MRI 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. 
A positron emission tomography (PET) scan will additionally be conducted. 
9.2. 
SAFETY EVALUATIONS 
All patients who receive AUTO4 will be considered evaluable for toxicity assessment. Any 
clinically relevant changes occurring during the study must be recorded on the AE section of 
the eCRF. Safety assessments will be based on medical review of AE reports and the results of 
vital sign measurements, 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 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 12.3.1. 
Toxicity will be graded using the NCI CTCAE version 5.0 criteria and collected according to 
Section 12.3.1. 
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 chemotherapy or AUTO4 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 AUTO4 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 

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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 12. 
Table 12: 
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). All 
tests must be performed prior to pre-conditioning chemotherapy, and prior to 
AUTO4 infusion on Day 0 of any treatment stage. 
Coagulation 
Prothrombin time, international normalised ratio, activated partial thromboplastin 
time, fibrinogen. Tests must be performed as per the Schedule of Assessments, 
including Day 7 after AUTO4 infusion. 
Biochemistry (full 
panel) 
Sodium, phosphate, potassium, magnesium, chloride, bicarbonate, alanine 
aminotransferase, aspartate aminotransferase, serum uric acid (on Days 0, 1 and 7 
of AUTO4 treatment stage), urea or blood urea nitrogen, creatinine, serum 
creatinine phosphokinase, lactate dehydrogenase, glucose, total bilirubin, calcium 
(albumin adjusted), total protein, albumin. On Day 0, all tests must be performed 
prior to AUTO4 infusion.  
Ferritin, C-reactive 
protein  
Ferritin, C-reactive protein as per the Schedule of Assessments and as clinically 
necessary and during CRS if necessary. 
Pregnancy test 
Serum (β-human chorionic gonadotropin) or urine pregnancy testing for females of 
childbearing potential. 
Infectious Disease 
Screen - Serology 
(at screening and 
then repeated at 
leukapheresis or 
within 7 days after 
leukapheresis) 
• 
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. 
Monitoring for 
infection.  
• 
CMV, HHV6, EBV & adenovirus. Other, such as JCV, toxoplasmosis and 
fungal pathogens will be monitored as per institutional guidelines for bone 
marrow transplant patients, or as clinically necessary. Monitoring beyond 3 
months should be done if there is complete T cell aplasia or if clinically 
indicated. 
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 
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 and when patient 
experiences CRS 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 
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9.2.4. 
Echocardiogram or Multiple Gated Acquisition Cardiac Scan 
Echocardiogram is the preferred method to assess cardiac ejection fraction and cardiac valve 
abnormalities; MUGA cardiac scan 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, oxygen saturation, respiratory rate, and 
blood pressure (systolic and diastolic), 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. Please refer to the Schedule of Assessments for timings and 
frequency of measurement. 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 and complete neurological 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 and neurological 
examinations is provided in the Schedule of Assessments. 
9.2.7. 
Concomitant Medications 
Concomitant medications are to be collected as described in the Schedule of Assessments. 
9.2.8. 
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. 
PHARMACOKINETICS, 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-AUTO4 treatment. Assessment at additional or fewer time points may be performed based 
on emerging data. Details regarding sample collection and processing are provided in the 
laboratory manual. 
9.3.1. 
Evaluation of AUTO4 Persistence in Peripheral Blood 
Two validated assays will be used to measure the expansion/persistence of 
RQR8/aTRBC1-CAR positive T cells at the time points indicated in the Schedule of 
Assessments. Flow cytometry will be used to measure the frequency of RQR8/aTRBC1-CAR 
positive T cells per microliter of whole blood and/or a PCR assay will be used to quantify the 
number of copies of the RQR8/aTRBC1-CAR transgene per microgram of genomic DNA 
and/or per cell in peripheral blood. Please refer to the AUTO4-TL1 laboratory manual for the 
handling and storage of samples.  

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9.3.2. 
Evaluation of AUTO4 Persistence and TRBC1 Expression in Lymph Node 
Tumour  
When possible, a lymph node tumour biopsy sample should be sent to the Sponsor for the 
assessment of presence of CAR T-cells and TRBC1 expression in the tumour. These 
assessments will be performed using flow cytometry or immunohistochemistry. Biopsy 
samples should be taken at the timepoints outlined in the Schedule of Assessments (Table 1, 
Footnote 9). 
9.3.3. 
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 AUTO4-TL1 
laboratory manual for the handling and storage of samples. 
9.3.4. 
TRBC1 Positive T Cell Aplasia 
AUTO4 will target polyclonal TRBC1+ T-cells. If AUTO4 expansion is observed, TRBC1 
positive T-cells aplasia may occur.  Blood samples will be collected for the analysis of the 
levels of TRBC1 positive and TRBC1 negative T cell subsets (including those that are CD4+ 
and CD8+) in accordance with the Schedule of Assessments (Table 1). Samples will be 
analyzed centrally with a validated Flow Cytometry assay.   
9.3.5. 
Insertional Mutagenesis 
Blood samples will be stored but not analysed (unless clinical evidence dictates) as per the 
Schedule of Assessments for insertional mutagenesis unless there is evidence that AUTO4 is 
no longer present. The result will allow identification of any potential relationship between 
AUTO4 treatment and the development of any new malignancy. 
9.3.6. 
Exploratory Biomarker Assessments 
Serum cytokine profile: The serum cytokine profile (using a minimum dataset of TNF-α, 
interferon-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 may 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 of PBMCs will be evaluated at 
selected time points (per the Schedule of Assessments) and dependent upon a minimum 
frequency of RQR8/aTRBC1-CAR positive cells  
TRBC1 expression on lymphoma tissue: If sufficient FFPE tumour tissue is provided at 
baseline, the expression of TRBC1 on lymphoma cells may be evaluated by IHC.  
PD-L1 expression on lymphoma cells: If sufficient FFPE tumour tissue is provided at 
baseline, the expression of PD-L1 on lymphoma cells may be evaluated by IHC, and where 
possible from tumour tissue samples collected between Day 7 and 21 and/or at progression of 
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If a patient is declared to have disease progression outside of scheduled time points, blood and 
tumour tissue/bone marrow samples will be collected to help elucidate the reasons for primary 
or acquired resistance using appropriate methods. 
9.3.7. 
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 3 to 6, may be analysed 
if clinically indicated. Additional samples may be analysed if clinically indicated e.g., if 
AUTO4 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. 
9.4. 
EFFICACY EVALUATION 
Response evaluations will be conducted as specified in the Schedule of Assessments and will 
include the following: CT and PET using [18F]-fluorodeoxyglucose (FDG), physical 
examination, and other procedures as necessary. MRI 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. These assessments should be performed throughout the 
study at each time point in the Schedule of Assessments using the same method of assessment 
used to assess disease at baseline. 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. If progression is suspected from scan(s), but the patient is otherwise not 
showing clinical progression/deterioration, the disease progression must be confirmed not less 
than 28 days after initial finding (to rule out a pseudo-progression). The Medical Monitor will 
review the data to confirm that the criteria for disease progression have been met. 
In cases of starting new treatment during response, an efficacy assessment is required prior to 
new treatment as specified in the Schedule of Assessments.  
9.4.1. 
Radiographic Image Assessments (CT/MRI) 
During the study, disease response will be assessed using CT scans with i.v. (and oral as 
necessary) 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 may have CT scans performed without i.v. 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 

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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.  
Radiological assessments will be performed as outlined in the Schedule of Assessments. 
9.4.2. 
Positron Emission Tomography 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) 
is required at Screening and then performed as outlined in 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 bone marrow uptake within weeks after treatment. 
9.4.3. 
Tissue Biopsy 
If relapse occurs after CMR or disease progression is suspected (e.g. new or enlarging lesion(s) 
detected on PET/CT scan), tissue biopsy should be used as unscheduled assessment to confirm 
PD, if in an accessible location which would not put the patient at any safety risk per treating 
physician judgment. Newly acquired tumour tissue can be provided from either an excisional 
biopsy or core needle biopsy. Although an excisional biopsy is preferred, the Investigator may 
choose to provide a core needle biopsy if a lesion is suitable. 
9.4.4. 
 Efficacy Criteria  
Assessment of Disease Response and Progressive Disease 
Efficacy assessments for the purpose of the study result analyses will be performed by the 
Investigators according to the Lugano Classification (Cheson et al. 2014) (Appendix 1).  
For suspected baseline disease that may not be detected by PET, e.g. skin, eye, GI wall change, 
appropriate screening assessments, e.g. skin biopsy, eye imaging assessment, endoscopy, are 
required. In the efficacy follow up, these disease locations should be re-examined and a CR 
can only be called if disease from all anatomical locations are resolved, evidenced by relevant 
assessments.  
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 

