Phase I/Ib Clinical Trial of Autologous CD22 Chimeric Antigen Receptor (CAR) T Cells in Adults With Recurrent or Refractory B Cell Malignancies
Phase: PHASE1
Conditions: B-ALL, B-cell Non Hodgkin Lymphoma, DLBCL, Follicular Lymphoma Grade 3B
Sponsor: Matthew Frank

Protocol Short Title: CD22 CAR T-cell in Adults with B cell malignancies 
CCT5029/ IRB-50836 
1 of 150 
Amd 3 Version 2022-0722 
 
 
 
Phase I/Ib Clinical Trial of Autologous CD22 Chimeric Antigen Receptor (CAR) T cells in 
Adults with Recurrent or Refractory B Cell Malignancies 
 
 
DEPARTMENT OF MEDICINE-BLOOD & MARROW TRANSPLANTATION 
STANFORD CANCER INSTITUTE 
 
 
Principal Investigator: 
Matthew Frank, MD, PhD 
IND-holder: 
Stanford University 
Study Agent: 
Autologous T cells Transduced with lentiviral vector (CD22.BB.Z) 
chimeric antigen receptor (CD22-CAR); following lymphodepleting 
chemotherapy 
Protocol Version: 
Amd 3, version 22 July 2022 
Confidentiality Statement 
This document contains confidential information of Stanford University School of Medicine.   
Do not copy or distribute without written permission of the sponsor. 
 
 
NCT04088890 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
PRINCIPAL INVESTIGATOR’S SIGNATURE PAGE 
Matthew Frank, M.D., PhD 
Assistant Professor of Medicine 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
mjfrank@stanford.edu 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
3 of 150 
Amd 3, Version 2022-0722 
 
 
SPONSOR DETAILS 
Name of IND Sponsor:   
Stanford University 
Sponsor’s 
Medical Representative 
David Miklos, MD, PhD 
Address: 
265 Campus Dr  G3141A,   MC5456 
Stanford, California, 94305 
Telephone Number: 
1-650-725-9670 
STANFORD CO-INVESTIGATORS 
David Miklos, M.D., Ph.D. 
269 Campus Dr.  CCSR 2205 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-498-6159 
dmiklos@stanford.edu 
Lori Muffly, M.D. 
300 Pasteur Drive, H0101 
Stanford, CA 94305-5623 
T: 650-721-2785 
F: 650-736-8092 
lmuffly@stanford.edu 
Sally Arai, M.D. 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
sarai1@stanford.edu  
Robert Lowsky, M.D. 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
rlowsky@stanford.edu  
Laura Johnston, M.D. 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
korb@stanford.edu  
Robert Negrin, MD 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
negrs@stanford.edu  
Everett Meyer, M.D., Ph.D. 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
evmeyer@stanford.edu  
Judith Shizuru, MD, PhD 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
jshizuru@stanford.edu  
Andrew Rezvani, MD 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
arezvani@stanford.edu  
Parveen Shiraz, MD 
300 Pasteur Drive, H0101 
Stanford, CA 94305-5623 
T: 650 272-8445 
F: 650 736 8092 
pshiraz@stanford.edu 
Wen-Kai, Weng, MD, PhD 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
wkweng@stanford.edu  
Surbhi Sidana, MD 
300 Pasteur Drive, H0101c 
Stanford, CA 94305 
T: 650 723-1389 
F: 650 736-8092 
sidanas@stanford.edu 
Melody Smith, MD 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
melodysm@stanford.edu 
Sushma Bharadwaj, MD 
300 Pasteur Drive, H0101 
Stanford, CA 94305 
T: 650-723-0822 
F: 650-736-8092 
sushmab@stanford.edu 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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BIOSTATISTICIAN 
Kristen Cunanan, PhD 
1070 Arastradero Road Rm 235 
Palo Alto, CA 94304 
T: 650-723-7356 
cunanank@stanford.edu 
STUDY COORDINATOR 
Maria Iglesias,  
300 Pasteur Dr., Rm A009 
Stanford, CA 94305 
T: 650-723-4247 
mariaigl@stanford.edu 
Consulting Investigator: Crystal L. Mackall, M.D.: Assist in the design of the trial, reviewing results, and 
contributing to reports of the trial. 
Coordinating Center/Participating Sites: 
Single Site 
 