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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 bone marrow; 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. 
Efficacy Endpoints 
The efficacy endpoints are ORR, DOR, DFS, PFS, and OS:  
Overall response rate: CR or PR by the Criteria for Response Assessment of NHL 
(i.e. Lugano Classification). The proportion of patients achieving PR and CR at 1 and 3, and 
6 months post-AUTO4 infusion will also be determined.  
The time to response (PR+CR) and the time to CR will be calculated. These are defined as 
the time from the first treatment of AUTO4 to the response (either PR or CR as appropriate). 
Duration of response: DOR is defined as the time from the first observed CR or PR to 
documented disease progression or death due to any cause, for patients who are considered as 
responders.  
Progression-free survival: PFS is defined as the time from the first treatment of AUTO4 to 
documented disease progression/relapse or death due to any cause.  
Overall survival: OS is defined as the time from the first treatment of AUTO4 to death due to 
any cause. Date of death will be recorded. 
9.5. 
BLOOD VOLUME COLLECTIONS 
In general blood, will be taken from a Hickman line or other central venous access for the 
administration of pre-conditioning treatment and for AUTO4 administration, and then for the 
first year after AUTO4 infusion so that venepuncture will not be needed. The total estimated 
volume of blood collected for safety, biomarkers and immunological assessments (with the 
exception of the leukapheresis procedure) across the entire study will not normally exceed 
900 mL (this is expected volume for females with serum pregnancy test). The maximum 
volume of blood collected for study related assessments on any one day will generally not 

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exceed 80 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. 
10. 
GUIDELINES FOR PREVENTION, MONITORING, AND 
MANAGEMENT OF ADVERSE EVENTS 
The following guidance 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 
The guidelines detailed in Table 13 are suggested ways of supporting patients receiving CAR 
T cell therapy. 
Table 13: 
General Supportive Care Guidelines for Patients Receiving CAR T Cell 
Therapy 
Toxicity 
Preventive and Supportive Care Interventions 
General 
Administer paracetamol for symptomatic management of fevers in patients; 
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.  
If thrombocytopenia, avoid non-steroidal anti-inflammatory drugs. 
Infection Prophylaxis 
Patients should receive prophylaxis with antimicrobials due to the use of fludarabine 
and 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 6 
months post AUTO4 infusion or longer as per institutional guidelines. Consider 
starting prophylaxis from the time of leukapheresis.  
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, 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% in the setting of CRS should receive 
treatment with Tocilizumab (see Section 10.4). 
Cardiovascular 
Stop or taper antihypertensive medications prior to cell infusion. 
Monitor vital signs at least every 4-8 hours on an inpatient unit during hospital stay. 
Monitor vital signs at least every 2 hours in patients with fevers and tachycardia. 

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Toxicity 
Preventive and Supportive Care Interventions 
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 80% 
of their pre-infusion baseline and poor peripheral perfusion. 
In patients receiving >2 i.v. fluid bolus for hypotension, consider transfer to the 
intensive care unit, an ECG and an ECHO should be performed to evaluate for 
cardiac toxicity. 
For support and vasopressor use in the context of CRS See Section 10.4. 
Hematologic 
Initiate allopurinol and i.v. fluid prophylaxis for TLS prophylaxis at start of 
lymphodepletion in patients with high disease burden (See Section 10.7). 
Monitor complete blood count with differential at least daily. 
Maintain haemoglobin ≥80 g/L; 
Maintain platelets ≥20,000/μL; 
If absolute neutrophil count<500/μL at 30 days post CAR-T infusion (or earlier if 
clinically indicated), initiate granulocyte colony stimulating factor support. Continue 
until absolute neutrophil count increases to ≥1000 μL; 
Transfuse fresh frozen plasma with a goal of normalisation of partial thromboplastin 
time (PTT) in patients with a PTT >1.5-fold above the ULN; and transfuse 
cryoprecipitate to maintain fibrinogen of ≥1g/L. If patient is bleeding, a higher level 
of fibrinogen should be maintained. 
Neurologic 
Conduct focused neurologic examinations every 4-6 hours in patients experiencing 
neurologic toxicity (See Section 10.6) 
Perform brain magnetic resonance imaging (MRI) in any patient experiencing 
neurologic toxicity. 
Consider a neurology consultation for any patient experiencing neurologic toxicity. 
Standard antiepileptic medications for patients with active seizures.  
Prophylactic antiepileptic medications are not required. 
CMV = cytomegalovirus; ECG = electrocardiogram; ECHO = echocardiogram; i.v. = intravenous; MRI = magnetic 
resonance imaging; PTT = partial thromboplastin time; TLS = tumour lysis syndrome; ULN = upper limit of normal. 
10.2. 
PRE- AND POST-INFUSION SUPPORTIVE THERAPY 
AUTO4 is an autologous product and is unlikely to be immunogenic and induce an infusion or 
hypersensitivity reaction. The following medications should be given 30 minutes before the 
study drug infusion: paracetamol/acetaminophen orally and an intravenous antihistamine 
(chlorpheniramine or equivalent). Additional pre-infusion medications listed in Table 14 may 
also be administered if necessary.  
Post-infusion medication listed in Table 14 may be considered following AUTO4 infusion if 
necessary. Post-infusion medication 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. 

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Table 14: 
Pre- and Post-infusion Medications 
Medication 
Dose 
Administration 
Pre-infusion 
Post-infusion 
Antihistamine 
Chlorpheniramine  
(10 mg, 6 hourly). Refer to 
local prescribing information 
I.V. – administer at 
least 30 minutes prior 
to study drug 
Recommended 
Optional as 
clinically 
indicated 
Antipyretic 
Paracetamol /acetaminophen  
(1000 mg; 6 hourly). Refer to 
local prescribing information 
Oral - administer at 
least 30 minutes prior 
to study drug 
Recomended- 
Optional as 
clinically 
indicated 
Antiemetic 
Ondansetron  
8 mg or equivalent Refer to 
local prescribing information 
I.V. - start infusion 
30 minutes prior to 
study drug 
Optional 
Optional as 
clinically 
indicated 
Ondansetron  
(8 mg, twice daily) or 
equivalent. Refer to local 
prescribing information 
Oral - as clinically 
indicated 
- 
Optional as 
clinically 
indicated 
I.V. = intravenous;  
Note: Steroids should in general be avoided but may be used in case of severe reactions not controlled by other measures.  
10.3. 
MANAGEMENT OF INFUSION-RELATED REACTIONS 
Patients who experience infusion-related reactions to AUTO4 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 15 or as per institutional practice. All NCI CTCAE 
Grade 3 or 4 infusion-related reactions should be reported within 24 hours to the Sponsor as an 
AESI. Such events may also meet the criteria as an SAE and should be reported accordingly. 

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Table 15: 
Guidelines for the Management of Infusion-related Reactions 
NCI CTCAE Grade 
Treatment/Intervention 
Refer to local prescribing information for all described medications. 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
No intervention indicated 
Monitor patient as medically indicated until recovery from 
symptoms. 
Grade 2  
Moderate reaction;  
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment e.g., 
antihistamines, NSAIDS (if 
appropriate), narcotics, i.v. fluids; 
prophylactic medications indicated 
for <=24 hrs 
Interrupt infusion 
Start i.v. fluids; give chlorpheniramine (10 mg 6 hourly) (or 
equivalent) i.v. and/or paracetamol; consider bronchodilator therapy; 
may also consider corticosteroids if necessary; monitor patient 
closely until recovery from symptoms. 
Restart infusion if AUTO4 dose has not been fully administered. 
Symptoms recur: Stop and discontinue further infusion. 
The amount of AUTO4 infused must be recorded on the eCRF.  
Grade 3 or 4 
Severe reaction; 
 
Grade 3 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for clinical sequelae  
 
 
Grade 4: life-threatening; pressor 
or ventilator support indicated 
Stop infusion 
Start i.v. saline infusion; recommend bronchodilators and 
chlorpheniramine (10 mg 6 hourly) i.v. ± adrenaline 1 µg/kg for 
patients <50 kg and 50 µg for patients over 50 kg, injected slowly for 
i.v. administration or administer intramuscularly. If unresponsive, 
give with methylprednisolone 1 mg/kg (max 80 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.  
CTCAE = Common Terminology Criteria for Adverse Events (Grade 5.0); eCRF = Electronic Case Report Form; 
i.v. = intravenous; NCI = National Cancer Institute; NSAID = non-steroidal anti-inflammatory drug. 
Refer to local prescribing information for all described medications. 

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10.4. 
GRADING AND MANAGEMENT OF CYTOKINE RELEASE 
SYNDROME (CRS) 
Cytokine Release Syndrome (CRS) is a recognised toxicity with CAR T cell therapies and for 
some CAR-T therapies, can be severe (Grade 3 or 4) in 40% of patients, with Acute 
Lymphoblastic Leukaemia (ALL) and in 20% of patients, with Diffuse Large B Cell 
Lymphoma (DLBCL) (Kymriah (tisagenlecleucel) EU SmPC 2018, Kymriah US Prescribing 
Information 2018). 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 
disseminated intravascular coagulation (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 (LDH) level, 
early onset CRS (within 3 days of infusion) and elevation of some cytokine levels after infusion 
(Hay et al. 2017, Siddiqi et al. 2017, Santomasso et al. 2018). 
Macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) 
may occur in some 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 interleukin-2 receptor (sCD25), and triglycerides, together with a decrease of 
circulating NK 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 AUTO4 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 16 with recommendations regarding treatment provided 
in Table 17. 

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Table 16: 
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 (eg: CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading. 
ASBMT = American Society for Blood and Marrow Transplantation; ASTCT = American Society for Transplantation and 
Cellular Therapy; BiPAP = bilevel positive airway pressure CPAP = continuous positive airway pressure; CRS = cytokine 
release syndrome; CTCAE = Common Terminology Criteria for Adverse Events;  
† Fever is defined as temperature 38°C not attributable to any other cause. In patients who have CRS then receive antipyretics 
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 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. 

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Table 17: 
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 anti-IL-6 therapy for persisting (> 3 days) and refractory fever 
Grade 2 
Symptoms require and respond to moderate intervention 
 
Supportive care including fluid substitution is recommended. 
Low-flow-oxygen (<40% fraction of inspired oxygen). 
Consider anti-IL-6 therapy early if persistent fever of ≥39°C despite antipyretics for 10 hours (Lee et al. 
2014, Neelapu et al. 2018). 
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 18) 
Treat with Immunotherapy anti-IL-6 therapy (tocilizumab or siltuximab, See Table 18) 
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. 
Grade 4  
Life-threatening symptoms,  
Intensive care. 
Treat with Anti-IL-6 therapy with tocilizumab, ± siltuximab, (See Table 18) 
Treat with Corticosteroids (See Table 18). 
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 
 
CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; IL = interleukin; MAS = macrophage activation syndrome; NCI = National Cancer 
Institute; TNF = tumour necrosis factor. 

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Details of supportive medication and steroid doses are presented in Table 18.  
An overview of the CRS management is presented in Figure 4. 
Figure 4: 
Cytokine Release Syndrome Management Overview 
 
 

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Table 18:  
Pharmacologic Management of CRS and ICANS 
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 not available in all countries. 
Noradrenaline/norepinephrine monotherapy 
≥0.2 mcg/kg/minute 
Dopamine monotherapy ≥10 µg/kg/minute 
Adrenaline monotherapy ≥0.1 µg/kg/minute 
 
If on vasopressin: 
Vasopressin + Noradrenaline/norepinephrine 
equivalent of ≥10 μg/min* 
If on a combination vasopressors (not 
vasopressin): 
Noradrenaline/Norepinephrine equivalent of 
≥20 μg/min* 
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). 
Brundno and Kochenderfer (Brudno and Kochenderfer 2016) recommended the use of Anti-
IL6 therapy (specifically Tocilizumab) in the event of the following associated with CRS 
(CRS Grade ≥2 with associated conditions): 
• 
Left ventricular ejection fraction ,40% by echocardiogram; 
• 
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 h 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 FiO2 50% or more for more than 2 hours continuously; 
• 
Dyspnoea that is severe enough to potentially require mechanical ventilation; 
• 
Activated PTT >2 x the upper limit of normal; 
• 
Clinically-significant bleeding;  
• 
Creatine kinase >5 x the upper limit of normal for longer than 2 days 
 
 
 
Tocilizumab 
Adults:  The recommended dosing of 
Tocilizumab for the treatment of CRS given as a 
60-minute intravenous 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  

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Drug 
Indication 
Dose 
 
Use of tocilizumab may also be considered for persistent fever of ≥39°C despite antipyretics 
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 cytopaenias 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. 2015, Teachey et al. 2018) and may be used according to local institutional 
guidance. Siltuximab has been approved to treat Castleman’s disease (EU SmPC and US PI).  
 
Siltuximab may be added if there is no response to tocilizumab ± corticosteroids (Teachey et 
al. 2018, Neelapu et al. 2018). 
(Actemra Prescribing Information 2018, 
RoActemra SmPC 2018).  
Refer to local prescribing information and 
institutional guidance. 
 
 
 
 
 
 
 
 
Siltuximab 
11mg/kg over 1 hour as an i.v. infusion as a 
single dose (Neelapu et al. 2018, 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 neurotoxicity (ICANS) Grade 2 
and above (see Section 10.6).  Patients with ICANS in the absence of CRS should receive 
corticosteroids prior to Anti-IL6 therapy. 
Although 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 more efficient 
penetration of the blood brain barrier (Mitchell et al. 2005) (see Section 10.6). 
Patients on IV 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.  
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 
10mg i.v. every 6 hours (if refractory can 
increase to 20mg 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, macrophage activation 
syndrome and other syndromes (Prahalad et al. 2001, Gabay et al. 2010, Flammiger et al. 
2012, Ruella et al. 2017) 
 
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. 
* VASST (Russell et al. 2008) vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine (μg/min)] + [dopamine (μg/kg/min) ÷ 2] + [epinephrine 
(μg/min)] + [phenylephrine (μg/min) ÷10]. 
CAR = chimeric antigen receptor; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; ICANS = Immune Effector Cell-
associated Neurotoxicity Syndrome; IL = interleukin; MAS = macrophage activation syndrome; NCI = National Cancer Institute; PI = product insert; PPT = partial 
thromboplastin time; SBP = systolic blood pressure; SmPC = summary of product characterstics; TNF  = tumour necrosis factor; US = United States; 
VASST = Vasopressin and Septic Shock Trial. 
 

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10.5. 
MANAGEMENT OF MACROPHAGE ACTIVATION 
SYNDROME (MAS) 
Macrophage activation syndrome (MAS) and HLH encompasses 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 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.  
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 
HLH/MAS may be refractory to Anti-IL6 therapy and can be associated with a high mortality 
if not treated promptly. Patients with suspected HL/MAS should be treated with Anti-IL6 
therapy and corticosteroids (Neelapu et al. 2018) (See Table 18). If the patient has no 
improvement, clinically or serologically, within 48 hours, consider etoposide 75-100mg/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 neurotoxicity (Neelapu et al. 
2018). 
Uncontrolled HLH/MAS may also be treated with anakinra, an IL-1 receptor antagonist (See 
Table 18) (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 
neurotoxicity 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 central nervous system, endothelial 
activation, and macrophage activation syndrome 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 with 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, 

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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 neurotoxicity 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 (Gilbert 2017, Gust et al. 2017, Locke et al. 
2017). 
There appears to be no correlation between ICANS and CRS/MAS and both can occur together 
or separately. 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 expansion and early and higher elevations of serum cytokines may have a higher risk 
of neurotoxicity. Of note, patients can develop ICANS even after treatment with an nti-IL6 
therapy, after the resolution of CRS. 
Patients will be monitored closely after the AUTO4 infusion and closely monitored for 
neurological signs and symptoms of neurotoxicity. If neurotoxicity 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 21).  
In general, neurotoxicity is transient and resolves spontaneously with no long-term sequelae so 
that supportive care alone is sufficient in most patients. Steroids may be given for Grade 3 or 
4 neurotoxicity (See Table 21) 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 AUTO4.  
Neurotoxicity may also be caused by fludarabine but usually at higher doses than those being 
administered in this protocol (Helton et al. 2013). Symptoms of fludarabine neurotoxicity 
including objective weakness, agitation, confusion, seizures, visual disturbances, optic neuritis, 
optic neuropathy, blindness, and coma have been reported in CLL patients treated with multiple 
cycles of fludarabine.  
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 19 for grading of neurotoxicity as per the ASTCT/ASBMT guidelines for 
ICANS (Lee et al. 2019).  