 
DOCUMENT HISTORY 
NOTES 
Amd 0 Version Date: 13 May 2019  
Initial protocol submitted to SRC, FDA, IRB and APB 
Amd 0 Version Date: 30 Jun 2019 
Modification during FDA review.  Changes include: 
• 
Additional language clarifying weight-based dosing for subjects with 
BMI > 30 
• 
Change treatment stagger to 21 days for subjects with aggressive B-
cell NHL during dose escalation and 21 days for the first 3 subjects 
with ALL within a dose level. 
• 
Add data collection related to use of bridging anti-neoplastic therapy 
and subject disease response. 
• 
Update infectious disease marker testing in response to AABB Cell 
Therapy Standards 9th Edition to require HIV, HBV, and HCV testing 
within 28 days of enrollment.   
• 
Revise DLT definition for neurotoxicity.   
• 
Clarify additional doses of CD22-CAR will not be offered until 
preliminary safety data is submitted to FDA showing the dose is safe 
in the relevant disease cohort. 
• 
Update APB safety reporting criteria to report all SAEs assessed as 
possibly, probably or definitely related to CD22-CAR T cells, 
regardless of expectedness. 
Amd 0 Version Date: 08 Jul 2019 
Modification during APB review.  Changes include: 
• 
New section 2.3.1 discussing similarities and differences in CD22-
CAR T cell manufacturing process between Stanford product and NCI 
POB cell product. 
• 
Clarify steps before resuming enrollment after triggering a feasibility 
stopping rule. 
• 
Addition of enrollment table for each objective to Section 12.4. 
Amd 0 Version Date 08 Aug 2018 
Modification during SRC review.  Changes include  
• 
Modify maximum enrollment number for subjects with aggressive B-
cell NHL to account for a maximum of 18 subjects, rather than 15, 
during dose escalation 
• 
Remove BMI-adjustment for dose calculation. Cap weight at 100kg 
• 
Update Correlative Sample Collection Matrix (Section 13.7). 
Amd 1 Version Date 20 Sep 2020 
Changes include 
• 
Addition of LCGM manufacturing facility, update language regarding 
manufacturing and Action Plan for positive sterility result. 
• 
Remove Adaptive collaboration language. 
• 
Personnel change 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
5 of 150 
Amd 3, Version 2022-0722 
Amd 2 Version Date 20 Oct 2020 
Modifications include: 
• 
Change PI from Dr. Muffly to Dr. Frank 
• 
Remove wash out period specific to inotuzumab 
• 
Clarify circulating CAR testing in patients previously receiving CAR 
therapy. 
• 
Added Appendix to allow two stages for enrollment: 1st stage for 
leukapheresis and 2nd stage for investigational intervention, if required 
by patient or manufacturing scheduling. 
• 
Re-organize procedure schedules to refer to Calendar of Events to 
reduce discrepancies and inconsistencies. 
• 
Updated laboratory testing to reflect data accumulated to date. 
• 
Updated to most current disease evaluation criteria for ALL 
• 
Updated Appendix B to be consistent with Adult CCT team practice 
• 
Minor revisions to eligibility for clarity 
Amd 2-1 Version Date 24 Feb 2022 
Modifications include: 
• 
Administrative changes to personnel 
• 
Correction to lymphodepletion chemotherapy eligibility and study 
calendar 
• 
Add collaborations with Adaptive and Syncopation Life Sciences 
Amd 3 Version Date 22 July 2022 
Modifications include: 
• 
Given the shortage of fludarabine, allows for lymphodepletion with 
clofarabine and cyclophosphamide or bendamustine. Adds potential 
risks of these agents 
• 
Cell dose to be calculated from a weight collected within 14 days of 
start of cell manufacture 
• 
Change IV hydration instructions to follow current institutional 
practice. 
• 
Clarify targeted adverse event collection required for long term gene 
therapy followup, and update reporting requirements for Stanford 
APB 
• 
Remove patient RCL sample banking after Year 1, if all testing was 
negative 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
6 of 150 
Amd 3, Version 2022-0722 
SYNOPSIS 
Protocol Number 
 IND 19103/ CCT5029 / IRB-50836 
Protocol Title 
Phase I/Ib Clinical Trial of Autologous CD22 Chimeric Antigen Receptor (CAR) T 
cells in Adults with Recurrent or Refractory B Cell Malignancies 
Sponsor 
Stanford University 
Principal Investigator 
Matthew Frank, M.D., Ph.D. 
Name of Investigational 
Product 
Autologous T cells transduced with lentiviral vector (CD22.BB.Z) Chimeric Antigen 
Receptor (CD22-CAR); following lymphodepleting chemotherapy 
Clinical Phase  
Phase I/Ib 
Background and Rationale 
Relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) is a 
predominantly CD19+/CD22+ hematologic malignancy that is associated with 
dismal long-term survival in both children and adults.  Complete response (CR) to 
conventional salvage chemotherapy occurs in < 30% and long-term survival 
following salvage therapy with or without allogeneic stem cell transplant (SCT) 
occurs in < 25% of younger adults and < 10% of adults ≥ 50 years[1],[2], [3].  
Newer agents such as blinatumomab, a bi-specific T-cell engaging antibody 
targeting CD19+, and inotuzumab ozogamicin, a humanized anti-CD22 antibody 
conjugated to calicheamicin, result in higher response rates but are rarely durable 
responses without subsequent definitive therapy such as SCT[4],[5],[6].   
Similarly, R/R diffuse large B-cell lymphoma (DLBCL) is a CD19+/CD22+ 
non-Hodgkin lymphoma that represents the most common aggressive B-cell 
non-Hodgkin lymphoma (NHL) in adults.  Subjects who are not cured with up-front 
rituximab-containing therapy regimens are typically offered salvage therapy followed 
by autologous SCT.  Subjects with chemorefractory disease, or those who relapse 
within one year of autologous SCT have very poor outcomes with long-term 
event-free survival (EFS) of < 20%[7].   
CARs are non-native receptors that link an antigen-binding domain to cell signaling 
domain(s).  When expressed in T cells, CARs endow MHC-unrestricted antigen 
specificity.  Most commonly, CARs utilize a single chain variable fragment (scFv) 
coupled to TCR zeta and CD28 or 4-1BB endodomains.  CAR T cells targeting 
CD19 (CD19-CAR) in subjects with R/R B-ALL demonstrate dramatic activity in 
both children and adults with complete responses (CR) in ≥ 70% 
[8],[9],[10],[11],[12],[13],[14],[15].  CD19-CAR in R/R DLBCL similarly is 
associated with response rates of >70% and CR rates of approximately 50%[16, 17].  
Further, in some patients, responses appear to be durable beyond one year 
suggesting for the first time the possibility of cure of R/R B-cell ALL and R/R 
DLBCL without SCT.   
Despite the enthusiasm and potential for CD19-CAR therapy for B-cell 
malignancies, CD19-CAR resistance and disease relapse are ongoing challenges.  
As the experience with CD19-CAR in B-cell ALL and DLBCL has expanded, 
CD19 immune escape has emerged as a primary etiology of CAR resistance.  
[18],[10],[19].  For example, amongst 16 relapses following tisagenlecleucel 
(Kymriah ®) reported in a Phase II trial of children and young adults, 15 patients 
had CD19-negative disease at the time of relapse[15].  Similar antigen negative 
relapse patterns have been reported in ALL following CD19/CD3 bispecific 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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therapy[20].  There is therefore a need to develop CARs targeting alternative 
antigens in B-cell ALL.  In DLBCL, approximately 25% of relapses following 
CD19-CAR are associated with loss of CD19 expression[21]. 
CD22 is a sialic acid binding adhesion molecule, which belongs to the Siglec 
superfamily.  Signaling via CD22 mediates inhibitory signals on B cell receptor 
signaling via immunoreceptor tyrosine-based inhibitory motifs, which are essential 
for maintenance of B cell tolerance[22]; [23]; [24].  CD22 expression is restricted to 
cells of the B-lineage, and is not found on pluripotent hematopoietic stem 
cells[25],[26].  The vast majority of B-lineage malignancies express CD22 including 
B-ALL and B cell NHL[27],[28],[29],[30],[31],[32, 33].  Several therapeutics 
targeting CD22, including inotuzumab ozogamicin, have been studied in B-cell ALL 
and DLBCL with some success and no evidence of on-target, off-tissue toxicity has 
been observed[4].  A phase III study evaluating inotuzumab ozogamicin in 
relapsed/refractory adults with ALL achieved an 80% complete remission or 
complete remission without hematologic recovery (CRi) rate leading to FDA 
approval of this targeted agent for adults with relapsed/refractory ALL.[4] Objective 
responses have also been seen following inotuzumab ozogamicin in DLBCL[34, 35] 
The Pediatric Oncology Branch of the National Cancer Institute has developed a CAR 
T cell construct targeting CD22 (CD22-CAR).  In a Phase I safety and dose escalation 
study conducted in 21 children and young adults ages 1-30 years with 
relapsed/refractory B-cell ALL, CR was achieved in 73% (11 of 15) of patients treated 
at the recommended dose level of 1x106 CD22-CAR T cells/kg[36],[37].  Many of 
those treated had relapsed with CD19-negative disease following CD19-CAR, and 
responses were seen in all CD19 dim/absent patients treated at this dose level.  
Cytokine release syndrome (CRS) occurred in 16 of 21 patients and was limited to 
Grade 1/2. Therefore, we believe that CD22-CAR is a potentially promising agent in 
adults with B-cell malignancies and in the current protocol we aim to evaluate this 
therapy in adults with B-cell ALL and aggressive B-cell non-Hodgkin lymphoma 
(NHL), including DLBCL, primary mediastinal large B-cell lymphoma (PMBCL) 
and transformed DLBCL (tDLBCL) arising from Follicular Lymphoma and Marginal 
Zone Lymphoma. 
The aims of this clinical trial are three-fold:  
1. To evaluate the feasibility of manufacturing CD22-CAR T cellular products 
in the Miltenyi CliniMACS Prodigy® system across both diseases, ALL and 
aggressive B-cell non-Hodgkin lymphoma.  The CliniMACS Prodigy® 
represents the next generation in automated cell processing, combining and 
streamlining cell processing workflows into one closed system.   
2. To establish safety in two adult disease populations.  CD22-CAR T cells 
have not been previously administered to subjects with aggressive B-cell 
non-Hodgkin lymphoma, and we will establish the maximum tolerated dose 
(MTD) or recommended Phase 2 dose (RP2D) of CD22-CAR T cells in this 
patient population.  Simultaneously, we will seek to expand the prior 
pediatric and young adult experience with this CD22-CAR T cell agent in 
adults with CD22+ expressing B-cell ALL at the established dose of 1x106 
transduced T cells/kg.  Once MTD/RP2D is determined in subjects with 
aggressive B-cell non-Hodgkin lymphoma, this disease population will 
undergo the same safety evaluation. 
3. To evaluate in a preliminary fashion efficacy of CD22-CAR T cells in two 
disease populations, subjects with relapsed/refractory ALL and subjects with 
relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. 
The precedent for conducting clinical trials of this scope was established by the 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
ongoing clinical trials CCT5001/IRB-41382 and CCT5007/IRB-41383 conducted by 
Stanford Center for Cancer Cell Therapy. 
Objectives  
Primary Objectives: 
✓ 
Determine the feasibility of manufacturing CD22-CAR T cells using the 
Miltenyi CliniMACS Prodigy® system for administration to adults with 
relapsed/refractory CD22 expressing B-cell ALL or relapsed/refractory 
aggressive B-cell NHL. 
✓ 
Establish the maximum tolerated dose (MTD)/recommended phase 2 dose 
(RP2D) of CD22-CAR T cells in adults with relapsed/refractory aggressive B-
cell NHL. 
✓ 
Determine the safety of an established dose of CD22-CAR T cells in adults 
with relapsed/refractory CD22 expressing B-cell ALL and the safety of the 
MTD/RP2D of CD22-CAR T cells in adults with relapsed/refractory 
aggressive B-cell NHL. 
Secondary Objective 
✓ 
Assess the clinical activity of CD22-CAR T cells in adults with R/R CD22 
expressing B-cell ALL and R/R aggressive B-cell NHL, including overall 
survival (OS) and progressive free survival (PFS). 
Exploratory Objectives 
✓ 
Analyze alterations in early B cell development induced by immune pressure 
exerted via CD22-CAR T cells.   
✓ 
Evaluate whether subjects receiving CD22-CAR T cells relapse with loss or 
diminished expression of CD22, when feasible. 
✓ 
Measure persistence of CD22-CAR T cells in the blood, bone marrow and 
CSF, and explore correlations between CD22-CAR T cell properties and CAR 
T cell efficacy and persistence.   
✓ 
Establish the utility of chromatin structure and epigenomic technology to 
characterize CAR T cell therapies.   
✓ 
Analyze CD22 expression in aggressive B-cell NHL and correlate with disease 
response. 
Primary Endpoint(s) 
The primary endpoints for this study are: 
✓ Feasibility defined by the rate of successful manufacture of the CD22-CAR T 
cells produced with the Miltenyi CliniMACS Prodigy® system to satisfy the 
targeted dose level and meet the required release specifications. 
✓ MTD/RP2D in adults with aggressive B-cell NHL as evidence by the number of 
dose limiting toxicities (DLTs).  MTD is defined as the feasible dose achieving 
0 DLTs out of 3 or 1 (or fewer) DLT(s) out of 6 patients. 
✓ Safety of CD22-CAR T cells as evidenced by the incidence and severity of dose 
limiting toxicities (DLT), adverse events, serious adverse events, laboratory 
abnormalities, changes in vital signs, and changes in physical examination 
following infusion of CD22-CAR T cells graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (see link) in two 
disease groups: adults with relapsed/refractory CD22 expressing B-cell ALL and 
adults with relapsed/refractory aggressive B-cell NHL. 
Secondary Endpoints 
The secondary endpoints for this study are: 
✓ Overall response rate (ORR) as measured by Guidelines for efficacy evaluation 
in Acute Lymphoblastic Leukemia (ALL)  (based on NCCN Guidelines (2013, 
Appelbaum, ASH and IWG guideline, Cheson 2003.) 
- Complete Response (CR)  
- CRi 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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- No Response 
- Relapsed Disease 
- Unknown 
✓ Overall response rate (ORR as measured by Response Criteria for Lymphoma 
(From: Cheson BD, et al  2014[38]): 
- Complete Response (CR)  
- Partial Response (PR) 
- No response or Stable Disease (SD) 
- Progressive Disease (PD) 
Study Centers 
This is a Stanford University, investigator initiated protocol conducted at Stanford 
Health Care (SHC). 
Sample Size  
This study has 3 part analysis to establish sample size:  
1. Feasibility of manufacture;  
2. Safety in subjects with relapsed/refractory aggressive B-cell non-Hodgkin 
lymphoma after establishing MTD/RP2D dose, and safety in subjects with 
relapsed/refractory ALL; and  
3. Efficacy of administration of CD22-CAR T cells in two disease groups:  
adults with relapsed/refractory CD22 expressing B-cell ALL or 
relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. 
For relapsed/refractory aggressive B-cell non-Hodgkin lymphoma patients, a 
maximum of 18+10+33 = 61 subjects may be required to establish safety and 
feasibility, and indicate sufficient efficacy.  
For relapsed/refractory ALL patients, a maximum of 28+6= 34 subjects may be 
required to establish safety and feasibility, and indicate sufficient efficacy.  
Overall Duration of the 
Study 
The recruitment period for this study is expected to be 2 – 3.5 years.  Subjects will be 
followed for a total of 15 years post treatment.  The total duration of this study is 
expected to be 7-8.5 years of active treatment and short term follow up, and a total of 
15 years of long term follow up after the last subject completes study therapy. 
Duration of Study per 
Subject 
Subject’s active participation in this study is expected to be 5 years, with a total of 15 
years of long term follow up from the time of cell infusion. 
Subject Population 
Subjects ≥ 18 years of age, with relapsed/refractory CD22 expressing B-ALL or 
relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, including DLBCL, 
PMBCL, and tDLBCL, after standard therapies, with no alternative curative options 
or have refused alternative options, who meet the eligibility criteria. 
Eligibility criteria 
✓ For ALL, Must have chemotherapy refractory disease (defined as progression or 
stable disease after a standard line of therapy), or relapsed disease after achieving 
CR.  
o 
Subjects with persistent or relapsed MRD require verification of MRD on 2 
occasions at least 2 weeks apart. 
o 
Subjects with Ph+ALL are eligible if have progressed, had stable disease, or 
relapsed after receiving a tyrosine kinase inhibitor 
o 
Subjects with recurrence of isolated CNS relapse after CR are eligible 
✓ For aggressive B-cell NHL, Must have histologically confirmed disease as 
defined by WHO 2008: 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
o 
DLBCL not otherwise specified; T cell/histiocyte rich large B cell 
lymphoma; DLBCL associated with chronic inflammation; Epstein Barr 
virus (EBV)+ DLBCL of the elderly; OR 
o 
Primary mediastinal (thymic) large B cell lymphoma, OR 
o 
transformation of follicular lymphoma, marginal zone lymphoma or chronic 
lymphocytic leukemia/small lymphocytic lymphoma to DLBCL 
o 
Follicular Lymphoma Grade 3B 
o 
Subjects with DLBCL, Follicular Lymphoma Grade 3B –or- subjects with 
transformed FL, MZL, or CLL/SLL who have not received chemotherapy 
prior to transformation: must have received an anthracycline regimen and an 
anti-CD20 monoclonal antibody (unless documented CD20-neg) and be 
relapsed/refractory after second line of DLBCL treatment. Subjects with PR 
to second line therapy must be ineligible for autologous transplant. 
o 
Subjects with transformed FL, MZL, or CLL/SLL who have received 
anthracycline-containing chemotherapy prior to transformation: must have 
progressed, had SD or recurred with transformed disease after initial 
treatment for DLBCL 
✓ Measurable Disease: Subjects with ALL must have evaluable or measurable 
disease (MRD positive by flow cytometry, NGS, or PCR is acceptable).  
Subjects with aggressive B-cell NHL must have evaluable or measurable disease 
according to the revised IWG Response Criteria for Malignant Lymphoma[38].  
Lesions that have been previously irradiated will be considered measurable only 
if progression has been documented following completion of radiation therapy. 
✓ CD22 expression: For ALL, must have confirmed positive CD22 expression of 
the malignant cells by immunohistochemistry or flow cytometry.  For aggressive 
B-cell NHL, CD22 expression at any level, including undetectable, will be 
acceptable and subjects must have archival tissue available for analysis of CD22 
expression, or must be willing to undergo biopsy of easily accessible disease. 
✓ Subjects who have progressed or relapsed after prior autologous SCT must be at 
least 100 days post-transplant, have no evidence of GVHD, and have been 
without immunosuppressive drugs at least 30 days. 
✓ Meet required prior therapy washout windows (see inclusion criteria for 
leukapheresis for details). 
✓ Subjects with prior CAR therapy must be at least 30 days post CAR infusion and 
have < 5% CD3+ cells express the previous CAR, if a validated assay is 
available. 
✓ Toxicities from prior therapy stable or resolved (except for clinically non-
significant toxicity and cytopenias covered in * footnote) 
✓ Age: ≥ 18 years of age.   
✓ Adequate performance status (ECOG 0, 1, or 2; or Karnofsky ≥ 60% 
✓ Adequate organ and marrow function as defined by: 
o 
ANC ≥ 750/uL *, platelet count ≥ 50,000/uL *, ALC  ≥ 150/uL * 
o 
Creatinine ≤ 2 mg/dL OR Creatinine Clearance ≥ 60 mL/min  
o 
Serum ALT/AST ≤ 10 times the ULN (institutional normal) [Elevations 
related to leukemia involvement of the liver will not disqualify a subject] 
o 
Total bilirubin ≤ 1.5 mg/dL (except in subjects with Gilbert’s disease)  
o 
Cardiac ejection fraction (LVEF) ≥ 45% and no evidence of pericardial 
effusion 
o 
No clinically significant ECG findings 
o 
No clinically significant pleural effusion 
o 
SaO2 > 92% on room air 
✓ Subjects with CNS involvement or a history of CNS involvement are eligible 
only in the absence of neurologic symptoms that may mask or interfere with 
neurological assessment of toxicity. 
✓ Females of child-bearing potential must have negative pregnancy test. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
✓ Females of child-bearing potential and males of child-fathering potential must be 
willing to practice birth control from time of enrollment and for 4 months post 
preparative lymphodepletion regimen. 
✓ Must be able to provide informed consent (LAR is permitted if subject able to 
provide verbal assent). 
✓ May NOT have ALL limited to isolated testicular disease. 
✓ May NOT have hyperleukocytosis (≥ 50,000 blasts/μL) or rapidly progressive 
disease that in the estimation of the investigator and sponsor would compromise 
ability to complete study therapy. 
✓ May NOT have history of other malignancies, apart from non-melanoma skin 
cancer or carcinoma in situ, unless disease free for at least 3 years, or in remission 
1-2 years and Principal Investigator assesses other malignancy as unlikely to 
return within 1 year or interfere with CAR T cell safety. 
✓ May NOT have active fungal, bacterial, viral or other infection requiring 
intravenous antimicrobials   Simple UTI or uncomplicated bacterial pharyngitis 
is permitted if responding to active treatment. 
✓ May NOT have ongoing HIV, HBV or HCV infection. History of HBV or HCV 
is permitted if viral load is undetectable by qPCR and/or nucleic acid testing. 
✓ May NOT have active cerebrovascular ischemia/hemorrhage, dementia, 
cerebellar disease, or autoimmune disease with CNS involvement that in 
investigator’s judgement impair ability to evaluate neurotoxicity. 
✓ May NOT have history of MI, cardiac angioplasty or stenting, unstable angina 
or other clinically significant cardiac disease with 12 months of enrollment. 
✓ May NOT have severe, immediate hypersensitivity reaction attributed to 
compounds of similar chemical or biologic composition to any agents used in 
study. 
✓ May NOT be pregnant or breastfeeding. 
✓ May NOT have primary immunodeficiency or history of autoimmune disease 
(e.g. Crohns, rheumatoid arthritis, systemic lupus) requiring systemic 
immunosuppression/systemic disease modifying agents within the last 2 years. 
✓ May NOT, in investigator’s judgment, have any medical condition likely to 
interfere with assessment of safety or efficacy, or be unlikely to complete all 
protocol-required visits and procedures. 
* A subject will not be excluded because of pancytopenia ≥ Grade 3 if it is felt by the 
investigator to be due to underlying leukemia/lymphoma. 
Subjects may be enrolled using two stages (1) Leukapheresis and 2) Lymphodepletion 
Chemotherapy and Cell Infusion) using these same criteria (see Section 13.8 
Appendix H) if patient or manufacturing scheduling require. 
Investigational Product, 
Dose, and Mode of 
Administration 
Autologous peripheral blood mononuclear cells (PBMC) will be obtained by 
leukapheresis and cryopreserved.  Cryopreserved PBMC stored from participation in 
other institutional cell therapy or cell collection studies or standard of care may be 
used to generate the cellular product on this study as long as they meet the criteria 
established in this IND.  PBMC will be transported to the manufacturing facility (MBI 
or LCGM), where they will undergo selection, activation, transduction with the 
lentiviral vector, expansion, and formulation for the manufacture of CD22-CAR T 
cells.  The product will be cryopreserved and returned to Stanford’s Cell Therapy 
Facility (CTF), from which the product will be distributed to the patient care unit for 
infusion.  Autologous CD22-CAR T cells will be administered intravenously at Dose 
Level 1 in subjects with ALL.  Autologous CD22-CAR T cells will be administered 
in 3 escalating doses (Dose Level 1, 2, and 3) in subjects with aggressive B-cell NHL 
to determine MTD/RP2D.  A conditioning lymphodepletion chemotherapy regimen  
will be administered prior to cell infusion.  If the rate of DLT ever exceeds the 
maximum acceptable rate in a disease group, the next lower dose level will be 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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explored in that disease group. 
▪ 
Dose Level -1:    3 x 105 transduced T cells/kg (± 20%) 
▪ 
Dose Level 1:     1 x 106 transduced T cells/kg (± 20%) 
▪ 
Dose Level 2:     3 x 106 transduced T cells/kg (± 20%) 
▪ 
Dose Level 3:     1 x 107 transduced T cells/kg (± 20%) 
Lymphodepletion chemotherapy regimenprior to CD22-CAR T cell infusion (Day 0) 
will occur according to one of the following regimens, at the discretion of the 
investigator: 
• 
Fludarabine 30 mg/m2 per day IV for days -5, -4, -3 
• 
Cyclophosphamide 500 mg/m2 per day IV for days -5, -4, -3 
OR 
• 
Bendamustine (Bendeka®) 90 mg/m2 per day IV over 10 minutes on Days 
-3, -2 
OR 
• 
Clofarabine 40 mg/m2 per day IV over 2 hours on Days -6, -5, -4, -3 
Cyclophosphamide 500 mg/m2 per day IV over 60 minutes on days -6, -5 
 
Study Design and 
Methodology 
This is a Phase 1 study in adult subjects with B-ALL and aggressive B-cell NHL who 
have relapsed or refractory disease after standard therapies.   
Subjects will receive a conditioning lymphodepletion chemotherapy regimen 
followed by infusion of CD22-CAR T cells.  Subjects in each disease cohort will be 
evaluated after treatment for toxicity, antitumor effects and for persistence of CAR in 
blood samples and functionality of transduced T cells.   
Feasibility will be assessed initially in each disease population. Subjects with ALL 
will receive CD22-CAR T cells at the established dose of 1 x 106 transduced 
T cells/kg (± 20%) based on previous experience, whereas the dose has yet to be 
established in subjects with aggressive B-cell NHL.  Hence, a standard 3 + 3 dose 
escalation design will be used in subjects with aggressive B-cell NHL to establish 
MTD/RP2D.  The safety of CD22-CAR T cells will be evaluated in subjects with 
ALL at the established dose and subjects with aggressive B-cell NHL at the 
MTD/RP2D separately.  In addition a futility analysis will be conducted in each 
disease group (ALL at the established dose and aggressive B-cell NHL at the 
MTD/RP2D) to evaluate whether the treatment regimen is efficacious enough to 
warrant a Phase 2 study. 
Statistical Considerations 
This is a Phase I trial simultaneously evaluating feasibility and safety with a possible 
dose-expansion cohort to indicate efficacy in patients with relapsed/refractory ALL 
and aggressive B-cell NHL. Initially, 50% feasibility is required in the first 6 and 10 
patients with R/R aggressive B-cell NHL and R/R ALL, respectively; after which, 
80% feasibility is desired and will allow the study to replace a total of 10 or 6 patients 
with R/R aggressive B-cell NHL and R/R ALL, respectively.  The expected DLT rate 
is 20% for each disease population, however, the maximum acceptable DLT rate is 
30%. The traditional ‘3+3’ design will be used for possible dose-escalation in patients 
with R/R aggressive B-cell NHL across three dose levels.  If a feasible dose is 
established as MTD/RP2D for this disease population, the trial will expand for these 
patients to investigate an overall response rate (CR or PR at 3 months) greater than 
25% (using a Minimax Simon two-stage design to motivate sample sizes and decision 
rules). At the previously established dose level for R/R ALL patients, the trial will 
continuously monitor safety for a maximum 30% DLT rate and investigate an overall 
response rate (CR at 28 days) greater than 50% (using a Minimax Simon two-stage 
design to motivate sample sizes and decision rules). 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
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SCHEMA 
 