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Table 19:  
Assessment & Grading of ICANS 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE Score for Adults^ 
(See Table 20) 
7-9 
3-6 
0-2 
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 (any age) 
N/A 
N/A 
Any clinical seizure 
focal or generalized that 
resolves rapidly; or Non-
convulsive seizures on 
EEG that resolve with 
intervention 
Life-threatening prolonged 
seizure (>5 min); or 
Repetitive clinical or 
electrical seizures without 
return to baseline in 
between. 
Motor weakness 
(any age)§ 
N/A 
N/A 
N/A 
Deep focal motor weakness 
such as hemiparesis or 
paraparesis 
Raised ICP / Cerebral 
Oedema (any age) 
 
 
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 
Adapted from (Lee et al. 2019), ASBMT ICANS Consensus 
ICANS grade is determined by the most severe event (ICE or CAPD score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral oedema) not attributable to any other cause. 
ASBMT = American Society for Blood and Marrow Transplantation; CAPD = Cornell Assessment of Paediatric Delirium; 
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. 
^ A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is awake with global aphasia. But 
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 v5.0 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 v5.0. 
Table 20:  
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; 
7-9, grade 1 ICANS; 
3-6, grade 2 ICANS; 
0-2, 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. 

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Patient may be managed as per the suggested guidelines below (Table 21) but may also be 
managed as per institutional management guidelines.   
Table 21:  
Management of ICANS 
Grade 
Recommended Management 
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 central nervous system depression  
Low doses of lorazepam (0.25 to 0.5 mg i.v. every 8) 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 papilloedema  
MRI of the brain with and without contrast; diagnostic lumbar puncture with measurement 
of opening pressure; MRI 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  
Daily 30 min 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 algorithm (Table 22) 
Consider Anti-IL-6 therapy if neurotoxicity 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 neurotoxicity without concurrent CRS.  
Consider transferring patient to ICU if neurotoxicity 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 neurotoxicity 
and if not administered previously.  
Dexamethasone 10 mg i.v. every 6 hours or methylprednisolone 1 mg/kg IV every 12 hours 
if refractory to anti-IL-6 therapy, or for neurotoxicity without concurrent CRS; continue 
corticosteroids until improvement to Grade 1 neurotoxicity and then taper (see Table 18). 
Stage 1 or 2 papilloedema with CSF opening pressure <20 mmHg should be treated as per 
algorithm (Table 23). 
Consider repeat neuroimaging (CT or MRI) every 2 to 3 days if patient has persistent Grade 
≥3 neurotoxicity. 

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Grade 
Recommended Management 
Grade 4 
neurologic 
toxicity of 
any duration  
 
Any 
generalised 
seizures 
Supportive care and neurological work-up as outlined for Grade 1 neurotoxicity. 
ICU monitoring; consider mechanical ventilation for airway protection.  
Anti-IL-6 therapy and repeat neuroimaging as described for Grade 3 neurotoxicity.  
High-dose corticosteroids continued until improvement to Grade 1 neurotoxicity 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 18).  
For convulsive status epilepticus, treat as per algorithm (Table 22). 
Stage ≥3 papilloedema, with a CSF opening pressure ≥20 mmHg or cerebral oedema, should 
be treated as per algorithm (Table 23). 
Worsening: May consider use of lymphodepleting drugs such as cyclophosphamide (Garfall 
et al. 2015) or other drugs (Klinger et al. 2016) if unresponsive to standard 
immunosuppressive therapies. 
Adapted from (Neelapu et al. 2018). Grading of neurotoxicity as per the ASTCT/ASBMT guidelines for Immune effector 
Cell-Associated Neurotoxicity Syndrome (ICANS) (Lee et al. 2019). 
AE = adverse event; ASBMT = American Society for Blood and Marrow Transplantation; ASTCT = American Society for 
Transplantation and Cellular Therapy; CRS = cytokine release syndrome; CSF = cerebrospinal fluid; CT = computerised 
tomography; EEG = electroencephalogram; ICU = intensive-care unit; i.v. = intravenous; MRI = magnetic resonance 
imaging.  
Table 22:  
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 min, as needed, up to a 
total of 2 mg to control electrographical seizures.  
Levetiracetam 500 mg IV 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. 
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 1–3 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) 
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 23:  
Recommendation for Management of Raised Intracranial Pressure (ICP) 
After CAR T Cell Therapy 
Condition  
Management 
Stage 1 or 2 papilloedema* 
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 
papilloedema*, 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 18 
Elevate head end of the patient’s bed to an angle of 30 degrees.  
Hyperventilation to achieve target partial pressure of arterial carbon dioxide 
(PaCO2) 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/h while monitoring electrolytes every 
4 hours, and withhold infusion if serum Na 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 IV 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) 
CSF = cerebrospinal fluid; CT = computerised tomography; i.v. = intravenous. 
*Papilloedema grading should be performed according to the modified Frisén scale (Frisen 1982) 
10.7. 
MANAGEMENT OF TUMOUR LYSIS SYNDROME 
Treatment with CAR T cells can lead to rapid killing of malignant cells, which can occasionally 
result in Tumour Lysis Syndrome (TLS) associated with a release of intracellular ions and 
metabolic by-products into the systemic circulation in patients with a high leukaemic/tumour 
burden. Clinically, TLS can be characterised by rapid development of hyperuricemia, 
hyperkalaemia, hyperphosphatemia, hypocalcaemia, and potentially acute renal failure.  
Patients with a high leukaemic/ tumour burden (such as >25% bone marrow blasts in 
leukaemia) should be given allopurinol and i.v. fluids from the start of lymphodepletion to 
prevent TLS. Patients should be monitored vigilantly for early signs and symptoms of TLS 
with daily clinical review and blood biochemistry.  
Should TLS occur, supportive care will be given as per standard institutional practice 
Management of TLS will usually include i.v. fluids, aggressive correction of abnormal 
laboratory test results such as hyperkalaemia, hyperuricemia, and hypocalcaemia, together with 
rasburicase (refer to local prescribing information) to increase urate excretion if needed.  

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10.8. 
T CEL APLASIA 
Hypogammaglobulinaemia has been seen as a consequence of depletion of normal B cells by 
CAR-T therapy. T cell aplasia may occur because of depletion of normal T cells by AUTO4. 
Potentially this may increase the risk of infections. However, since only a proportion of the 
T cell population is being targeted for depletion, and polyclonal nature of the immune response 
this risk is likely to be low. The duration of partial T cell aplasia is likely to be variable 
depending on the persistence of CAR T cells. 
Patients will be monitored for CD4 and CD8 T-cell levels as well as for infections as per the 
Schedule of Assessments for CMV, HHV6, EBV and adenovirus. Other infections such as 
JCV, toxoplasmosis and fungal infections will also be monitored per institutional guidelines 
used for bone marrow transplant patients, or as clinically indicated. In the event of active 
infection, patients will be managed as per the institutional standards or as clinically indicated.  
Additionally, where possible, unprocessed leukapheresate will be stored. Should a patient 
develop complete T cell aplasia or, severe and/or recurrent infections, then the rituximab safety 
switch can be activated to deplete AUTO4. Since stem cells are not expected to be impacted, 
normal haematopoiesis should lead to recovery of the T cell compartment. In addition, the 
unprocessed leukapheresate can be infused to facilitate rapid immune re-constitution. Should 
this be unsuccessful then the patient could be rescued with an allogenic stem cell transplant. 
The patients recruited in this study are naïve for allogenic stem cell transplant. 
In the event of any impact on B-cells, management of hypogammaglobulinaemia associated 
with CAR-T therapy will be according to local institutional practice.  
10.9. 
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS 
DUE TO ON-TARGET BUT OFF-TUMOUR TOXICITY 
Though it is unlikely that AUTO4 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 immune related AEs, which may allow for an early recognition of these events. Special 
attention should be paid to vital organs and immune related AEs 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 immune related AE, not successfully managed by general supportive care, treatment 
with steroids and other agents may be considered. 
11. 
CONCOMITANT MEDICATIONS AND THERAPIES 
All concomitant medication the patient is receiving at Day -7 (-1 day) or receives during 
pre-conditioning chemotherapy, or in the 28-day DLT period and up to Month 2 (Day 60) must 
be recorded. Outside these timeframes (that is, before Day -7 [-1 day] and after 2 months), only 
concomitant medication given for AUTO4 treatment-related SAEs and treatment-related 
Grade 3 to 4 AEs, AESIs or study related procedures will be collected.  
The following must be recorded: 
• Reason for use. 
• Dates of administration, including start and end dates. 
• Dosage information including dose, route and frequency. 

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Concomitant medication may be given as medically indicated for AEs, and these details 
(including doses, frequency, route and start and stop dates) of the concomitant 
medication/treatment given must be recorded in the patient’s medical records and details 
entered to the eCRF. The period for collection of AE related concomitant medication is the 
whole study. 
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, between leukapheresis and admission for 
pre-conditioning therapy, prior to AUTO4 infusion. 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 AUTO4 infusion. Other therapies 
should also have an adequate washout as indicated in exclusion criteria. Patients should have a 
baseline PET/CT after the bridging chemotherapy is given and prior to starting 
pre-conditioning. 
11.2. 
ALLOWED CONCOMITTANT 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 AUTO4 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 AUTO4 infusion supportive therapies: 
Please refer to Section 10.2. 
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 60 following AUTO4 infusion, unless recommended by the 
Principal Investigator.  
Corticosteroids and other immunosuppressants (except for managing treatment-related 
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Patients should not be receiving corticosteroids at doses of >5 mg prednisolone or equivalent 
within 72 hours of leukapheresis and pre-conditioning chemotherapy administration and, at the 
time of AUTO4 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 AUTO4. Corticosteroids may be used in the context of severe CRS, neurotoxicity, 
other inflammatory pathologies or infusion reactions (See Section 10). 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 
drugs after administration of AUTO4. 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 AUTO4 and subsequently require 
alternative anti-cancer therapy will complete the End of Study visit and roll on to a follow-up 
protocol. 
Live vaccinations: 
Administration of live vaccinations is generally not recommended. On a case by case basis 
where specific live vaccines may be appropriate without other options, the Investigator or 
delegate is to follow institution guidelines and discuss with the patient. Generally, live 
vaccinations should not be administered unless the T cell lymphocyte count has recovered and 
for at least 24 months post AUTO4 infusion. 
Investigators can use any medication based on their clinical judgement and local 
institutional practice to optimise patient’s safety. All medications should be recorded in the 
eCRF. 
11.4. 
OVERDOSAGE 
There is currently no experience of overdose of AUTO4 as no clinical studies have been 
performed to date. There is no specific treatment for an overdose of AUTO4. In the event of 
overdose, any adverse reactions should be treated symptomatically. In the event of 
unmanageable toxicity, steroids and/or rituximab may be used to deplete AUTO4. 
AUTO4 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. 

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12. 
SAFETY AND PHARMACOVIGILANCE 
12.1. 
DEFINITIONS 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product which does not necessarily have a causal relationship 
with the treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.  
12.1.1. 
Definition of an Adverse Reaction 
An adverse reaction is any untoward and unintended responses to a medicinal product 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 Investigator 
Brochure (IB). 
12.1.2. 
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 in 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 above seriousness criteria. Resolution of the SAE should also be considered 
when the event no longer is serious and 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). 
Events NOT considered as SAEs: 
• Hospitalisations not intended to treat an acute illness or AE (e.g. social reasons such as 
pending placement in a long-term care facility). 
• The administration of blood or platelet transfusion as routine treatment of studied 
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• A procedure that is planned (i.e. planned prior to starting of treatment on study)*  
• An elective treatment of a pre-existing condition unrelated to the studied indication.  
• A procedure requiring hospitalisation for protocol/disease-related investigations (e.g. 
surgery, scans, endoscopy, sampling for laboratory tests, and BM sampling)* 
• Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria (i.e. Medically Significant). 
• Routine treatment or monitoring of the indication not associated with any deterioration 
in condition. 
• Hospitalisation or prolongation of hospitalisation for technical, practical, or social 
reasons, in absence of an AE. 
• Extension of planned in-patient hospital stay beyond 30 days for general management 
purposes / management of underlying disease.  
• An event which is part of the natural course of the disease under study (i.e. disease 
progression or hospitalisation due to disease progression, or 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 Case Report Form 
and is not considered an Adverse Event, as this is an expected outcome of the disease 
(See Section 12.1.4). 
Note *Hospitalisation or prolonged hospitalisation for a complication of those indicated above 
remains a reportable SAE. 
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 12.1.2).  
Assessment of expectedness will be made by the Sponsor, or delegated through a vendor, with 
reference to the Reference Safety Information (RSI) in the Investigator Brochure. 
12.1.3. 
Adverse Events of Special Interest 
The following are AESIs:  
• Grade 2-5 CRS. 
• Grade 2-5 neurotoxicity (including depressed level of consciousness, dysphagia, ataxia, 
seizures and cerebral oedema). 
• Grade 3-4 Infusion Related Reaction to AUTO4 
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 (Section 
12.3.6). 
12.1.4. 
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 adverse event, 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 

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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 the 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 to 
AUTO4 treatment (as applicable), outcome and whether the event meets criteria as an SAE 
according to the guidelines presented in Section 12.1.2. 
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 by the NCI CTCAE should be evaluated for severity 
according to the following scale: 
Table 24: 
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 because of this AE. 
AE = adverse event. 
It is important to distinguish between serious and severity of an adverse event. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 12.1.2. 
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 Adverse Events 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 product. The patient either 
did not receive the investigational product or the event is related to an 
aetiology other than the investigational product (the alternative aetiology 
must be documented in the study patient’s medical record). 

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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.  
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 adverse event, unless no other appropriate 
diagnosis can be made.  This should be updated when a cause of death has been established. 
In principle all Adverse Events, including Serious Adverse Events should be collected from 
the time that that patient consents to the study.  However, due to the long period between 
consent and treatment with AUTO4, any AEs/SAEs related to holding 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 conditioning chemotherapy (Day -6 [-
1 day]). Due to the patient’s disease state and expected effect of chemotherapy on laboratory 
values, not all laboratory value abnormalities will be considered as adverse events (see 

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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 25. 
Table 25: 
Reporting Period for All AEs 
From: ICF signature 
Until: Month 6 
From: Month 6 
Until: End of Study/patient withdrawal 
OR, when patient initiates a new treatment for their 
disease 
• 
All AEs  
• 
All SAEs  
Note:  Events associated with disease 
progression do not need to be reported as AEs. 
• 
All AEs (regardless of grade) considered related to 
AUTO4  
• 
All AEs of special interest (regardless of relationship 
to AUTO4) (Section 12.3.6) 
• 
All AEs related to study procedures regardless of 
relationship to AUTO4 
• 
All SAEs (regardless of relationship to AUTO4) 
 
If a patient starts a new treatment for disease progression 
or undergoes a SCT: 
• 
Only AEs (serious and non-serious) that are 
considered related to AUTO4 to be reported. 
 
AE = adverse event; ICF = informed consent form; SAE = serious adverse event; SCT = stem cell transplant. 
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 
If a drug related AE and/or any SAE is ongoing at the time of study completion (2 years after 
dosing or disease progression, whichever happens first) 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 or  
• Patient lost to follow-up 
Patients who enter a long-term safety study will have their events considered 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, thrombocytopenia requiring blood product support are anticipated (due 
to disease and preconditioning) and are therefore not considered adverse events, unless they 

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persist beyond Day 30 after CAR-T infusion or are considered clinically significant and/or 
require advanced intervention above blood product and G-CSF support. 
Grade 1-2 laboratory abnormalities, at any time point are extremely frequent in this patient 
population and are too not considered adverse events unless 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 (ANC) in laboratory 
sections of the eCRF.  
It should be noted that clinically, 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 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, or values, 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 (CRS)  
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 adverse events (or signs and symptoms), as separate AEs, with the appropriate 
CTCAE grading as applicable (e.g. fever, hypotension etc.).   
12.3.4. 
Adverse Events Associated with CAR-T Neurotoxicity (ICANS) 
As Immune Effector Cell-associated Neurotoxicity Syndrome (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 appropriate grading 
(see Section 10.6) in the eCRF, please also add the associated adverse events (or signs and 
symptoms), as separate AEs, with the appropriate CTCAE grading as applicable (e.g. 
confusion, aphasia, encephalopathy, seizure).   
12.3.5. 
Serious Adverse Events Reporting 
All SAEs (as described in Section 12.3.1) occurring during the study must be reported to the 
Sponsor within 24 hours of becoming aware of the event. Additional or follow-up SAE reports 
should be submitted with relevant information promptly. Should a regulatory authority require 