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR’S SIGNATURE PAGE .......................................................... 2 
SPONSOR DETAILS ................................................................................................................... 3 
STANFORD CO-INVESTIGATORS ......................................................................................... 3 
SYNOPSIS ..................................................................................................................................... 6 
SCHEMA ..................................................................................................................................... 14 
TABLE OF CONTENTS ........................................................................................................... 15 
TABLE OF FIGURES ................................................................................................................ 18 
TABLE OF TABLES .................................................................................................................. 18 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 19 
1 OBJECTIVES ....................................................................................................................... 22 
1.1 
PRIMARY OBJECTIVE ......................................................................................................... 22 
1.2 
SECONDARY OBJECTIVE .................................................................................................... 22 
1.3 
EXPLORATORY OBJECTIVES ............................................................................................... 22 
2 BACKGROUND AND RATIONALE ................................................................................ 22 
2.1 
RELAPSED/REFRACTORY B-CELL MALIGNANCIES IN ADULTS ........................................... 22 
2.2 
CHIMERIC ANTIGEN RECEPTOR (CAR) THERAPY .............................................................. 24 
2.3 
AUTOMATION OF CELLULAR THERAPY PRODUCT MANUFACTURING ................................ 35 
2.4 
SAFETY CONSIDERATIONS FOR CD22_CAR THERAPY ...................................................... 37 
2.5 
CORRELATIVE STUDIES BACKGROUND .............................................................................. 41 
2.6 
STUDY DESIGN .................................................................................................................. 43 
2.7 
PROTOCOL RATIONALE AND SUMMARY ............................................................................. 43 
3 PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ........................ 47 
3.1 
SCREENING PARTICIPANT ELIGIBILITY CHECKLIST ............................................................ 49 
3.2 
INFORMED CONSENT PROCESS ........................................................................................... 56 
3.3 
SUBJECT SCREENING ASSESSMENTS AND REGISTRATION .................................................. 56 
4 TREATMENT PLAN ........................................................................................................... 57 
4.1 
OVERVIEW ......................................................................................................................... 57 
4.2 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ................... 58 
4.3 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA ............. 61 
5 SUBJECT STUDY PROCEDURES ................................................................................... 62 
5.1 
SUBJECT SCREENING .......................................................................................................... 62 
5.2 
LEUKAPHERESIS FOR CELL ACQUISITION: .......................................................................... 64 
5.3 
CONDITIONING LYMPHODEPLETION CHEMOTHERAPY REGIMEN ....................................... 65 
5.4 
INVESTIGATIONAL AGENT ADMINISTRATION AND RESEARCH PROCEDURES ..................... 68 
5.5 
EVALUATIONS AND FOLLOW UP ........................................................................................ 73 
5.6 
OPTION FOR ADDITIONAL DOSE(S) OF CD22-CAR T CELLS.............................................. 80 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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6 INVESTIGATIONAL AGENT AND COMMERCIAL DRUG INFORMATION ........ 81 
6.1 
AUTOLOGOUS T CELLS TRANSDUCED WITH LENTIVIRAL VECTOR (CD22.BB.Z) CHIMERIC 
ANTIGEN RECEPTOR (CD22-CAR); FOLLOWING FLUDARABINE AND CYCLOPHOSPHAMIDE ......... 81 
6.2 
FLUDARABINE .................................................................................................................... 82 
6.3 
CYCLOPHOSPHAMIDE ......................................................................................................... 83 
6.4 
PRE-MEDICATIONS ............................................................................................................ 86 
7 ADVERSE EVENTS AND REPORTING PROCEDURES ............................................. 87 
7.1 
POTENTIAL ADVERSE EVENTS ........................................................................................... 87 
7.2 
ADVERSE EVENT DEFINITIONS........................................................................................... 88 
7.3 
ADVERSE EVENT REPORTING............................................................................................. 90 
7.4 
FDA REPORTING CRITERIA ............................................................................................... 92 
8 CORRELATIVE/SPECIAL STUDIES .............................................................................. 94 
8.1 
CORRELATIVE STUDIES ...................................................................................................... 94 
8.2 
MONITORING GENE THERAPY TRIALS: PERSISTENCE, AND RCL, AND TOXICITY .............. 95 
9 STUDY CALENDAR ........................................................................................................... 97 
10 MEASUREMENTS AND MONITORING ...................................................................... 100 
10.1 
PRIMARY AND SECONDARY ENDPOINTS .......................................................................... 100 
10.2 
INSTITUTIONAL REVIEW OF PROTOCOL ............................................................................ 101 
10.3 
DATA AND SAFETY MONITORING PLAN ........................................................................... 101 
10.4 
DATA MANAGEMENT PLAN ............................................................................................. 102 
11 COLLABORATIVE AGREEMENTS.............................................................................. 102 
12 STATISTICAL CONSIDERATIONS .............................................................................. 102 
12.1 
PRIMARY OUTCOMES: ...................................................................................................... 103 
12.2 
SECONDARY OUTCOMES .................................................................................................. 107 
12.3 
PROTOCOL STOPPING RULES ............................................................................................ 108 
12.4 
SAMPLE SIZE .................................................................................................................... 108 
13 APPENDICES ..................................................................................................................... 111 
13.1 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................. 111 
13.2 
APPENDIX B:  GUIDELINES TOXICITY ASSESSMENT AND MANAGEMENT ........................... 112 
13.3 
APPENDIX C:   RESPONSE CRITERIA .................................................................................. 118 
13.4 
APPENDIX D: MONITORING GENE THERAPY TRIALS: REPLICATION COMPETENT LENTIVIRUS 
(RCL) 122 
13.5 
APPENDIX E:  DRAFT LETTER AND QUESTIONNAIRE TO SUBJECTS FOR LONG TERM 
FOLLOW-UP FOR DELAYED ADVERSE EVENTS ............................................................................. 123 
13.6 
APPENDIX F:  PHYSICIAN (LOCAL MEDICAL PROVIDER) LETTER..................................... 125 
13.7 
APPENDIX G: CORRELATIVE SAMPLE SCHEDULE ............................................................. 126 
13.8 
APPENDIX H: ENROLLMENT 
USING TWO STAGES: 1) LEUKAPHERESIS 
AND 2) 
LYMPHODEPLETION CHEMOTHERAPY AND CELL INFUSION ......................................................... 127 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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14 REFERENCES .................................................................................................................... 142 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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TABLE OF FIGURES 
Figure 1: Constructs Created to Evaluate CD22 CAR vector formats ......................................... 29 
Figure 2: CD22 scFv binding sites ............................................................................................... 30 
Figure 3:  CTL Activity of CAR T cells ....................................................................................... 31 
Figure 4: CD22-CAR activity, dose escalation experiment .......................................................... 32 
Figure 5: Demonstrating equivalency of RV and LV vector transduction in disease-bearing mice
....................................................................................................................................................... 32 
Figure 6: CD22 Site Density with CD22 CAR T cell Therapy .................................................... 35 
 
TABLE OF TABLES 
Table 1: Surface Expression of CD22 in Cases of B-lineage ALL and DLBCL ......................... 27 
Table 2. Manufacturing Differences at Stanford and NCI for CD22-CAR T cells ...................... 36 
Table 3. CD22-CAR Dose Levels ................................................................................................ 46 
Table 4. Conditioning Lymphodepletion Chemotherapy Regimen .............................................. 67 
Table 5. CD22-CAR Product Rapid Release Criteria ................................................................... 68 
Table 6. Dose Escalation Rules for Subjects with Aggressive B-cell NHL ................................. 71 
Table 7. Maximum DLTs during Dose Expansion in Subjects with Aggressive B-cell NHL ... 106 
Table 8. Maximum DLTs during Dose Expansion in Subjects with ALL ................................. 106 
Table 9. Enrollment Table by Objective ..................................................................................... 109 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
ADL 
Activities of daily living 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALL 
Acute lymphoblastic leukemia 
ALT/ AST 
aspartate transaminase/ alanine transaminase 
ANC 
Absolute neutrophil count 
APB 
Administrative Panel on Biosafety 
BID 
Twice daily 
BITE 
Bi-specific T-cell Engager 
BLA 
Biologic license application 
BSA 
Body surface area 
CAR 
Chimeric Antigen Receptor 
CBC 
Complete blood count 
CI 
Confidence interval 
CLS 
Capillary Leak Syndrome 
CMAX 
Maximum concentration of drug 
CMS 
Centers for Medicare & Medicaid Services 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
COA 
Certificate of Analysis 
CR 
Complete response 
CRF 
Case report/Record form 
CRi 
complete response with incomplete blood count recovery 
CRP 
C reactive peptide 
CRS 
Cytokine release syndrome 
CSF 
cerebral spinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTF 
Cellular Therapeutics Facility 
DIC 
Disseminated intravascular coagulation 
DLBCL 
Diffuse large B-cell lymphoma 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
DLT 
Dose Limiting Toxicity 
DMSO 
Dimethyl Sulfoxide 
DOR 
Duration of Recovery 
DSMC 
Data Safety Monitoring Committee 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event free survival 
ELISA 
enzyme-linked immunosorbent assay 
FDA 
Food and Drug Administration 
FIH 
First in Human 
FL 
Follicular lymphoma 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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GI 
Gastrointestinal 
GMP 
Good Manufacturing Practices 
GvHD 
Graft versus Host Disease 
HbsAG 
Hepatitis B surface antigen 
HDT 
high dose platinum-based therapy 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HLH 
Hemophagocytic lymphohistiocytosis 
HPF 
High-power field 
HSCT 
Hematopoietic Stem Cell Transplant 
HSV 
herpes simplex virus 
HTN 
Hypertensions 
HUS 
Hemolytic Uremic Syndrome 
IDB 
ideal body weight 
IL-2 
interleukin-2 
IRB 
Institutional Review Board 
IV 
Intravenous 
LAR 
Legally Authorized Representative 
LCGM 
Stanford’s Laboratory for Cell and Gene Medicine 
LLN 
Lower limit of normal 
LP 
Lumbar puncture 
LV 
Lentivirus 
LVEF 
left ventricular ejection fraction 
MAS 
macrophage activation syndrome 
MHC 
Major Histocompatibility Complex 
MI 
myocardial infarction 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA scan 
multigated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
Next generation sequencing 
NHL 
Non-Hodgkin lymphoma 
OKT3 
anti-CD3 antibody 
OR 
Overall response 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
Progressive disease 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PFT 
Pulmonary function test 
PLT 
Platelet 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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PMBCL 
Primary mediastinal large B-cell lymphoma 
POB 
Pediatric Oncology Branch 
PR 
Partial response 
QD 
Once daily 
R-CHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone 
R/R 
Relapsed/refractory 
RCL 
Replication competent lentivirus 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended phase 2 dose 
RR 
Response rate 
RV 
Retrovirus 
SAE 
Serious adverse event 
SaO2 
oxygen saturation level 
scFv 
single chain variable fragment 
SCT 
stem cell transplant 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
SRC 
Scientific Review Committee 
TCR 
T-cell Receptor 
TCS 
T-cell selection 
tDLBCL 
transformed DLBCL 
TLS 
Tumor lysis syndrome 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
VZV 
varicella zoster virus 
WBC 
White blood cell 
WHO 
World Health Organization 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
22 of 150 
Amd 3, Version 2022-0722 
1 
OBJECTIVES 
1.1 
PRIMARY OBJECTIVE 
o Determine the feasibility of manufacturing CD22-CAR T cells using the Miltenyi 
CliniMACS Prodigy® system for administration to adults with relapsed/refractory CD22 
expressing B-cell ALL or relapsed/refractory aggressive B-cell NHL. 
o Establish the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of 
CD22-CAR T cells in adults with relapsed/refractory aggressive B-cell NHL. 
o Determine the safety of an established dose of CD22-CAR T cells in adults with 
relapsed/refractory CD22 expressing B-cell ALL and the safety of the MTD/RP2D of 
CD22-CAR T cells in adults with relapsed/refractory aggressive B-cell NHL. 
1.2 
SECONDARY OBJECTIVE 
o Assess the clinical activity of CD22-CAR T cells in adults with R/R CD22 expressing B-
cell ALL and R/R aggressive B-cell NHL, including overall survival (OS) and progressive 
free survival (PFS). 
1.3 
EXPLORATORY OBJECTIVES 
As part of participation  
o Analyze alterations in early B cell development induced by immune pressure exerted via 
CD22-CAR T cells.   
o Evaluate whether subjects receiving CD22-CAR T cells relapse with loss or diminished 
expression of CD22, when feasible. 
o Measure persistence of CD22-CAR T cells in the blood, bone marrow and CSF, and 
explore correlations between CD22-CAR T cell properties and CAR T cell efficacy and 
persistence.   
o Establish the utility of chromatin structure and epigenomic technology to characterize CAR 
T cell therapies.   
o Analyze CD22 expression in aggressive B-cell NHL and correlate with disease response. 
2 
BACKGROUND AND RATIONALE 
2.1 
RELAPSED/REFRACTORY B-CELL MALIGNANCIES IN ADULTS 
2.1.1 Acute Lymphoblastic leukemia (ALL)  
Relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) is a predominantly 
CD19+/CD22+ hematologic malignancy that is associated with dismal long-term survival in both 
children and adults.  The incidence of ALL follows a bimodal distribution with the first peak 
occurring in early childhood, and a second occurring in older adults.  Although survival rates for 
pediatric ALL have consistently improved over the last 20 years with most recent estimates of 
long-term disease free survival of 90% in children with standard-risk B-cell ALL,[39] outcomes 
for children and adults with relapsed/refractory B-cell have remained particularly poor.   
In 2017, FDA approved Kymriah™ (CTL019, tisagenlecleucel) the first chimeric antigen receptor 
(CAR) T cell therapy for children and young adults (up to 25 years of age) with R/R B-cell 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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ALL[40].  The approval was based on an overall remission rate of 83% (52/63).  Two other studies 
conducted using CTL019 reported overall remission rates of 69%-95%, while all three reported 
similar complete remission rates (62-69%)[12],[18, 41].  Importantly, OS at 12 months was 
improved relative to OS reported with other therapeutic agents such as clofarabine, blinatumomab 
or combination therapy with clofarabine/etoposide/cyclophosphamide.   
Despite improvements in pediatric ALL survival rates, the survival rate in adult ALL has remained 
flat at 30-40%[42].  Outcomes for adults with relapsed/refractory B-cell ALL have been 
particularly poor.  For these subjects, complete response (CR) to conventional salvage 
chemotherapy occurs in < 30% and disease-free survival following salvage therapy with or without 
allogeneic SCT has been reported to be < 25% in younger adults and < 10% in adults 
≥ 50 years[1],[2],[43],[3].  Toxicity associated with chemotherapy and SCT are substantial, and 
adult subjects who relapse following SCT rarely experience long-term survival[44].   
Therapeutic advances in adult B-cell ALL have been achieved in recent years.  Notably, the 
development and FDA approval of the anti-CD19/CD3 bi-specific T-cell engaging (BITE) agent 
blinatumomab has resulted in complete response rates in adult subjects with R/R B-cell ALL of 
50-80%[45],[46] and 30-40% in children[47]; however, the responses are often not durable and 
many subjects relapse without consolidative allogeneic stem cell transplant.  Further, 
approximately 20% of subjects treated with CD19 targeting BITE therapy will experience CD19 
escape, relapsing with CD19 negative leukemia[20].   
Inotuzumab ozogamicin, a humanized anti-CD22 antibody conjugated to the cytotoxic molecule 
calicheamicin, was FDA-approved in August 2017 for the treatment of R/R B-cell ALL in adults.  
In the pivotal Phase III trial conducted in adults with R/R B-cell ALL expressing CD22, CR was 
achieved in approximately 80%, but remission duration was only a median of 4.6 months (95% CI, 
3.9 to 5.4 months[6]).  Additional agents are thus needed in order to improve the outcomes of 
adults with B-cell ALL.   
2.1.2 Lymphoma 
Diffuse Large B-Cell Lymphoma (DLBCL) is a CD19+/CD22+ non-Hodgkin lymphoma that 
represents the most common aggressive lymphoid malignancy in the United States and Europe, 
accounting for approximately 30-40% of all non-Hodgkin lymphoma (NHL)[48],[49].  There are 
approximately 25,000 new cases of DLBCL in the US each year[50].   
Therapeutic advances have been achieved in standard first-line treatment of DLBCL with the 
addition of the anti-CD20 monoclonal antibody rituximab to cyclophosphamide, doxorubicin, 
vincristine, and prednisone (R-CHOP)[51],[52].  Despite this, about one-third of subjects with 
DLBCL do not achieve durable remission and/or relapse following intial response. [53],[54],[55]. 
The current approach to R/R DLBCL is salvage chemotherapy followed by high dose platinum-
based therapy (HDT) and autologous stem cell transplantation (SCT)[56].  Unfortunately, half of 
subjects with primary relapsed/refractory disease are not eligible for HDT and autologous SCT 
right because of age (typically older than 70-75 years), comorbidities, or lack of adequate social 
support to help with the care needed after transplantation [57].  Of the remaining 50% initially 
eligible, an additional 50% do not receive HDT-SCT mainly because their disease shows no 
sensitivity to salvage chemotherapy[7].  Thus, only a fraction of patients with relapsed DLBCL 
will be cured with HDT followed by autologous SCT[54].   

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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The large SCHOLAR-1 retrospective study highlights the poor outcomes across all subgroups of 
chemorefractory DLBCL.  For these subjects, expected median OS is only 6-7 months, with the 
lowest OS rates observed in subjects refractory to second or later line therapy and those who 
relapse less than 12 months after SCT.  In aggregate, response to therapy in refractory DLBCL 
was 26%, with a CR rate of only 7%[58].   
Similarly, the recently reported REFINE collaborative retrospective study analyzed the outcomes 
of subjects with primary refractory DLBCL.  They reported an overall response rate [(OR) = 
complete response (CR) + partial response (PR)] of approximately 40% to salvage therapy.  For 
the subgroup undergoing autologous SCT, the 2-year OS rate was only 54.9%, with the subgroup 
with germinal center B type DLBCL with positive c-myc expression (by FISH) having a far worse 
OS rate of 23.7%[59]. Thus, there is a pressing need to develop and incorporate novel therapeutic 
agents into the treatment of subjects with R/R  DLBCL. 
In October 2017, CAR T cell therapy directed at CD19+ R/R B-cell lymphomas entered the clinical 
landscape as a very promising new approach.  Objective response rates of approximately 70% and 
CR rates of approximately 50% in heavily pre-treated R/R adult DLBCL patients led to the recent 
FDA approval of axicabtagene ciloleucel (Yescarta™) and tisagenlecleucel (Kymriah™) in 
DLBCL refractory to at least two lines of previous therapy[60];[15]. 
2.2 
CHIMERIC ANTIGEN RECEPTOR (CAR) THERAPY  
Chimeric Antigen Receptor (CAR) expressing T-cells is a new therapy wherein a subject’s own 
T-cells are harvested and subsequently genetically modified in order to target cell surface antigens 
on specific cancer cells.  CARs are non-native receptors that link an antigen-binding domain to 
cell signaling domain(s).  When expressed in T cells, they endow major histocompatibility 
complex (MHC)-unrestricted antigen specificity.  Most commonly, CARs utilize a single chain 
variable fragment (scFv) coupled to TCR zeta and CD28 or 4-1BB endodomains.  In addition to 
their specificity, these CAR T-cells can be modified to be highly proliferative and possess the 
ability to negate immunosuppressive mechanisms making them ideal agents against highly 
aggressive cancers.  Beginning in 2010, several groups published clinical results using CAR 
T cells targeting CD19 for B cell malignancies.   
2.2.1 CD19 CAR T Cell Therapy 
CD19 is a 95 kD transmembrane protein with expression restricted to the B cell lineage.  
Expression of CD19 is present from the time of immunoglobulin rearrangement through B cell 
development and maturation until it is lost with terminal plasma cell differentiation[61].  It is not 
expressed on primitive hematopoietic stem cells.  CAR T cells targeting CD19 (CD19-CAR)first 
demonstrated impressive clinical efficacy in small case series in adults with B cell lymphomas and 
chronic lymphocytic leukemia [62-64].  The first pediatric report followed shortly after and 
demonstrated striking responses in two children with refractory B-ALL[18].  The demonstration 
of exquisite sensitivity of acute B cell leukemias inspired multiple centers to advance translation 
of CD19 targeting CARs.  Despite utilizing varying strategies, clinical trials from multiple 
institutions have consistently shown dramatic activity of CD19-CAR T cells in pediatric and adult 
subjects with relapsed and refractory B-ALL with complete responses rates of ≥ 70% across trials  
[8],[9],[10],[6, 11, 15, 47].   
Independent of the infused T cell dose, anti-leukemic effects generally do not occur in the absence 

Protocol: CD22 CAR T-cell in Adults 
  
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of expansion of the CD19-CAR T cells in vivo.  Dramatic CD19-CAR T cell expansion can be 
observed, with > 1000-fold expansion occurring within 1-2 weeks in subjects with high tumor 
burden.  CAR T cell expansion can be quantified using polymerase chain reaction (PCR) to 
measure the number of cells with integrated virus or by flow cytometry, where is it not uncommon 
to observe during expansion that > 70% of all circulating T cells express the engineered 
CD19-CAR receptor.  Expansion of CAR T cells is antigen driven, but is greatly enhanced 
following a lymphodepleting preparative chemotherapy regimen.  Extensive preclinical work has 
demonstrated that lymphopenia induces elevations in the availability of cytokines that drive T cell 
expansion, notably IL-7 and IL-15, and that increased availability of such factors leads to enhanced 
expansion and improved efficacy[65].  Based upon this paradigm, the vast majority of clinical 
trials using CAR T cells incorporate a pre-infusion preparative regimen comprising 
cyclophosphamide and fludarabine, agents known to induce profound lymphocyte depletion.   
Another major insight gleaned from the substantial clinical experience with CD19-CAR T cells 
for B cell malignancies is the differential impact of distinct costimulatory domains on T cell 
function.  It has become evident that CD28 costimulation facilitates more rapid and higher peak 
T cell expansion[9, 10]; it also predisposes T cells to early exhaustion, which leads to poor 
long-term T cell persistence as a result of activation induced cell death[36].  In contrast, 4-1BB 
costimulation is associated with a slower expansion rate, lower CAR T cell peak level, a 
diminished risk of T cell exhaustion and more prolonged persistence following adoptive 
transfer[36].  Although remission induction rates do not appear to differ between CD28 and 4-1BB 
costimulatory domain containing CD19-CARs, sustained remission likely requires T cell 
persistence and thus 4-1BB CARs may confer improved long-term outcomes. 
2.2.2 CD19 Immune Escape Following CD19 Directed Immunotherapy 
CD19 is universally expressed at high levels on B-ALL and DLBCL at diagnosis, and levels of 
expression do not change appreciably following cytotoxic therapy.  Indeed, CD19-based flow 
cytometry provides powerful prognostications by measuring minimal residual disease (MRD) 
following standard cytotoxic therapy in B-ALL[66],[67],[68].  However, with the introduction of 
CD19-based immunotherapies, relapse with diminished or absent surface CD19 has been 
increasingly observed.  CD19 immune escape was first reported following blinatumomab 
therapy[69], and has been observed by several groups following CD19-CAR therapy for B-ALL 
and DLBCL [18],[10, 19],[16].  In a recent report from Children’s Hospital of Philadelphia of 50 
subjects rendered into remission with CD19-CAR therapy, 40% of subjects had relapsed with a 
median follow-up of 10.5 months; and loss of the CD19 target accounted for 65% of the total 
relapses[70].  Similarly, in an expanded cohort of 75 subjects, loss of CD19 was seen in 15 of 16 
subjects studied at the time of relapse[15].  Finally, in a report of CD19-CAR therapy for B-cell 
NHL, low expression of CD19 was reported in over 25% of patients with relapsed disease 
following CAR therapy[13].  While the true incidence of relapse due to CD19 immune escape has 
not yet been established, our CD19-CAR experience to date has implicated CD19 escape as the 
most common cause of post CD19-CAR relapse in B-ALL and B-cell NHL.   
Investigation into the biology of CD19 immune escape has identified a complex biology guiding 
the loss or downregulation of CD19 expression.  The two distinct patterns of tumor remodeling 
that have been recognized are categorized as the “isoform switch” and “lineage switch”.  The 
majority of cases of CD19 loss in ALL fall into the “isoform switch” category, wherein the cells 
retain all other characteristics of B-ALL and there is no clear evidence for alteration in fitness.  In 

Protocol: CD22 CAR T-cell in Adults 
  
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the majority of “isoform switch” cases, mRNA specific for CD19 is retained, but is enriched for 
CD19 isoforms that preferentially remain intracellular, lack a transmembrane domain, and/or lack 
the epitopes targeted by all CD19-CARs currently under study as well as blinatumomab[71].  Such 
B-ALL cells resultantly express reduced total surface levels of wild-type CD19 or express aberrant 
CD19 that lack the epitope targeted by CD19-CARs and blinatumomab.  In “lineage switch” cases, 
tumor cells undergo switching from the lymphoid to the myeloid lineage with a resultant 
population with myeloid markers and features that clonally relates to the parental B cell 
leukemia[19].    
2.2.3 CD22 Expression in ALL and B-cell NHL 
CD22 is a 140-kD phosphoglycoprotein member of the Ig superfamily that functions as a B-cell 
receptor signal transduction modifier and a cellular adhesion molecule[72],[73],[74],[75].  CD22 
is restricted to cells of B-lineage and is expressed on the surface of mature B cells[76].  A variety 
of B-lineage malignancies are CD22+, including 96 to 100% of cases of childhood B-precursor 
ALL and 66 to 100% of Burkitt’s lymphoma, with the majority of malignant cells expressing this 
antigen[77],[78],[79],[80],[81],[82].  In addition, CD22 expression is restricted to the B 
lymphocyte lineage beginning at the stage at which IgD expression is initiated[73],[83],[84],[85].  
Targeting CD22 is especially important in the growing era of CD19 targeted therapy for two 
reasons: 1) Not all patients respond to CD19 targeted therapies and 2) CD19-negative escape has 
been observed following CD19-CAR therapy, as well as following anti-CD19/CD3 bispecific 
antibody.  Thus, additional targeted strategies are needed. 
A recent study performed at the National Cancer Institute (NCI) evaluating CD22 expression in 
children, adolescents and young adults with relapsed/refractory ALL (Table 1), demonstrated that 
CD22 was expressed on 100% of all samples (n=132)[86].  Median antigen site density of surface 
CD22 was 3,470 sites/cell (range 417-19,653, n=128).  In those with known 11q23 MLL 
rearrangement, site density was lower (median 1,734 sites/cell (range 417-3,624, n=18)) 
(p=<0.0001) and 5 of 19 cases had sub-populations of blasts lacking CD22 expression (22%, 29%, 
73%, 75% and 82% CD22+).  CD22 expression was maintained in serial studies of 58 subjects, 
including those treated with anti-CD22 immunotoxins.  The levels of soluble CD22 measured in 
the blood and marrow by ELISA were low and would not affect the pharmacology of anti-CD22 
directed agents.  CD22 expression was recapitulated in 9 of 9 human ALL-murine xenografts 
established with limiting dilution studies, suggesting the presence of CD22 expression on leukemia 
initiating cells.  These characteristics make CD22 an excellent target in ALL, though cases with 
MLL rearrangement may warrant further study[87].  
CD22 has been reported to be nearly universally expressed in B-cell NHL, including in samples 
obtained from patients with newly diagnosed and/or R/R disease and evaluated for CD22 
expression by flow cytometry[32],[88] (Table 1).  However, a recent study evaluated CD22 
expression in 32 patient samples of patients with R/R DLBCL and found variable CD22 expression 
by immunohistochemistry ranging from 0-100% expression on lymphoma cells[89].  Interestingly, 
several studies evaluating anti-CD22 agents including antibody-drug conjugates have 
demonstrated no association between CD22 expression level and response to these agents in 
CD22+ DLBCL[89],[32],[90]. 

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Table 1: Surface Expression of CD22 in Cases of B-lineage ALL and DLBCL 
Series 
Cases CD22 +a 
CD22 + % Blasts 
Median (range, if 
available) 
CD22 Site Density 
Sites/cell 
Median (range) 
Bostrom[91] 
31/31 (100%) 
N/A 
N/A 
Lones[92]  
55/55 (100%) 
96% (74-99%) 
N/A 
Yusuf[93] 
48/50 (96%) 
N/A 
N/A 
Chevallier[31] 
42/45 (95.5%) 
(95.5%) with greater than 
90% 
N/A 
Raponi[28] 
397/427 (93%) 
(79.9%) with CD22+ on 
100% blasts 
(13.1%) with partial 
expression 
1450 (548-2487) pro-B ALL 
2356 (412-8294) B-common 
ALL 
2810 (793-9143) Pre-B ALL 
Iwamoto[94] 
70.3% (of 1250 early pre-B cases) 
87.6% (of 248 pre-B cases) 
60.5% (of 45 mature B cases) 
N/A 
N/A 
Shah, et al. 
132/132 (100%) 
100% (22-100%) 
3,470 (417-19,653) 
Polson (2010)[32] 
59/59 (100%) in DLBCL 
N/A 
N/A 
Boyd (2013)[88] 
34/35 (97%) in DLBCL 
N/A 
N/A 
Pfeifer (2015)[89] 
26/32 (81%) in DLBCL  
N/A 
N/A 
Importantly, CD22 is not expressed on pluripotent hematopoietic stem cells.  While destruction of 
normal B cells is a drawback to targeting CD22, clinical experience suggests that destruction of 
normal B cells is a tolerable toxicity of leukemia-directed therapy.  When patients receive the anti-
CD20 monoclonal antibody rituximab, the number of normal B cells is severely depressed for 
several months[95], yet patients that receive chemotherapy plus rituximab do not have an increased 
rate of infections when compared to patients that receive chemotherapy alone[96].  Similarly, 
patients with congenital absence of B cells have prolonged survival and acceptable quality of life 
as a result of intravenous infusions of IgG (IVIG).   
Several monoclonal antibodies, including epratuzumab[62] a fully humanized unconjugated 
monoclonal antibody targeting CD22; inotuzumab ozogamicin[97],[98] an anti-CD22 monoclonal 
antibody conjugated to the calichaemicin toxin; and moxetumomab pasudotox[99],[100], an anti-
CD22 immunotoxin monoclonal antibody conjugated to the pseudomonas exotoxin, have been 
studied in the treatment of CD22 expressing hematologic malignancies.  Experiences to date have 
demonstrated safety and efficacy of targeting CD22 in patients with relapsed/refractory disease, 
although the optimal dosing, schedule and incorporation of this approach with combination therapy 
are under study.   
2.2.4 Development of an CD22-CAR for Clinical Adoptive T Cell Transfer 
Chimeric antigen receptors (CARs) were developed that could be used to re-target activated T 