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the Sponsor to submit additional data on the event, the Investigator will be requested to provide 
additional data to the Sponsor promptly.  
Information to be Provided for an SAE: 
Although much information will have been provided in the eCRF, this information may not 
always be readily available at the time of evaluating each Serious Adverse Event, or when 
reporting to the regulatory authorities, so it is essential that as much relevant information is 
included on the AESI/SAE form.  At a minimum, the following is required. 
• An identifiable patient (patient number)  
• Reporter details 
• The AUTO product (if not clear on the AESI/SAE form and if administered) 
• The Protocol (if not clear on the AESI/SAE form) 
• The AE, with a description of the event and a causality assessment 
Please also ensure that this information is accurate, at the time of reporting. Missing 
information, or information that is inconsistent with the eCRF will automatically generate 
queries. The initial SAE report will be provided to the Sponsor (or designee) using the 
AEI/SAE form. The Sponsor or designee will require the following information related to the 
event: 
The SAE form completion and reporting must not be delayed, even if all of the information is 
not available at the time of the initial report.  
The AESI/SAE report should be submitted to the following by fax or email: 
SAE Fax number: +44 (0) 1189 195 200 
Email: Autolus@tmcpharma.com 
The 24-Hour Safety Hotline: 
TMC Pharma 
Hartley Wintney 
Hampshire 
RG27 8AS, UK 
Tel: +44 (0)1252 842255 
Fax numbers and email address are listed on the SAE form and in the SAE form completion 
guidelines. 
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 recovery 
• Additional narrative information on the clinical course of the event 

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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.  
Suspected Unexpected Serious Adverse Reaction Reporting 
If the event is evaluated as a SUSAR, i.e. unexpected events that are related (reasonable 
possibility) to AUTO4, the Sponsor will submit the SUSAR to the regulatory authorities and 
the Research Ethics Committee 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, or in accordance with local regulatory requirements, if 
different. Where there are conflicting evaluations of causal relationship, between the 
Investigator and the company, the more conservative will be used for reporting purposes. 
All reporting to regulatory authorities will be by Autolus, or through an Autolus designated 
vendor. 
The Sponsor (or designee) will notify Investigators of all SUSARs, in accordance with local 
regulations. The Investigator must immediately review with the Investigator’s site team and 
retain the documentation in the Investigator Site File. 
12.3.6. 
Adverse Events of Special Interest Reporting 
Adverse events of special interest occurring during the study must 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 
(Section 12.3.5) within 24 hours. 
12.3.7. 
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 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. 

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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 
are 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.  
12.3.8. 
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  
• 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 of AUTO4 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 AUTO4 overdose or incorrect administration 
of AUTO4 should be noted on the corresponding eCRF page. All AEs associated with an 
overdose or incorrect administration of AUTO4 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’s Medical Monitor and membership will 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 (dose escalation), the SEC will meet:  
1. After the first patient in each cohort completes 28 days.  
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 are met.  
4. When clinically necessary based on emerging data. 
During Phase II (dose expansion), the SEC will meet:  
1. On a periodic basis (not exceeding 6 months) to assess cumulative safety data.  
2. After 10, 20, and 30 patients have completed 28 days following AUTO4 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, regulatory authorities and 
patients, 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 and the 
decision to assign the RP2D (the optimal dose) will be taken by the SEC. 
Dose escalation decision in Phase I of the study will be made by the SEC and may be subject 
to a substantial protocol amendment. The schedule of dose escalation meetings will depend on 
the time to completion of a cohort, frequency of DLT and when an RP2D is 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 (IDMC) 
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 3.6) are met. 
• During Phase I – once during Cohort 1. This may be via telephone or correspondence. 

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• Prior to opening Phase II. 
− At the interim analysis of Phase II (after 10 patients have been treated and had an 
opportunity for a minimum of 12 weeks post treatment follow-up) 
• Annually (6 monthly during active enrolment) during Phase II to review cumulative 
safety data. 
Throughout the trial, information regarding all treatment emergent SAEs and DLTs will be 
sent to the IDMC members to keep them informed on emerging safety findings. The IDMC 
can ask for and will be provided with 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 a RP2D decision is made by the SEC, the decision will need to be reviewed and endorsed 
by the IDMC prior to opening Phase II. 
Prior to any meeting or upon occurrence of a stopping criteria, detailed event summaries and 
cumulative safety data will be sent to the IDMC. A recomendation to continue or to hold or 
modify the study will be made by the IDMC to thesponsor. If, and when a study is halted, it 
will be re-started after a substantial protocol amendment has been approved by the regulatory 
authorities and ethics committees. 
Recommendations made by the IDMC will be communicated to the Principal Investigators at 
all active study centres and to the Regulatory Authorites, as applicable, by the Sponsor.  
Mandatory IDMC processes will be included in the IDMC Charter. 
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 
It is anticipated that approximately 200 patients are expected to be screened for eligibility for 
entry to this study (this includes both Phase I and II). This assumes that approximately 35% of 
patients will be identified as TRBC1 positive (a small number of patients will not provide 
sufficient evaluable tissue) Of those that are identified as TRBC1 positive, it is assumed that 
approximately 20% will fail the AUTO4 manufacture and/or will not continue to meet the 
inclusion and exclusion criteria. Up to 73 patients in total are anticipated to be treated with 
AUTO4 therapy. 
• Phase I (Escalation): Up to 25 patients in total (3 to 6 patients per dose cohort), 
following a rolling six design (Skolnik et al. 2008). 
• Phase I (Escalation) with Process B: Up to a total of 18 patients following a modified 
rolling six design. 
• Phase II (Expansion):  Up to 30 evaluable patients in total treated with AUTO4 
Process B product, using a Simon’s two-stage optimal design. 

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Using Simon’s 2-stage design (Simon 1989) the null hypothesis that the true response rate is 
10% will be tested against a one-sided alternative. In the first stage, 10 evaluable patients will 
be accrued (12 weeks post treatment of tenth evaluable patient). If there is only one or no 
responses in these 10 evaluable patients, the study will be stopped. Otherwise, if two responses 
or more are confirmed before the end of the first stage, the recruitment will continue, and 
19 additional evaluable patients will be accrued for a total of 29. The null hypothesis will be 
rejected if six or more responses are observed in 29 evaluable patients. This design yields a 
type I error rate of 5% and power of 80% when the true response rate is 30%. 
14.2. 
DESCRIPTION OF ANALYSIS DATASETS 
14.2.1. 
Enrolled Set 
The Enrolled set will consist of all patients registered and enrolled into the study. The number 
of patients who fail screening, together with the reason for screen failure will be summarised. 
14.2.2. 
Infused Set 
The Infused Set comprises all patients who have received at least one infusion of AUTO4 
treatment. 
14.2.3. 
Safety Set  
The Safety Set comprises all patients who receive at least one dose (complete or partial dose) 
of AUTO4 treatment. 
14.2.4. 
Efficacy Analysis Set 
All patients in the Infused Set with PET-positive disease prior to start of pre-conditioning 
therapy will be included in the Efficacy Analysis Set (EAS).  Patients with PET-negative 
disease after bridging chemotherapy will not be included in the primary efficacy analysis set. 
Patients who did not receive bridging therapy and did not repeat disease assessment prior to 
pre-conditioning will be included if there is PET positive disease prior to enrollment.  
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 Kaplan-Meier method. Summary statistics 
will be presented for baseline characteristics. 
In all analyses, the Study day refers to the study day from AUTO4 infusion defined per CDISC 
(Clinical Data Interchange Standards) conventions as: 
• (date of event/assessment - date of first AUTO4 infusion + 1), if event is on or after the 
date of first AUTO4 infusion 
• (date of the event/assessment - date of first AUTO4 infusion), if event precedes the date 
of first AUTO4 infusion. In this case, the study day will be negative. 
Note: In terms of statistical analysis only, the date of AUTO4 infusion will be considered Day 
1 under the CDISC analysis convention. 
14.3.1. 
Primary Endpoints 
The primary endpoints of the study are as follows: 

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Phase I: Safety and RP2D 
• Incidence of Grade 3 to 5 toxicity occurring within 60 days of AUTO4 infusion.  
• Frequency of DLT occurring within 28 days of AUTO4 infusion. 
Phase II: Anti-tumour effects  
• Overall response rate (CR+PR), where the denominator will be the number of patients 
in the EAS. 
Phase I: Safety 
Safety associated with AUTO4 administration (only those who received AUTO4). 
Summary statistics and analyses will be provided by dose level and overall. The safety analysis 
set for the study and study treatment 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. The following AEs will be tabulated: 
• Treatment-emergent AEs, where “treatment-emergent” is defined as any AE that occurs 
during or after administration of AUTO4 up to 60 days after the infusion.  
• Adverse events that are 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.  
• Adverse events that are considered related to treatment (possibly, probably, or 
definitely related).  
• Adverse events of special interest, together with grade. 
• 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. 
Phase I: RP2D and MTD 
At the end of the Phase I dose escalation phase, the RP2D will be identified based on the safety 
data and evaluation of the activity data collected in the dose escalation phase. The RP2D may 
also be determined prior to completion of all cohorts in Phase I.  