Protocol: CD22 CAR T-cell in Adults 
  
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lymphocytes to recognize and eliminate CD22+ leukemias.  The T cells are derived from 
peripheral blood and activated in tissue culture with either anti-CD3 antibody alone (OKT3) or 
with beads that have been conjugated to both OKT3 and an anti-CD28 antibody, in the presence 
of interleukin-2 (IL-2).  Activated T cells can be readily transduced with either retrovirus-based 
(RV) or lentivirus-based (LV) gene vectors.  Vectors are produced by transfecting a producer cell 
line (293-GP for retrovirus) with a plasmid encoding a viral envelope glycoprotein and a second 
plasmid containing the viral vector backbone construct which includes the gene of interest, 
bounded by sequences that will insure its packaging into a RV or LV particle and subsequent 
expression of that backbone gene in the target cell of interest, the activated T cell.  The safety of 
RV or LV is assured by splitting the envelope genes, the backbone containing the gene insert, and 
the packaging genes, between different plasmids or in the packaging cell itself.  The LV system 
contains even more safety features with regard to segregating the genes required to make a vector 
particle, and thus making the re-emergence of an infectious particle essentially impossible; 
although it is tested for replication competency each time a new batch of vector is created.  The 
engineered receptor is called “chimeric” because it is a fusion between an extracellular antibody-
derived binding domain (usually called the scFv), and T cell derived transmembrane signaling 
domains that activate a T cell bearing the CAR once it associates with another cell bearing the 
target antigen that the scFv can bind to.  In short, the CAR gene of interest combines the antigen 
binding capacity of an antibody with the T cell activation domains that are activated when the T 
cell recognizes cognate antigen by virtue of the antigen T cell receptor (TCR).   
With the assistance of Dr. Ira Pastan, whose group developed the binding domains used in the 
recombinant CD22 immunotoxin, NCI Pediatric Oncology Branch (POB) investigators 
incorporated the identical binding domains into CAR constructs.  The Pastan lab at NCI had 
developed both BL22, the original anti-CD22 binding scFv, and HA22, a high-affinity anti-CD22 
scFv.  HA22 is a specifically mutated version of BL22, where 3 key amino acids in the CDR3 
binding domain were changed to increase soluble immunotoxin’s potency approximately 10-
fold[10].  Through molecular cloning, the BL22 and HA22 CD22 binding sites (the scFv) were 
ligated to DNA sequences encoding T lymphocyte specific transmembrane and signaling 
domains[29].  Additional CD22-CAR constructs were generated using another anti-CD22 scFv 
binding motif, called M971, that had been developed by the laboratory of Dr. Dimiter Dimitrov at 
NCI Frederick[9] .   
We have also collaborated with Dr. Steven Rosenberg and Dr. Richard Morgan in NCI Surgical 
Oncology Branch.  They had developed a series of retroviral vector backbone vector constructs 
that could be used to rapidly test new binding motifs for CARs.  These vectors feature either a 
second generation signaling package, comprised of CD28 and the CD3 zeta chain, or a third 
generation signaling package, featuring CD28, 4-1BB (CD137), and CD3-zeta signaling motifs.  
These vectors also differed in that the second-generation vectors used the native CD28 
transmembrane domain, while the third-generation vectors used the transmembrane domain from 
CD8 (see Zhao, Y., 2009 J Immuno[101], for a full description of these combinations).  We also 
re-engineered the Surgery Branch backbone vectors to create a second generation retroviral 
backbone that expressed the CD8 transmembrane linked to the 4-1BB (CD137) and CD3-zeta 
signaling domains.  One other major variable we tested for in our vector formats was the inclusion 
of the CH2CH3 domains from IgG1 in the membrane proximal extracellular domain.  To date 
there is no clear rule with regard to vector format construction, and some vector formats benefit 
from having the scFv binding domain extended away from the transduced T cell plasma 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
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membrane.  
Figure 1: Constructs Created to Evaluate CD22 CAR vector formats 
 
The inclusion of this constant domain was not beneficial in any of the anti-CD22 CAR constructs 
tested and so it was not included in the final vector format.  Thus, we extensively tested three 
different scFv specific for CD22 (BL22, HA22, M971), the optimal distance of the scFv from the 
T cell membrane by including the IgG CH2CH3 domain, and both second and third generation 
signaling packages, see Figure 1.  Of note, the most important variable turned out to be the actual 
binding site of the scFcv on CD22 itself.  M971 differed from BL22 and HA22 in that it bound to 
a different portion of the CD22 molecule, and it was this attribute, more proximal binding to the 
membrane, that provided the most active CAR construct[73].  M971 has the further advantage of 
being entirely derived from human sequences.  M971 was derived from a human B cell derived 
cDNA library and thus there is no need to “humanize” the sequence, which is often carried out for 
scFv derived from murine monoclonal antibodies.  The relative binding sites of HA22, M971, and 
a comparison to CD19 are illustrated in Figure 2. 
Figure 1.  In this figure some of the constructs created to evaluate CD22 CAR vector formats are illustrated.  All constructs are 
bounded by the RV-derived LTR sequences.  Not shown but implied are the SA/SD and packaging sites following the 5’ LTR 
that allow RNA from the linear plasmid sequence to be packaged into vector particles as they bud from the plasma membrane 
of the producer cell line.  In addition to transfection with these backbone vectors, an env encoding plasmid vector (we use 
RD114 for RV and VSV-G for LV) must also be transfected into the producer line.  Shown above the constructs is a large 
arrowhead where the transmembrane region of the protein transcribed from this vector would be located.  Vectors are oriented 
around this point to communicate the general orientation of the domains with regard to the T cell surface.  Illustrated are three 
different scFv (HA22, in gray; M971, orange; FMC63 (anti-CD19), blue), and the IgG1 derived CH2CH3 domain for the “Long” 
vector formats.  Third generation vectors encode the CD28 (white), 4-1BB (CD137, light blue), and CD3-zeta chain (pink) 
signaling motifs.  For illustration we show the anti-CD19 CAR currently used in NCI clinical trials, which is a CD28-CD3-zeta 
second generation whose scFv is derived from the FM63 antibody. 

Protocol: CD22 CAR T-cell in Adults 
  
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Figure 2: CD22 scFv binding sites 
 
 
To test for the anti-leukemic activity of CD22-CAR T cells, retroviral vector-containing 
supernatants were generated for each of the constructs described.  The variables in domain 
structure included either two (second-generation CARs) or three (third-generation CARs) 
signaling domains, and either a “long” (containing the IgG CH2CH3 domain) or “short” (just the 
scFv) extracellular formats (Figure 1).  Second-generation CARs were composed of either CD28 
and CD3-zeta chain derived signaling domains or CD137 (4-1BB) and CD3-zeta chain motifs.  
Third generation CARs, which combined CD3-zeta, CD137, and CD28 motifs, always had lower 
surface expression on transduced T cells and provided no advantage in in vitro killing assays (using 
CD22+ leukemia cell lines as targets) or in cytokine production assays (not shown), and so efforts 
were concentrated on developing the two second generation formats.  Our primary screening tool 
was to measure the ability of T cells transduced to express CARs to kill leukemia cells bearing 
CD22.  Representative cytotoxic T lymphocyte (CTL) killing assays are shown in Figure 3.  For 
a positive control we used the CD19-CAR construct, and for a negative control we used non-
transduced T cells that were cultured and activated in parallel (Mock).  In this assay the superiority 
of the M971 construct is seen, as killing at equivalent effector-to-target ratios is superior to that of 
HASH 28z-CAR construct for all leukemia lines tested (see Figure 3).  T cells that were not CAR 
transfected (mock) did not kill leukemia cell lines.  When cytokine production was measured by 
CAR-expressing T cells, the levels of interferon gamma uniformly matched the activity of that 
CAR in cell killing assays (not shown).   
Figure 2.  CD22 scFv binding sites.  In this schema the relative 
positions of the HA22/BL22 and the M971 binding epitopes on 
the CD22 molecule are shown.  For comparison, the CD19 
molecule (filled circles), which has only 2 Ig-like structural 
domains as opposed to the 7 present in CD22 is shown.  FMC63 
is the scFv upon which the CD19-CAR is based. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
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Figure 3:  CTL Activity of CAR T cells 
 
The ability to transduce T cells and to function in in vitro assays of immune activity, such as in the 
CTL assay, was the first level of CAR construct evaluation.  CD22-CAR constructs with the 
highest activity were then tested in in vivo assays.  In these assays, NSG immunodeficient mice 
were injected intravenously (IV) with the NALM6 leukemia cell line that has been permanently 
transfected to express the luciferase gene (termed NALM6-GL, gift of S. Grupp and D. Barret, 
Children’s Hospital of Pennsylvania).  When NALM6-GL grows as a xenograft in the 
immunodeficient mice, the leukemia can be detected by imaging the mice with sensitive CCD 
camera that can measure photons produced by the luciferase enzyme following injection of the 
mice with the substrate luciferin.  Although numerous experiments were carried out with the 
differing constructs, the optimal in vivo results were obtained when the leukemia-bearing mice 
were treated with a CAR that expressed the M971 scFv linked to the 4-1BB and CD137 signaling 
domains, Figure 4.  In this assay, human T cells were activated with anti-CD3/anti-C28 beads in 
the presence of 40 U/mL IL-2 and a transduction rate of 90% was achieved.  A half-million 
NALM-6 human leukemia cells were injected on day 0, and three days later, CAR-expressing 
human T cells were injected (day 10 following initial activation).  Mice were treated with non-
transduced, or 1x105, 1x106, 5 x106, or 15 x106 CD22-CAR T cells.  A clear dose response 
relationship was seen (Figure 4).  Mice receiving 1 x105 transduced T cells showed no effect and 
were indistinguishable from mice treated with the non-transduced T cells.  Mice receiving 15 x106 
cells were completely cleared of disease.   
Figure 3.  CTL Activity of CAR T cells.  Human PBMC were activated in vitro then transduced 48 hours later with RV 
vector-containing supernatants encoding either CD19-CAR (upper right), the M971-CAR (lower left), or the CD22-specific 
HASH 28z-CAR (lower right).  Cells were transduced for two consecutive days and then expanded 4-5 more days in IL-2 
containing media.  All vectors in this figure used second-generation, CD28-CD3 zeta chain, signaling motifs, and hence 
differed only in their extracellular binding domains.  Also compared was a third generation HA22 vector and a second 
generation CD22 vector with 4-1BB signaling motifs.  These did not have better killing than the HASH 28z construct shown 
here.  Leukemia cell lines positive for both CD19 and CD22 (REH, SEM, NALM6, KOPN8, Daudi, Raji) and a control cell 
line (K562) were labeled with 51Cr and used in a standard 5-hour Cr-release assay.  Results are reported as percent lysis of 
targets versus the ratio of effector cells (CAR-Ts) to targets cells (leukemia cells) in triplicate wells. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
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Figure 4: CD22-CAR activity, dose escalation experiment 
 
While there is no expectation that a LV-based CAR would function any differently in a transduced 
T cells than a RV-based CAR, a series of animal studies were carried out with LV constructs 
generated by the Mackall laboratory and using LV vector produced by the GMP-based protocol at 
Lentigen, Corp.  Figure 5 demonstrates the equivalency of both methods of T cell transduction. 
Figure 5: Demonstrating equivalency of RV and LV vector transduction in disease-bearing 
mice 
 
Figure 5.  Demonstrating equivalency of RV and LV vector transduction in disease-bearing mice.  Conditions identical to Figure 4 
were used to analyze identical activated T cell populations transduced with either the anti-CD22 M971-BBz vector produced in a 
LV format or RV format.  Mice treated with non-transduced T cells (mock) had to be sacrificed due to disease burden as per animal 
facility requirements prior to assessment on day 26. 
Figure 4.  CD22 CAR activity, dose escalation experiment.  NSG (immunodeficient) mice were injected with 0.5 x106 
NALM6-GL cells on day 0, and imaging performed on day 3, using luciferin substrate, to demonstrate the presence of 
leukemia in all animals.  On day 3, indicated groups of mice were injected IV. with 0.1, 1, 5, 10, or 15 x106  CD22-CAR 
transduced T cells.  The CAR used expressed the m971 scFv and the CD3-zeta chain and CD137 signaling motifs.  T cells 
were stimulated with anti-CD3/CD28 beads, cultured in 40 units/mL interleukin-2, and used 10 days after the initial 
stimulation.  Mice were imaged again on day 5 and day 8, and complete elimination of the leukemia was seen with the highest 
dose level by day 8. 

Protocol: CD22 CAR T-cell in Adults 
  
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2.2.5 CD22-CAR Therapy for B-ALL: Clinical Experience 
The emergence of CD19 immune escape has prompted interest in the development of 
immunotherapies targeting alternative B-ALL cell surface molecules, such as the CD22-CAR.  
Clinical testing of this first chimeric antigen receptor targeting CD22 in children and young adults 
with R/R B-cell ALL up to the age of 30 years was recently reported by the NCI POB [37].  Doses 
of CD22-CAR T cells were administered in a standard 3 + 3 dose escalation design.  The results 
from the first twenty-one subjects enrolled, including 17 who received prior CD19-CAR therapy, 
are encouraging.  Lymphoblasts were CD19-negative or dim in 10 subjects at enrollment, and 
median blast percentage was 70.5% and all were CNS classification CNS1 (<5 WBC/mcL and no 
blasts, see Appendix 13.3.1).  Median CD22 site density was 2839 molecules per cell (range 613-
13452) at baseline. 
Response varied with administered cell dose in this dose escalation study.  The first dose level 
tested was 3 x 105 cells/kg; chosen to be lower than the current standard CD19-CAR dosing 
because this was a first-in-human (FIH) study.  Six subjects received this dose, with one 
experiencing an MRD-negative CR.  A second subject demonstrated signs of clinical activity as 
evidenced by a substantial reduction in circulating blasts, but the subject subsequently developed 
rapid disease progression and did not achieve a CR.  At doses ≥ 1 x 106 cells/kg CD22-CAR T 
cells (dose level 2), CR occurred in 9/10 subjects who had received prior CD19-directed 
immunotherapy.  There was no evidence that previous CD19-directed immunotherapy or 
diminished expression of CD19 impacted response to the CD22-CAR T cell therapy[37]. 
The primary toxicity reported was Grade 1 and Grade 2 cytokine release syndrome (CRS) with 
onset correlating with CAR T cell expansion on or after day 5.  One subject experienced Grade 4 
hypoxia, a dose limiting toxicity (DLT), at dose level 3 (3 x 106 cells/kg CD22-CAR T cells).  
Additional toxicities in the first 16 subjects included transient visual hallucinations (n=2), mild 
unresponsiveness (n=1), mild disorientation (n=1) and mild-moderate pain (n=2), which resolved 
to baseline by day 28 post-infusion.  B-cell aplasia (< 50 cells/mcL) was noted in all subjects 
achieving remission, including subjects who were not previously B-cell aplastic.  Subject #14 died 
in remission as a result of sepsis after resolution of CRS and resolution of treatment-induced 
neutropenia.  Additional Grade 3-4 toxicities included: anemia, febrile neutropenia, sinus 
tachycardia, diarrhea, fever, multi-organ failure, catheter related infections, sepsis, altered liver 
function tests, expected toxicities of chemotherapy preparative regimen, electrolyte alterations, 
tumor lysis syndrome, hypotension and respiratory failure.  Based on the single DLT at dose level 
3 and evidence of clinical activity at dose level 2, 1 x 106 cells/kg CD22-CAR T cells was identified 
as the recommended phase 2 dose (RP2D) by NCI POB investigators.   
From this small series, the investigators conclude that the CD22-CAR shows many characteristics 
that are similar to the CD19-CAR clinical experience.  Response occurs rapidly within 28 days 
and correlates with CD22-CAR expansion.  Cytokine release syndrome did occur, but the maximal 
severity was Grade 2.  The CD22-CAR T cells traffic to the spinal fluid at levels similar to that 
observed with CD19-CAR.  Although a cyclophosphamide/fludarabine based preparative regimen 
was used, neurotoxicity was limited to Grade 1 and observed in only 2 subjects.  No evidence of 
unexpected toxicity was seen.  As anticipated, since the CD22-CAR incorporates a 4-1BB 
costimulatory domain, subjects maintained CAR persistence and persistent B cell aplasia at 90 
days, with some evidence for persistent CAR cells out to 9 and 18 months seen in those subjects 
who are in the longest remission.   