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Phase II: Anti-tumour effects 
The primary objective in the Phase II part of the study is to evaluate the clinical efficacy of 
AUTO4 treatment. The primary endpoint is the overall response rate (ORR), defined as 
proportion of patients who achieve a best overall response (BOR) of CR or PR as assessed per 
Lugano criteria. The primary analysis will be performed on the EAS. The associated two-sided 
95% confidence interval will be presented. 
Patients in the study who are of unknown clinical response will be treated as non-responders. 
Patients who have a non-evaluable scan or with PET-negative disease prior to pre-conditioning 
therapy will be excluded in the EAS and hence excluded in the primary analysis of efficacy. 
14.3.2. 
Secondary Endpoints 
Objective: Safety and tolerability of AUTO4 
• Frequency and severity of all AEs and SAEs.  
• Incidence and severity of opportunistic infections following AUTO4 infusion. 
Objective: Feasibility of AUTO4 manufacture in this patient population (all patients)  
Feasibility of product generation will be examined by assessing the number of patients for 
whom AUTO4 was successfully manufactured as a fraction of the number of patients 
undergoing leukapheresis (all patients who are TRBC1 positive and undergone leukapheresis).  
Objective: Clinical efficacy of AUTO4 
• Determine the CR rate following treatment with AUTO4. 
• The number of patients achieving objective response within 1, 3, & 6 months post 
AUTO4 infusion. The median time to response (PR+CR) and to CR will be calculated. 
• Response rate per histology will be summarised. 
• Evaluate clinical outcomes including DOR, PFS, DFS and OS. 
− Duration of response will be calculated from the date of first observation of CR or 
PR, to the date of progression, relapse or death, for patients who are considered as 
responders. Patients who have not progressed, relapsed or died will be censored at 
the last adequate disease assessment. 
− Progression-free survival will be calculated from the date of AUTO4 treatment to 
the date of progression, relapse, or death. Patients who have not progressed or 
relapsed will be censored at the last adequate disease assessment. 
− Overall survival will be calculated from the date of AUTO4 treatment to the date 
of death. Patients who have not died will be censored at the date of last contact 
(clinic visit or telephone contact).  
• Time to response will be calculated from the start date of treatment to the date of first 
observation of CR or PR for patients who are considered as responders. 
• Time to CR will be calculated from the start date of treatment to the date of first 
observation of CR for patients who are considered as complete responders  
Of Note: In the Phase 1 portion of the study, the same analysis conventions specified for the 
primary efficacy of Phase 2 will apply. 

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Objective: Biomarker, pharmacodynamics and pharmacokinetic effects of AUTO4 
The following analyses on the pharmacodynamic and pharmacokinetic effects of AUTO4 will 
be performed for patients who received AUTO4: 
• Duration of TRBC1 positive cell aplasia as determined by flow cytometry in the 
peripheral blood. 
• Expansion and persistence of RQR8/aTRBC1-CAR positive T cells as determined by 
PCR and flow cytometry will be summarised using the appropriate statistical methods: 
− Expansion is defined as the maximum level of RQR8/aTRBC1-CAR expression in 
both PCR and flow cytometry assays during the treatment stage and follow-up.  
− Engraftment is defined as detection of any level of RQR8/aTRBC1-CAR 
expression in circulating T cells (i.e. PBMCs) by PCR and/or flow cytometry 
following infusion above baseline controls.  
− Persistence is defined as the duration of detectability, from infusion to the first 
negative result. 
• The cellular kinetics of RQR8/aTRBC1-CAR positive T cells will be documented over 
time for each patient and the area under the curve calculated, then summarised for all 
patients.  
14.3.3. 
Exploratory Objectives 
Timing and magnitude of cytokine release, evaluated in serum using a cytokine assay:  
• Data on timing (kinetic of change) will be summarised as the mean (or median) number 
of days post-infusion.  
• Magnitude – kinetic and peak of cytokine levels, e.g., TNFα, IL-6 and IFN-γ (pg/mL), 
will be plotted for each patient and summarised. 
14.3.4. 
Immunogenicity Data 
Analyses of immunogenicity data will be documented in the SAP (Statistical Analysis Plan). 
14.3.5. 
Other Analyses 
Not applicable. 
14.3.6. 
Interim Analyses 
At the end of Phase I, the safety data will be summarised and reviewed by the SEC. The 
Phase II dose recommendation will be reviewed and endorsed by the IDMC prior to 
commencement of Phase II. 
In Phase II of the study, an interim analysis will be performed after 10 evaluable patients are 
treated and had an opportunity for a minimum of 12 weeks post treatment follow-up. The study 
will be stopped in this first stage if no more than one response has been observed. If the 
response rate exceeds the interim analysis stopping criteria, the study will continue to full 
enrolment. Even if ≥ two patients are known to have responded prior to 10 evaluable patients 
having been treated, the formal interim analysis will still be performed after the tenth evaluable 
patient. 
Recruitment will continue during the period of follow-up and during the interim analysis. 

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14.3.7. 
Final Analysis 
If the study continues beyond the interim analysis, the final Phase II statistical analysis will be 
performed after up to 30 evaluable patients have had the opportunity to be followed for a 
minimum of 24 weeks (6 months) or earlier if the last patient has died or prematurely 
withdrawn.  
Subsequent statistical analyses will be considered, as appropriate, up to the point of 
AUTO4-TL1 Last Patient Last Visit (24-month follow-up of the last patient entered).  
15. 
STUDY COMPLETION, PREMATURE DISCONTINUATION 
AND WITHDRAWAL FROM AUTO4-TL1 
15.1. 
COMPLETION OF STUDY 
Patients enrolled will be considered to have completed the study when they have completed all 
assessments until the EoS visit (LPLV – 24 months after last patient dosed).  
15.2. 
PATIENT WITHDRAWAL FROM AUTO4-TL1 
A patient should be withdrawn before the end of the study if the following happens: 
• Withdrawal of consent 
• Lost to follow-up 
• 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. 
Future data collection and withdrawal of consent: Informed consent is a continuous and 
dynamic process. Patients are free to withdraw their consent at any point in the clinical study 
and without detriment to their future medical care. However, patients who wish to withdraw 
their consent from further intervention/study visits may be willing to be followed in the clinical 
trial so as to enable the collection of key safety information such as (but not limited to) follow-
up information on SAEs. In this case, the Investigator will discuss this possibility with the 
patient to continue in the study and be contacted by a suitable means of communication 
agreeable to the patient to enable collection of information (survival status and evaluation of 
safety). In this event, the details should be recorded in the patient’s hospital records and only 
key information such as (but not limited to) date of death will be entered into the eCRF 
thereafter. The above information will be presented in the PIS/ICF Part B to ensure the patient 
understands the available options. 
Withdrawal from the use of samples in future research: The patient may withdraw consent 
for use of samples for future research. In such a case, samples will be destroyed after they are 

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no longer needed for the clinical study. Details of the sample retention for research are 
presented in both PIS/ICF Part A and Part B. 
15.2.1. 
Procedures for Handling Premature Withdrawal from the Study 
A patient may, of their own volition, 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. 
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. 
In the event that AUTO4 does not meet the specifications of the release criteria, the case will 
be discussed with the Investigator. It may be necessary to generate AUTO4 again if time 
permits (and biological screening repeated if necessary), otherwise the patient will be 
withdrawn from the study. 
15.3. 
REPLACEMENT POLICY 
In Phase I, 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. 
16. 
END OF TRIAL/TERMINATION BY SPONSOR 
For clinical trials located in the EU, a declaration of the end of the clinical trial will be made 
according to the procedures outlined in Directive 2001/20/EC, Article 10(c); for those countries 
outside the EU, local regulations will be followed.  
The study will be considered complete when the last patient completes their final follow-up 
visit. A final Clinical Study Report will be provided to the relevant authorities within 
12 months after the end of the study.  
The Sponsor reserves the right to terminate the study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation of the study will be appropriately 
documented per local requirements (e.g., IEC/IRB, regulatory authorities). The study will be 
stopped in Phase II at the interim analysis if ≤1 patient (out of 10) has an objective response. 
In addition, the Investigator or the Sponsor has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as: 
• Significant non-compliance with contractual enrolment timelines and targets. 
• Serious or continued Good Clinical Practice (GCP) non-compliance. 
• Inaccurate, incomplete, or delayed data collection. 
• Failure to adhere to the study protocol. 
• Failure to provide requested follow-up information for data queries. 

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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 Part A and Part B, 
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 Part A or Part B during the study, an 
IEC/IRB approval of the amended protocol and/or relevant 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 relevant 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. 

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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. 
17.3.3. 
Informed Consent 
In this study, there are two separate informed consents. Firstly, the patient is asked to consent 
to provide an archival tumour tissue sample or have a new tumour tissue biopsy to determine 
their T-NHL TRBC1 status (PIS/ICF Part A); secondly, having been confirmed as having 
TRBC1 positive disease, the patient is asked to consent to the main study (PIS/ICF Part B). It 
is the responsibility of the Investigator to obtain written informed consent from patients prior 
to conducting any study-related procedure. 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 relevant and appropriate ICF after she/he has received 
and read the relevant and appropriate PIS and received an explanation of what the screening 
process involves and what the main 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 sufficient time to consider PIS/ICF Part A before signing and dating the ICF. 
Patients may be given both PIS/ICF Part A and Part B at the same time; however, the patient 
cannot provide consent to the main study until their disease is confirmed as TRBC1 positive. 
Once a patient is confirmed as TRBC1 positive, adequate time to evaluate the information and 
to have any questions answered should be given before signing and dating the PIS/ICF Part B.  
It will also be explained to the patients that they are free to refuse entry into the study at any 
time and without prejudice to future treatment. Each ICF must also be signed and dated by the 
person obtaining consent. The original signed ICF(s) for each patient will be retained on file 
by the Investigator and the second signed original(s) will be given to the patient. 
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(s) during the study, the Investigator must always use the 
most current IEC/IRB approved form for documenting written informed consent for ongoing 
and new patients. 
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 Independent Ethics Committee/Institutional Review 
Board 
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 or Sponsor should have written and dated approval of the study 
protocol, the patient ICF(s), 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 submitted to the 
relevant IEC/IRB for evaluation before the study start. The IEC/IRB’s unconditional approval 

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statement will be acknowledged by the Sponsor or be transmitted by the Investigator to the 
Sponsor or a designee prior to shipment of AUTO4 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(s) 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. 
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 identification 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(s).  
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(s) 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 Autolus Ltd. for up to 15 years (or according 
to local regulations) for additional research. Samples will only be used to further understand 
AUTO4, to understand advanced cancers, to understand differential drug responders, and to 
develop tests/assays related to AUTO4 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. Good Manufacturing Practice AUTO4-derived 

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samples will be stored according to local GMP rules and procedures. Patients may withdraw 
their consent for their samples to be stored for research. 
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(s) must be revised and submitted to the IEC(s)/IRB(s) for review and 
approval/favourable opinion; (2) the revised ICF(s) 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(s) must be used to obtain contact 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. 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 an important 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 nonreporting 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 Food and Drug Administration (FDA). 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. 
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 maybe outlined in the study specific monitoring plan. 
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 Case 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. 
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 

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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.  
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 Part A and Part B. 

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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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Abstract 973 American Society of Hematology (ASH) 2020 

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21. 
APPENDICES 
Appendix 1: Patients with T-NHL will be Evaluated Using Response Criteria for Non-
Hodgkin Lymphoma for Documenting Disease Response 
Lugano Classification (Cheson et al. 2014) 
Response  
Site  
PET-CT-Based Response  
CT-Based Response  
Complete  
 
Complete metabolic response  
Complete radiologic response  
(all of the following)  
 
Lymph nodes 
and 
extralymphatic 
sites 
Score 1, 2, or 3a with or without a 
residual mass on 5PSb  
It is recognised that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or marrow 
(e.g., with chemotherapy or 
myeloid colony-stimulating 
factors), uptake may be greater 
than normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response may 
be inferred if uptake at sites of 
initial involvement is no greater 
than surrounding normal tissue 
even if the tissue has high 
physiologic uptake  
Target nodes/nodal masses must 
regress to ≤1.5 cm in the longest 
transverse diameter of the lesion 
(LDi).  
No extralymphatic sites of disease 
Non-measured 
lesion  
Not applicable  
Absent  
Organ 
enlargement  
Not applicable  
Regress to normal  
New lesions  
None  
None  
Bone marrow  
No evidence of FDG-avid disease 
in marrow  
Normal by morphology; if 
indeterminate, IHC negative  
Partial  
 
Partial metabolic response  
Partial remission (all of the 
following)  
 
Lymph nodes 
and extra-
lymphatic 
sites 
Score 4 or 5b with reduced uptake 
compared with baseline and 
residual mass(es) of any size  
At interim, these findings suggest 
responding disease  
At end of treatment, these findings 
indicate residual disease  
≥50% decrease in sum of the product 
of the perpendicular diameters for 
multiple lesions (SPD) of up to 6 
target measurable nodes and 
extranodal sites  
When a lesion is too small to 
measure on CT, assign 5 mm × 5 mm 
as the default value  
When no longer visible, 0 × 0 mm  
For a node >5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation  
Non-measured 
lesion  
Not applicable  
Absent/normal, regressed, but no 
increase  
Organ 
enlargement  
Not applicable  
Spleen must have regressed by >50% 
in length beyond normal  

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Response  
Site  
PET-CT-Based Response  
CT-Based Response  
New lesions  
None  
None  
Bone Marrow 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in the 
context of a nodal response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan 
Not applicable 
No response 
or stable 
disease  
 
No metabolic response  
Stable disease  
 
Lymph nodes 
and 
extralymphatic 
sites 
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
<50% decrease from baseline in SPD 
of up to 6 dominant, measurable 
nodes and extranodal sites; no 
criteria for progressive disease are 
met. 
Non-measured 
lesion  
Not applicable  
No increase consistent with 
progression  
Organ 
enlargement  
Not applicable  
No increase consistent with 
progression  
New lesions  
None  
None  
Bone marrow  
No change from baseline  
Not applicable  
Progressive 
disease  
 
Progressive metabolic disease  
Progressive disease requires at 
least 1 of the following: 
 
Individual 
target 
nodes/nodal 
masses  
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
Cross product of the LDi and 
perpendicular diameter (PPD) 
progression:  
 
Extranodal 
lesions 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-
treatment assessment 
An individual node/lesion must be 
abnormal with:  
LDi >1.5 cm, and  
increase by ≥50% from PPD nadir, 
and  
an increase in LDi or SDi from nadir:  
0.5 cm for lesions ≤2 cm  
1.0 cm for lesions >2 cm  
In the setting of splenomegaly, the 
splenic length must increase by 
>50% of the extent of its prior 
increase beyond baseline (e.g., a 15-
cm spleen must increase to >16 cm). 
If no prior splenomegaly, must 
increase by at least 2 cm from 
baseline.  
New or recurrent splenomegaly 

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Response  
Site  
PET-CT-Based Response  
CT-Based Response  
Non-measured 
lesions  
None  
New or clear progression of pre-
existing non-measured lesions  
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 undertreatment). 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 and Acceptable Methods of Birth Control 
For females of childbearing potential (defined as <2 years 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.  
For females who are not postmenopausal (<24 months of amenorrhea) or surgically sterile 
(absence of ovaries and/or uterus), highly effective methods of contraception must be used 
from the start of the pre-conditioning stage 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, including a barrier 
method of contraception are used from the start of the pre-conditioning stage and for at least 
12 months after the last dose of AUTO4 (one by the patient – usually a barrier method, and one 
by the patient’s partner) 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:  
− Oral  
− Intravaginal  
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1: 
− Oral 
− Injectable 
− Implantable2  
• Intrauterine device2  
• Intrauterine hormone-releasing system2  
• Bilateral tubal occlusion2  
• Vasectomised partner2, 3  
• Sexual abstinence4 
1  
Hormonal contraception may be susceptible to interaction with the AUTO4, which may reduce 
the efficacy of the contraception method.  
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 childbearing 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 

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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. 
Acceptable methods of birth control 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 
• 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 

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contraception. Acceptable documentation includes written or oral documentation 
communicated by clinician or clinician's staff of one of the following: 
• Demographics show age <11 years. 
• 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. 

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