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NCI POB investigators have continued to treat children and younger adults with the CD22-CAR.  
As of June 22, 2018, a total of 44 patients have been treated (personal communication).  After the 
initial publication[37],[102], the investigators altered their CD22-CAR product to include a T-cell 
selection (TCS) step.  Following this shift in production method, an additional 7 patients were 
treated at the recommended 1 x 106 cells/kg dose.  Three patients experienced DLTs (2 experienced 
disseminated intravascular coagulation [DIC]; one experienced macrophage activation syndrome).  
The investigators subsequently reduced the dose to 3 x 105 cells/kg using the TCS strategy.  At this 
dose, three patients experienced DLTs (hypoxia, CRS, and one patient with capillary leak 
syndrome resulting in acute respiratory distress syndrome).  Thirteen of the 17 patients treated 
with CD22-CAR with TCS manufacturing step experienced a bone marrow CR; all but one were 
MRD-negative complete remissions.  In addition to CRS and neurotoxicity, the investigators noted 
that a side effect of the CD22-CAR product appears to be capillary leak pulmonary syndrome that 
is reversible with steroids.  It is unclear whether this toxicity is related to CRS, but appears to occur 
without the typical CRS related hypotension.  It is also unclear whether this side effect was related 
in part to the production method using TCS.   
The experience at the POB NCI represents the first data to demonstrate that a chimeric antigen 
receptor targeting a molecule other than CD19 can also mediate potent antileukemic activity.  This 
CD22-CAR is the first alternative to CD19 for CAR based immunotherapy for pediatric B-ALL.  
We now seek to test this CD22-CAR in an expanded population of adults with R/R CD22+ B-cell 
malignancies, including ALL and lymphoma.  We do not plan to employ the TCS strategy used 
by the POB NCI in the most recent 17 patients treated.  Therefore, we plan to use a CD22-CAR 
target dose of 1 x 106 cells/kg for subjects with ALL in this Phase Ib study.  Because CD22-CAR 
T cells have not been previously administered to subjects with aggressive B-cell NHL, a Phase I 
dose escalation will be implemented to establish the recommended dose in this population. 
2.2.6 CD22 Escape following CD22 targeted immunotherapy 
Changes in CD22 surface expression has been observed at relapse following CD22-directed 
therapies.  One notable example is seen following CD22-directed antibody therapy (inotuzumab), 
where several subjects emerged with partial loss of CD22 on leukemia blasts after this therapy.  
Similarly, in the CD22-CAR T cell trial reported by Fry, et al[37], alterations in CD22 site density 
were observed in a few of the relapsed subjects (see Figure 6).  Following CD22-CAR therapy, 
Subject #8 revealed a decrease in CD22 site density at the 6-month restaging evaluation from over 
10,000 sites/cell prior to CD22-CAR therapy to approximately 1000 sites/cell at relapse in the 
presence of circulating CD22-CAR T cells.  Subject #9, known to be CD19 negative at the time of 
CD22-CAR infusion, developed relapsed leukemia at 5 months post-CD22 CAR therapy that was 
partially positive for both CD19 and CD22.  Subject #15, who was known to be CD19 negative 
prior to CD22-CAR therapy and who had received inotuzumab prior to receiving her CD22-CAR 
T cells, had a bimodal CD22 population noted in her peripheral blood flow with 89% of blasts 
expressing CD22; bone marrow flow cytometry showed complete CD22+ population at that time.  
Despite this, at 1-month post CD22 CAR therapy, she had a complete MRD negative remission 
with 41% circulating CD22-CAR T cells in her bone marrow.  At her 2-month restaging visit, 
despite a high level of circulating CD22-CAR T cells, she relapsed with CD19-/CD22- ALL (see 
Figure 6, Subject #15).  Additionally, Subject #11 who was previously refractory to blinatumomab 
and CD19-CAR, attained a complete remission but had a decrease in CD22 site density from 
approximately 3,500 sites/cell prior to CD22 CAR therapy to less than 500 sites/cell at 1 month 

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post infusion.  The mechanism for CD22 surface expression alteration is unknown at this time; 
however, constant CAR immune pressure as seen in CD19-CAR treated subjects may contribute 
to this phenomenon.  
Figure 6: CD22 Site Density with CD22 CAR T cell Therapy 
 
2.3 
AUTOMATION OF CELLULAR THERAPY PRODUCT MANUFACTURING 
Cell-based therapies, one of the latest advances in cancer immunotherapy, require complex 
manufacturing with significant regulatory implications.  The U.S. Food and Drug Administration 
(FDA) has recently approved biologic license applications (BLA) for CAR T cell therapy from 
Kite Pharma, Inc. (Yescarta [axicabtagene ciloleucel) and Novartis (Kymriah™ [CTL019]) for 
CD19-CAR T cells based on remission rates in patients with refractory B-cell ALL and patients 
with large B cell lymphoma, respectively.  These two new biologics offer an excellent option to 
many patients who previously did not have curative treatment options, but also unfortunately are 
accompanied by several limitations, such as: 1) costly therapy; 2) lengthy process for cell 
generation; and 3) CD19 immune escape, which has been described in Section 2.2.2. 
The list price in the U.S. for Yescarta per dose is $373,000, while the price for Kymriah is 
$475,000[103].  As of April, 2018, the Centers for Medicare & Medicaid Services (CMS), said it 
would pay $395,380 to health care providers who use Yescarta on an outpatient basis (net price 
plus 6%)[104].  The agency set the co-payment for Yescarta at $79,076, but indicated that the 
patients’ costs would be limited to the annual inpatient hospital deductible of $1,340 in 2018.  
Similarly, CMS stated their payment rate for Kymriah is $500,839[104].  While additional 
reimbursement has been requested for inpatient cell therapies, which may reach a total cost of as 
much as $1.5 million, CMS has not announced their final decision. 
It has been suggested that the Miltenyi CliniMACS Prodigy® ‘all-in-one’ cell processing system 
can produce a cellular product meeting the same release criteria for safety and functional analysis 
as the FDA approved manufacturers, for less than one-third of the cost.  This closed system 
completes the cell preparation, enrichment, activation, transduction, final formulation, and 
Pre-Treatment
Relapse
1
10
100
1000
10000
CD22 Site Density, Sites/cell
Patient 2
Patient 8
Patient 9
Patient 11
Patient 15

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sampling in one machine.  Such a savings to the hospital, patient and insurance companies would 
be very attractive. 
In addition, the time to treatment favors an in-house cell manufacturing process.  Treating patients 
with Yescarta or Kymriah™ requires patients meet the stringent criteria for treatment, undergo 
apheresis at the treatment facility with shipment of the apheresis product to the pharmaceutical 
manufacturer.  The cell therapy product is generated, tested and then returned to the treatment 
facility, which may take as long as a month or more.  Upon receipt, the patient undergoes 
chemotherapy conditioning regimen followed by infusion of the cell product.  The length of time 
from apheresis to cell infusion using the Miltenyi CliniMACS Prodigy® ‘all-in-one’ cell 
processing system may be as short as 10 days depending upon product testing time, a significant 
reduction in time to treatment, which may be a major advantage for patients with advanced disease.  
This study will utilize the Miltenyi CliniMACS Prodigy® ‘all-in-one’ cell processing system and 
determine its feasibility, defined as the rate of successful manufacture of the CD22-CAR T cells 
produced to satisfy the targeted dose level and meet the required release specifications. 
2.3.1 Differences in Manufacturing CD22-CAR T cells between Stanford and NCI POB  
The investigational CD22-CAR T cell product manufactured by Stanford under IND 19103 uses 
the identical CAR vector (Ef1a-BBZ-CD22-CAR) produced at Lentigen (referenced in BB-MF 
13987) as tested in the NCI POB protocol #15-C-0029 described in Section 2.2.5.  The 
manufacturing process for CD22-CAR T cells varies in that the product to be produced at Stanford 
University will be manufactured in the CliniMACS Prodigy® system, using the Miltenyi Biotech 
immunomagnetic beads for enrichment and TransAct T cell Reagent (Miltenyi Biotec) for 
activation.  The NCI product in protocol #15-C-0029 is stimulated using Dynabeads and the 
transduction and expansion is performed in bags.  In February 2017, NCI added a T cell selection 
step to their cell processing in the CliniMACS Plus System, while the Stanford process is 
completely undertaken in the CliniMACS Prodigy® system.  In addition, the MOI used at NCI is 
15, while testing at Stanford determined the best MOI for product manufacturing is 18.  Table 2 
below summarizes the similarities and differences with the proposed manufacturing at Stanford 
and the current manufacturing at NCI on protocol #15-C-0029. 
Table 2. Manufacturing Differences at Stanford and NCI for CD22-CAR T cells 
Characteristic 
Stanford IND #19103 
Protocols CCT5029 & CCT6003 
NCI IND #16180  
Protocol #15-C-0029 
Manufacturing System 
CliniMACS Prodigy® system 
In bags at the bench 
T cell selection 
CliniMACS Prodigy® system 
CliniMACS Plus 
CAR Construct 
same 
same 
Expansion 
CliniMACS Prodigy® system 
In bags  
End of process 
formulation 
7 day manufacturing process, 
with cryopreservation of cell 
product 
9 day manufacturing process, 
with ability to administer fresh or 
cryopreserved cell product 

Protocol: CD22 CAR T-cell in Adults 
  
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Since the manufacturing process is not identical for the two CD22-CAR T cell products, it is 
possible that the toxicities observed in NCI POB protocol #15-C-0029 will differ from the 
toxicities observed in this protocol and the corresponding protocol in pediatric and young adult 
subjects (CCT6003 / IRB-50878).  For this reason, we have designed an early safety evaluation in 
10 evaluable subjects with ALL before expanding the cohort, and will follow a 21-day treatment 
stagger for the first 3 to 6 subjects with ALL.  CD22-CAR T cells have not previously been tested 
in subjects with aggressive B-cell NHL, so we will evaluate initial safety using a 3 + 3 dose 
escalation design using a 21-day treatment stagger.  We have also included a Dose Level -1 in each 
disease cohort for dose de-escalation in the event of unexpected toxicity. 
However, the manufacturing processes are quite similar, so we anticipate a similar bioactivity and 
toxicity profile for the CD22-CAR T cells produced under Stanford IND 19103 as tested 
previously at NCI POB in protocol #15-C-0029. 
2.4 
SAFETY CONSIDERATIONS FOR CD22_CAR THERAPY 
2.4.1 Risk of Lymphodepleting Chemotherapy  
Toxicities resulting from fludarabine and cyclophosphamide in the doses proposed in the current 
study are well known and are what have been used in the prior CD19-CAR and CD22-CAR 
protocols.  Such a preparative regimen is designed to decrease the number of endogenous T cells, 
including T regulatory cells that may otherwise suppress CAR T cell cytotoxicity, and to induce 
increased availability of homeostatic cytokines thereby allowing for better engraftment of the 
transferred CAR T cells.  The dose limiting toxicity for both fludarabine and cyclophosphamide is 
myelosuppression, however myelosuppressive effects are expected to be transient using the doses 
proposed.  Other toxicities including fever, nausea, vomiting, stomatitis, diarrhea, anorexia, 
edema, skin rashes, myalgias, headache, agitation, and fatigue should be easily managed with 
appropriate supportive care.  Sterile hemorrhagic cystitis occurs in about 20% of subjects who 
receive cyclophosphamide, but is unlikely given the relatively low dose administered in this trial 
and given that continuous intravenous infusion of normal saline will be used prophylactically as a 
uroprotective agent.  Tumor lysis syndrome (TLS) following fludarabine and cyclophosphamide 
administration can occur in subjects with advanced bulky disease.  To prevent this, subjects may 
be prescribed allopurinol at the investigator’s discretion, and will be appropriately hydrated; with 
close monitoring for the development of TLS.  Finally, opportunistic infections (protozoan, viral, 
fungal, and bacterial) have been observed post-fludarabine and cyclophosphamide, especially in 
heavily pre-treated individuals.  Subjects will receive appropriate antimicrobial prophylaxis (e.g., 
Bactrim for PCP and acyclovir for HSV and VZV prophylaxis) during and after treatment as per 
institutional standards. 
Bendamustine hydrochloride (Bendeka®) in the dose proposed has excellent anti-lymphocyte 
activity and is FDA approved for treatment of chronic lymphocytic leukemia (CLL) and Indolent 
B-cell non-Hodgkin’s lymphoma (NHL). Experience at Stanford using Bendamustine prior to 
CD19 CAR-T (commercial CAR therapy) for relapsed/refractory lymphoma shows a similar 
efficacy and possibly lower rated of neutropenia, infections and CRS, although a small sample 
size. Similar results have been reported recently with longer follow up based on 2-JULIET trial. 
Bendamustine 
causes 
myelosuppression 
including 
lymphopenia, 
anemia, 
leukopenia, 
thrombocytopenia and neutropenia. The most common non-hematologic adverse reactions include 
pyrexia, nausea and vomiting, diarrhea, constipation, anorexia, cough, headache, weight 

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decreased, dyspnea, rash and stomatitis. 
Clofarabine (Clolar®) injection is a purine nucleoside metabolic inhibitor and is FDA approved 
for treatment of children 1 to 21 years of age with relapsed/refractory ALL after at least two prior 
regimens. Based on laboratory data clofarabine has similar anti-B and T-cell activity and increase 
antileukemic activity compared to fludarabine. Using clofarabine will allow continued use of the 
regimen with cyclophosphamide. Clofarabine causes myelosuppression. High-dose clofarabine is 
associated with fevers, capillary-leak syndrome, and SIRS, often requiring premedication and 
management with corticosteroids. It should be discontinued if hypotension develops during the 5 
days of administration. The most common adverse reactions are nausea, vomiting, diarrhea, febrile 
neutropenia, headache, rash, pruritus, pyrexia, fatigue, palmar-plantar erythrodysethesia 
syndrome, anxiety, flushing, and mucosal inflammation.  
2.4.2 Risk of Autoimmunity  
Autoimmune toxicity is a risk of adoptive cell therapy trials for cancer and can occur if the 
transferred cell populations recognize the target antigen on normal tissues.  Thus far, on-target, 
off-tumor toxicity of both CD19-CAR and CD22-CAR T cells have been restricted to B cell 
aplasia, which can be managed with immunoglobulin replacement therapy.  Given that the 
CD22-CAR T cells tested in this study incorporate scFvs that have already been tested in clinical 
trials, it is unlikely that unexpected autoimmune toxicity will occur.  Subjects will be monitored 
closely for the occurrence of unexpected toxicity and, if it is observed, appropriate supportive care 
and modification to the clinical trial will be instituted. 
2.4.3 Risks of Gene Therapy  
Risks of gene therapy include insertional mutagenesis or emergence of replication-competent 
lentivirus (RCL).  While insertional mutagenesis is theoretically possible using retroviral vectors, 
this has only been observed in the setting of infants treated for X-linked severe combined 
immunodeficiency using retroviral vector-mediated gene transfer into CD34+ bone marrow stem 
cells.  In the case of retroviral or lentiviral vector-mediated gene transfer into mature T-cells, there 
has been no evidence of long-term toxicities associated with these procedures since the first NCI 
sponsored gene transfer study in 1989.  Lentiviral vectors are thought to carry a lower risk of 
mutagenesis because lentiviral integration patterns favor sites away from cellular promoters[105].  
The proposed protocol will test the cellular product for RCL and patient follow up will comply 
with all current FDA guidelines.  As the viral vectors used have been engineered to minimize the 
risk of emergence of replication competent lentivirus, subjects will be tested for RCL according to 
2018 FDA Draft Guidance ‘Testing of Retroviral Vector-Based Human Gene Therapy Products 
for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up’.  All 
participants will be followed for several years following receipt of this therapy; and in the case of 
the development of a second malignancy, all efforts will be made to determine whether replication 
competent lentivirus has emerged. 
2.4.4 Risk of Cytokine Release Syndrome  
Dramatic and rapid expansion of CD19-CAR T cells is often associated with toxicity that can be 
extrapolated to therapy with other CAR agents, including cytokine release syndrome and 
neurotoxicity.  Cytokine release syndrome (CRS) has been the topic of several reports and 

Protocol: CD22 CAR T-cell in Adults 
  
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reviews[8],[106].  In brief, CRS comprises a febrile, sepsis-like picture that results from 
hemodynamic and organ effects of supraphysiologic levels of inflammatory cytokines produced 
directly or indirectly by the activated T cells.  Among the most important of these cytokines are 
IL-6 and IFN-gamma[10],[9],[8].  CRS can be safely managed with supportive care and, in some 
cases, 
immunosuppression 
using 
anti-IL6R 
mAbs 
therapy 
(e.g. 
tocilizumab) 
and 
corticosteroids[106].  Notably, CRS is limited in subjects with low tumor burdens, as the CAR 
T cell expansion appears to be largely driven by the magnitude of the tumor burden with 
contributions from any existing normal B cell population, and CRS severity correlates with the 
degree of CAR T cell expansion.   
2.4.5 Risk of Neurotoxicity 
Neurotoxicity is also observed in a significant minority (20-30% in most series) of subjects, with 
toxicity ranging from mild to severe[10],[9],[8].  The pathobiology of CD19-CAR associated 
neurotoxicity is not fully understood, but the clinical syndrome is associated with increased 
expansion of CD19-CAR T cells and identification of CD19-CAR T cells in the cerebrospinal 
fluid.  Neurotoxicity may be seen more frequently in subjects with CNS leukemia[10], however 
subjects without documented CNS leukemia or lymphoma can also develop symptoms of 
neurotoxicity that range from mild to severe.  Hence, any direct association of CNS disease burden 
to neurotoxicity severity is unclear[10]  Neurotoxicity typically manifests clinically as confusion, 
aphasia and/or dysmetria, and occasionally seizures.  Radiographic changes are typically not 
observed and the syndrome typically resolves in 1-2 weeks and appears fully reversible.  The 
prevailing hypothesis regarding the pathophysiology of this syndrome is that it reflects 
non-specific neurotoxic effects of cytokines and/or activated T cells, rather than a direct on-target 
effect of CD19-CAR T cells.  Indeed, the dose limiting toxicity of IL-6 when administered in a 
Phase 1 trial was neurotoxicity; and transient aphasia was observed[107].  In further support of 
this hypothesis, the Jensen laboratory at Seattle Children’s Hospital has recently developed a 
rhesus model of neurotoxicity that utilizes a CD20-CAR rather than the CD19-CAR platform and 
the model appears to mirror the human syndrome well (ASH presentation, unpublished).  This 
provides further evidence against a direct, on-target effect involving CD19 in brain tissue. 
In the summer of 2016, three deaths were reported as a result of severe neurotoxicity in subjects 
treated with CD19-CAR T cells.  Given that more than 750 subjects have been treated with these 
therapeutics, and only one previous death was reported and attributed to neurotoxicity associated 
with status epilepticus, these events were unexpected and work is underway to understand the basis 
for this phenomena.  Subsequently, two additional deaths were noted in the same trial utilizing 
high dose cyclophosphamide (in the absence of fludarabine) and CD19-CAR T cells incorporating 
a CD28 costimulatory domain.  Notably, CAR T cells that incorporate a 4-1BB costimulatory 
domain do not typically undergo as rapid an expansion as those using a CD28 costimulatory 
domain, so the risk of fatal or very severe neurotoxicity may be reduced with a 4-1BB containing 
CAR.   
Cerebral edema is another potential cause of death associated with CD19-CAR T cells.  In our own 
experience at Stanford, we had one case of fatal cerebral edema associated with CD19-CAR T 
cells incorporating a CD28 costimulatory domain in April 2017.  Additionally, with respect to 
4-1BB costimulation, a fatality occurred in February 2017 (personal communication - Seattle) in 
which a patient died from cerebral edema associated neurotoxicity following a CAR incorporating 
the 4-1BB costimulatory domain.  The CAR being utilized in this study will incorporate a 4-1BB 

Protocol: CD22 CAR T-cell in Adults 
  
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costimulatory domain. 
2.4.6 Risk of B-Cell Aplasia 
The cumulative CD19-CAR experience affirms that prolonged B cell aplasia is an expected 
consequence of effective, persistent CD19-CAR therapy.  Similar to the management of subjects 
with congenital absence of B cells and subjects treated with chronic rituximab, CAR-mediated B 
cell aplasia can be managed effectively with immunoglobulin replacement therapy[108],[109].  
Thus far, significant increase in infection susceptibility or other toxicity related to chronic B cell 
depletion has not been noted in prior clinical studies[9].   
2.4.7 Other Risks 
2.4.7.1 Capillary Leak Syndrome 
Additional, potentially unforeseen toxicities may arise with any investigational agent.  One less-
frequently identified toxicity was observed in the NCI POB clinical trial administering CD22-CAR 
T cells reported by Fry et al [102] described as capillary leak syndrome (CLS) characterized by 
rapid symptom onset, dry cough with shortness of breath, diffuse patchy appearance on chest 
imaging, drop in albumin, and tachycardia out of proportion to fever.  Three patients developed 
Grade 3/4 CLS after receiving the cell infusion in the POB trial[110] (personal communication 
with N. Shah).  The CLS in this study was not associated with typical CRS hypotension, and 
generally occurred prior to peak CAR expansion was evident. 
Other investigational trials have also reported CLS.  FDA put a hold on two Phase I trials in 
September 2017 when a 78-year-old male with blastic plasmacytoid dendritic cell neoplasm 
developed CRS and a Grade 4 CLS on day eight after receiving a gene-edited allogeneic CAR T-
cell (UCART) therapy [UCART123], which despite treatment with corticosteroids and 
tociluzumab, was considered central in causing the patient’s death.  On a second study using 
UCART123, a 58-year old woman with acute myeloid leukemia developed Grade 3 CRS and 
reversible Grade 4 CLS nine days after cell infusion. 
Some investigators have attributed CLS to be one of the several symptoms displayed in the 
constellation of CRS, along with fevers, hypotension, hypoxia, respiratory distress and 
neurological disturbances[111],[112].  CLS is listed in the boxed warning for CRS on the Drug 
Fact Sheet for blinatumomab, a bispecific CD19-directed CD3 T-cell engager.   
2.4.7.2 Hemophagocytic lymphohistiocytosis (HLH)/ Macrophage Activation Syndrome 
(MAS) 
Primary hemophagocytic lymphohistiocytosis (HLH) is a rare inherited disorder of immune 
regulation, whereas macrophage activation syndrome (MAS) is a form of secondary HLH 
triggered by immune-activating processes in patients who may have heterozygous mutations in the 
same genes that are mutated in primary HLH, leading to dysfunctions in the same immune 
regulatory processes[9].  Cytokines 1L-10, IL-6 and IFN- are elevated in both CRS and 
HLH/MAS, and may be triggered in predisposed patients by the transient cytokine activation seen 
in response to CAR therapies[113].  Symptoms include new or persistent cytopenias, rising ferritin 
levels and rising liver function tests (personal correspondence N.  Shah).  Up to 32.8% of patients 
receiving CD22 CAR T cells have been reported to have HLH-like manifestations prompting 

Protocol: CD22 CAR T-cell in Adults 
  
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utilization of anakinra[110]. 
2.4.7.3 Hemolytic Uremic Syndrome 
Hemolytic uremic syndrome (HUS) was reported after treatment with moxetumomab pasudotox, 
a recombinant anti-CD22 immunotoxin, in a study conducted at the NCI in 5 of 55 patients 
(13%)[114].  In the CD22-CAR T cell trial conducted at NCI, HUS was characterized by ongoing 
‘hemolyzed’ labs, significant hypertension and proteinuria, and low complement levels which was 
effectively treated with eculizmab, a C5-complement inhibitor in approximately 5% of patients 
[110].   
2.4.7.4 Coagulopathy 
Coagulopathies have been reported with CAR T cell therapy, associated with CRS and MAS and 
characterized by significant hypofibrinogenemia[115].  The coagulopathy observed in the NCI 
POB CD22-CAR T cell trial reported dramatic falls in fibrinogen levels, but also was characterized 
by bleeding which appeared out of proportion to the degree of thrombocytopenia, and a 
hypogranular appearance, ‘grey’ platelets upon exam (personal correspondence N.  Shah).  
Treatment included platelet infusions, cryoprecipitate, topical thrombin administration and 
infusions of fresh frozen plasma.   
2.4.7.5 Pancytopenia and Infection 
Cytopenias after CAR therapies are well documented[116],[117]. In a report of patients with 
relapsed/refractory DLBCL receiving Axi-cel, the incidence of grade 3 or greater neutropenia, 
anemia and thrombocytopenia was 78%, 43% and 38% respectively [117], with persistent (3 
months) neutropenia seen in 9% of patients, thrombocytopenia in 65% and anemia in 72% of 
patients. Filgrastim was required in 47% of patients to facilitate recovery of neutrophils [117]. A 
biphasic occurrence of cytopenias also appears to be characteristic of some CAR related toxicities, 
reported in 93% of patients’ hematologic toxicities which occurred 21 days or later after cell 
infusion[116]. Given the extent of cytopenias post CAR therapy, it is assumed there also exists a 
higher risk of infection post CAR therapy. In a recent study of 83 patients younger than 26 years 
of age receiving CAR T cells, 33 (40%) patients had 37 incident infections in the initial period (28 
days) after CAR infusion[118], while 54% of those patients had at least one infection prior to the 
CAR therapy. Of the 83 patients, 48 were followed post 28 days, with a median follow up of 51 
(29-90) days, and there were 7 viral infections, 5 bacterial infections and no fungal infections. This 
study identified pre-CAR infusion risk factors for infection included prior hematopoietic cell 
transplantation (HCT), immunoglobulin G (IgG) level < 400 mg/dL, and lymphodepletion other 
than cyclophosphamide and fludarabine, and post-CAR infusion risk factors included higher-
severity CRS and IgG level < 400 mg/dL[118]. Most patients with bacteremia (90%) were 
neutropenic, whereas viral infections occurred in similar numbers whether the patient was 
neutropenic or not. Institutions are addressing this CAR T cell therapy risk with prophylactic 
antibiotics and in some cases, prophylactic antiviral prophylaxis. 
2.5 
CORRELATIVE STUDIES BACKGROUND 
CAR T cell therapy targeting a single tumor-associated antigen has mediated striking remissions 
in B cell leukemia and lymphoma.  The clinical experience to date has demonstrated that 
anti-leukemic effects are associated with CAR T cell expansion[10],[41], and that sustained 

Protocol: CD22 CAR T-cell in Adults 
  
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remission is associated with CAR T cell persistence[119].  In subjects who have relapsed in the 
presence of persistent singular CD19-specific or CD22-specific CAR T cells, relapse has often 
been characterized by CD19 dim/negative or CD22 dim/negative phenotypes respectively.  The 
complex interplay of tumor, T cell and intrinsic CAR properties that influence these outcomes are 
not well understood.  We aim to utilize this safety study as an opportunity to collect correlative 
data that will permit extensive study of both the B cell and T cell compartment prior to and 
following CAR T cell therapy.  We aim to integrate multi-dimensional technologies to permit 
complex analyses of the apheresis product, the CAR T cell product pre-infusion and in vivo 
expanded CAR T cells following antigen encounter.  We additionally aim to investigate properties 
of B cell tumors that render them susceptible to CAR T cell cytotoxicity and study physiologic 
and malignant B cell remodeling under the pressure of CAR therapy. 
2.5.1 Factors Impacting Loss of CAR T cells  
Persistence of CAR T cells is associated with superior anti-leukemia effects in the setting of 
CD19-CAR T cell therapy for leukemia.  We hypothesize that there are three distinct causes of 
T cell loss following CAR T cell therapy.  First, in a subset of subjects, there is poor CAR T cell 
expansion following infusion of a product that appears to meet appropriate release criteria.  We 
hypothesize that such products can be identified by the presence of exhausted or terminally 
differentiated cells that lack progenitor capacity.  To explore the potential to identify such products 
a priori, we will analyze apheresis samples and manufactured products to enumerate the frequency 
of naïve, T stem cell memory, T central memory and T effective memory subsets.  We will also 
analyze apheresis and manufactured products for the presence of markers of T cell exhaustion 
including PD-1, Tim3 and LAG-3 among others.  Phenotypes will be correlated with the degree 
of expansion following CAR T cell infusion.   
Second, we hypothesize that a subset of subjects will undergo efficient early T cell expansion but 
will demonstrate loss of CAR T cell persistence associated with the acquisition of a terminally 
differentiated phenotype and/or characteristics of T cell exhaustion.  To test this, we will evaluate 
CAR-expressing T cells in vivo following adoptive transfer to identify characteristics associated 
with poor persistence.  These phenotypic analyses will include flow cytometry and mass cytometry 
with a goal of identifying T cell phenotypes associated with poor persistence in vivo.  We will also 
undertake epigenetic analyses to analyze correlations between T cell phenotype, persistence and 
enhancer profiles.  Where possible, we will also compare the phenotype of cells harvested from 
blood, bone marrow, CSF and lymph nodes to analyze whether the tissue microenvironment has 
substantial impact on T cell exhaustion, phenotype or function.   
Finally, we hypothesize that a subset of subjects lose their CAR T cell populations as a result of 
immune rejection.  To test this, we will analyze for the presence or development of anti-CAR 
mediated T cell responses using cell based assays, as well as overlapping peptide libraries to 
localize the targets of anti-CAR reactivity.   
2.5.2 Impact of Persistent CD22 Immune Pressure on B cell Differentiation 
CD19 and CD22 are acquired during the process of normal and malignant B cell differentiation.  
Persistent immune based pressure targeting either of these antigens has the potential to induce 
profound changes on both normal and malignant B cell differentiation.  In this study, we will use 
mass cytometry, flow cytometry and ATAC-Seq to monitor changes in normal and malignant B 
cell differentiation in the presence of persistent CAR T cells targeting CD22.  We will explore loss 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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of antigen and whether such antigen loss is associated with a particular differentiation state, a 
particular genotype and/or are associated with increased or diminished fitness as evidenced by 
clinical behavior, or where possible growth patterns ex vivo.  Similar analyses will focus on 
subjects with remission marrows, analyzing whether normal B cell development can proceed in 
the absence of CD22 subpopulations.  This will provide a novel opportunity to characterize the 
impact of CD22 changes on normal lymphoid and/or myeloid cells development. 
2.5.3 Utility of Minimal Residual Disease Assessment 
The role of Minimal Residual Disease (MRD) testing by next-generation sequencing (NGS) in 
subjects with ALL treated with CAR-T cells has not been well studied.  In this study we will 
prospectively collect MRD evaluations before and after CAR-T therapy in subjects with ALL with 
identifiable clones and analyze using NGS.  MRD by NGS will be correlated with flow cytometry 
and with peripheral blood MRD when available.   
2.6 
STUDY DESIGN 
2.6.1 Short Title for Study 
CD22-CAR T cells in adults with B-cell malignancies  
2.6.2 Interventional model 
Two arm, open label single treatment.  Phase I dose escalation study for aggressive B-cell NHL 
disease cohort; Phase Ib safety of previously selected target dose for ALL disease cohort. 
2.7 
PROTOCOL RATIONALE AND SUMMARY 
Most aggressive cancers eventually relapse or become refractory to current conventional 
treatments, necessitating the immediate development of new treatment modalities.  The most 
recent advances in cancer therapy involve the development of new immune stimulating agents 
designed to target T-cells to cancer cells and initiate cell death signaling pathways.  However, 
limitations to this type of immunotherapy include lack of tumor specificity, insufficient T-cell 
recruitment/numbers, and the existence of endogenous immunosuppressive agents which 
significantly attenuate or altogether block T-cell activity. 
The primary goals of this trial are threefold: 1) to evaluate the feasibility of generating CD22-CAR 
T cells from adults with B cell malignancies using the Miltenyi CliniMACS Prodigy® system to 
meet the manufacturing specifications; 2) to determine the MTD/RP2D for adult subjects with 
aggressive B-cell NHL, given that CD22-CAR T cells have not been previously administered to 
this disease group; and 3) to establish the safety of CD22–CAR T cells in adults with ALL at the 
recommended dose of 1x106 cells/kg.  The secondary aim is to assess the clinical activity of 
administering autologous CD22-CAR T cells that meet established release specifications in adults 
with R/R CD22+ B-ALL and R/R aggressive B-cell NHL following a lymphodepleting 
conditioning regimen.  Correlative analyses on this protocol or a companion study will: 1) Analyze 
alterations in early B cell development induced by immune pressure exerted via CD22-CAR 
T cells; 2) Evaluate whether subjects receiving CD22-CAR T cells relapse with loss or diminished 
expression of CD22, when feasible; 3) Measure persistence of CD22-CAR T cells in the blood, 
bone marrow and CSF (when feasible), and explore correlations between CD22-CAR T cell 
properties and CAR T cell efficacy and persistence; and 4) Establish the utility of chromatin 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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structure and epigenomic technology to characterize CAR T cell therapies.  The precedent for 
conducting clinical trials of this scope was established by the ongoing clinical trials 
CCT5001/IRB-41382 and CCT5007/IRB-41383 conducted by Stanford Center for Cancer Cell 
Therapy. 
Subjects with B cell malignancies, including ALL, and aggressive B-cell NHL defined as DLBCL, 
PMBCL, and tDLBCL arising from Follicular Lymphoma and Marginal Zone Lymphoma, or 
Follicular Lymphoma Grade 3B are eligible.  CD22 expression in ALL is well established and is 
a relevant indicator of CD22-CAR efficacy in this patient population, so all ALL subjects must 
demonstrate CD22 positivity for eligibility.  Little has been reported about expression in 
aggressive B-cell NHL in relation to therapeutic response, so archival tissue or lymph node 
biopsies will be collected at the time of enrollment/screening from subjects and any expression of 
CD22 will be acceptable for enrollment (including no detected expression).  If archival tissue is 
not available, a potential aggressive B-cell NHL subject must be willing to undergo a biopsy for 
tissue analysis. 
Subject eligibility requires relapsed or refractory disease after standard therapies; previous 
immunotherapy will not render subjects ineligible.  For subjects who have previously received 
CAR T cell therapy, the level of circulating CAR T cells must be < 5% of CD3+ cells that express 
the previous CAR at the time of leukapheresis, if a qualified assay exists.  Subjects who have 
undergone autologous SCT will be eligible, and subjects who have received allogeneic SCT will 
be eligible if, in addition to meeting other eligibility criteria, they have no evidence of active 
GVHD and have been without immunosuppressive agents for at least 30 days. 
In the only previous study using CD22-CAR T cells, conducted in children and young adults at 
the POB NCI, the MTD chosen for further study in subjects with ALL was 1 x 106 transduced T 
cells/kg (± 20%), despite not achieving the standard definition according to number of dose 
limiting toxicities.   
Because CD22-CAR T cells have not been previously administered to subjects with aggressive B-
cell NHL, a dose finding 3 + 3 dose escalation design will be used (see Table 3).  Once the 
MTD/RP2D is determined in aggressive B-cell NHL subjects, an expansion cohort will also be 
treated to further explore safety of CD22-CAR T cells.   
In addition, a preliminary evaluation of efficacy of the CD22-CAR T cells will be conducted in 
the two disease populations: subjects with R/R ALL and subjects with R/R aggressive B-cell NHL. 
This study will be conducted at Stanford as a single-site study by the principal investigator 
Matthew Frank, M.D., Ph.D.  The IND Sponsor of this study will be Stanford University. 
2.7.1 Primary Outcome Type 
Safety and Feasibility 
2.7.2 Investigational Agent 
Autologous T cells transduced with lentiviral vector (CD22.BB.Z) Chimeric Antigen Receptor 
(CD22-CAR); following Lymphodepleting Chemotherapy 
2.7.3 IND number:  
IND # 19103, Sponsor: Stanford University 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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2.7.4 Primary Outcome Measures  
This study will be registered on ClinicalTrials.gov but is not subject to the results reporting 
requirement. 
1. Title:  Rate of successful manufacture of CD22-CAR T cells using the Miltenyi 
CliniMACS Prodigy ® system  
• Outcome Measure1:  The percentage of apheresis samples (fresh or frozen) that are 
successfully processed and expanded to manufacture CD22-CAR T cells that satisfy 
the target dose level and meet release specifications will be determined for each dose 
cohort.   
• Outcome Timeframe1: 7-11 days from start of manufacturing. 
2. Title:  MTD/RP2D of CD22-CAR T cells in subjects with aggressive B-cell NHL 
• Outcome Measure2:  Incidence and severity of dose limiting toxicities (DLTs) 
following chemotherapy preparative regimen and infusion of CD22-CAR T cells, as 
recorded and graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0, at each dose level tested in subjects with aggressive B-cell NHL. 
• Outcome Timeframe2: 28 days after infusion of CD22-CAR T cells 
3. Title: Safe dose of CD22-CAR T cells in subjects with ALL  
• Outcome Measure3:  Incidence and severity of dose limiting toxicities (DLTs) 
following chemotherapy preparative regimen and infusion of CD22-CAR T cells, as 
recorded and graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0, at each dose level tested in subjects with ALL. 
• Outcome Timeframe3: 28 days after infusion of CD22-CAR T cells 
2.7.5 Secondary Outcome Measures 
1. Secondary Measure 1: Clinical activity of CD22-CAR T cells in adults with 
relapsed/refractory CD22-expressing B-cell ALL at target dose  
• Outcome Measure1:  Clinical activity will be assessed by Guidelines for efficacy 
evaluation in Acute Lymphoblastic Leukemia (ALL)  (based on NCCN Guidelines (2013, 
Appelbaum, ASH and IWG guideline, Cheson 2003.) (see Appendix C, Section 13.3.1).  
Results will be reported as best response (i.e. complete remission [CR], Complete 
remission with incomplete blood count recovery [Cri], No response, or Relapsed disease 
or Unknown) at Day 28 for adult subjects with ALL treated at the target dose. 
• Timeframe1: 28 months after infusion of CD22-CAR T cells 
2.  Secondary Measure 2: Clinical activity of CD22-CAR T cells in adults with 
relapsed/refractory aggressive B-cell NHL at MTD/RP2D 
• Outcome Measure2:  Clinical activity will be assessed by Lugano response criteria for 
lymphoma (see Appendix C, Section 13.3.2).  Results will be reported as best response 
(i.e. complete response [CR], partial response [PR], stable disease [SD], or progressive 
disease [PR]) at Month 3 for adult aggressive B-cell NHL subjects treated at 
MTD/RP2D. 
• Timeframe2: 3 months after infusion of CD22-CAR T cells 
2.7.6 General Study Design 
This is a Phase 1/1b study in adults with B cell malignancies (ALL and aggressive B-cell NHL) 
who have relapsed or refractory disease after standard treatment options.  Autologous PBMC will 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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be obtained by leukapheresis and transduced with CD22-CAR lentiviral vector.  Cryopreserved 
PBMC stored from participation in other institutional cell therapy or cell collection studies or 
standard of care may be used to generate the cellular product on this study as long as they meet 
the criteria established in this IND.  Cryopreserved PBMC will be transported to the manufacturing 
facility [Miltenyi Biotech Inc (MBI) or Stanford’s Laboratory for Cell and Gene Medicine 
(LCGM)], where they will undergo selection, activation, transduction with the lentiviral vector, 
expansion, and formulation using the Miltenyi CliniMACS Prodigy® system for the manufacture 
of CD22-CAR T cells.  The product will be cryopreserved and returned to Stanford’s Cell Therapy 
Facility (CTF), from which the product will be distributed to the patient care unit for infusion.   
Subjects will receive a lymphodepleting preparative regimen  prior to infusion of CD22-CAR 
T-cells.  Subjects will be evaluated sequentially after treatment for toxicity, antitumor effects and 
for persistence of CAR in blood samples and functionality of transduced T cells.  Subjects with 
ALL will be enrolled and evaluated separately from subjects with aggressive B-cell NHL.  
Additional blood, lymph node and bone marrow samples may be collected to complete correlative 
study analysis. 
Table 3. CD22-CAR Dose Levels 
Level 
Dose CD22-CAR 
transduced T cells† 
R/R ALL Cohort 
R/R aggressive B-cell NHL 
Cohort 
Dose Level -1 
3 x 105 cells/kg (± 20%) 
De-escalate if DLT rate 
>30% at Level 1 
Deescalate if DLT rate 
>30% at Level 1 
Dose Level 1 
1 x 106 cells/kg (± 20%) 
Target dose 
3+3 Dose escalation design 
until MTD/RP2D 
determined (see Section 
5.4.4) 
Dose Level 2 
3 x 106 cells/kg (± 20%) 
May escalate if no clinical 
activity and <30% DLT rate 
observed at Level 1 
Dose Level 3 
1 x 107 cells/kg (± 20%) 
Not tested in this cohort 
† Dose based on weight measured within 14 days of manufacturing start date, capped at 100 kg. 
The feasibility of generating this product using the Miltenyi CliniMACS Prodigy® ‘all-in-one’ 
cell processing system will be evaluated across both disease groups.  If initial feasibility of cell 
production is not met (i.e. 3 of the first 6 aggressive B-cell NHL subjects’ cells or 5 of the first 10 
ALL subjects’ cells cannot be produced to meet the established release criteria) further enrollment 
will be paused pending evaluation of the manufacturing process, and modifications made 
appropriate to improving feasibility prior to continuing enrollment.  This may require a protocol 
or IND amendment.  In any event, if 3 (or 5) of the first 6 (or 10) cell products manufactured do 
not meet established criteria, it will be reported to the IRB and APB and no manufacturing changes 
will be implemented until IRB and APB approval is obtained.   
The expected DLT rate is 20%, however, the maximum acceptable rate for DLT is 30% in each of 
the two disease cohorts.  Using a standard 3 + 3 dose escalation design to evaluate three dose 
levels, subjects with aggressive B-cell NHL will be sequentially enrolled to Dose Level 1 to 3.  
The MTD for subjects with aggressive B-cell NHL is declared as the feasible dose achieving 0 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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DLTs out of 3 subjects or 1 DLT out of 6 subjects (possible to be 0 out of 6 due to feasibility). 
Once the MTD/RP2D is established in this disease population, additional aggressive B-cell NHL 
subjects will be enrolled to further evaluate the safety of this regimen as outlined in Section 
12.1.2.1. Additional safety monitoring for possible de-escalation will be performed after 17 
evaluable aggressive B-cell NHL patients have been treated at the established MTD/RP2D and 
every 5 thereafter, until a total of 36 evaluable subjects with R/R aggressive B-cell NHL are 
treated. Initially, 10 subjects with ALL will receive the target dose of 1 x 106 transduced T cells/kg 
(± 20%) and be evaluated for safety.  Additional safety monitoring for possible de-escalation will 
be performed every 5 patients thereafter, until a total of 28 evaluable subjects with R/R ALL are 
treated.  
A futility analysis will be conducted to determine the secondary endpoint for efficacy in each of 
the disease groups (subjects with ALL and subjects with aggressive B-cell NHL treated at the 
MTD/RP2D).  For subjects with B-ALL, the analysis will be conducted when 15 evaluable 
subjects have reached Day 28 bone marrow assessment (primary efficacy endpoint); and if 7 or 
fewer subjects have a CR, further enrollment to that disease group will stop.  In addition, a futility 
analysis will be conducted when 17 evaluable subjects with aggressive B-cell NHL treated at 
MTD/RP2D have reached month 3 disease assessment (primary efficacy endpoint); and if 4 or 
fewer subjects have a CR or PR, further enrollment to that disease group will stop.  See Section 
12.3 for comprehensive details of study stopping rules.  In the event a stopping rule is met, the 
Safety Monitoring Committee (SMC) will be notified.  SMC findings and recommendations will 
be communicated to IRB and APB promptly via a safety report or protocol amendment. 
2.7.7 Study Duration 
2.7.7.1 Primary Completion 
Up to 1-2 subjects per disease group will be accrued per month, and therefore this study may 
require up to 2- 3.5 years to complete accrual.  The study primary and secondary objectives will 
be complete approximately 3 years after opening to accrual. 
2.7.7.2 Study Completion 
Subjects will be followed after treatment to evaluate toxicities, track disease progression, and to 
monitor for gene therapy effects.  Short term follow-up includes evaluations up until disease 
progression or subsequent alternative disease-directed therapy is initiated.  In addition, long term 
follow up for gene therapy according to the U.S.  Food and Drug Administration (FDA) Guidance 
for Industry: Gene Therapy Clinical Trials – Observing Participants for Delayed Adverse Events 
will be conducted on every infused subject for the required 15 years post infusion of gene-edited 
cells on this study or an alternative long term follow up protocol.  The study is expected to take 
17-18.5 years to complete all enrollment and follow-up.  The study may be concluded earlier if 
subjects are transitioned to a Long-Term Gene Therapy Follow Up protocol. 
3 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
All subjects must sign and date the Institutional Review Board (IRB) and Administrative Panel on 
Biosafety (APB) approved consent form(s) before initiating any study specific procedures or 
activities that are not part of a subject’s routine care.   

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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The Screening Participant Eligibility Checklist on the following page must be completed in its 
entirety for each subject prior to registration.  If patient or manufacturing scheduling requires, 
consenting and screening may be completed in two stages: 1) for leukapheresis, and 2) for 
lymphodepleting chemotherapy and CD22-CAR T cell infusion, as outlined with checklists for 
each stage in Section 13.8, Appendix H.   
The completed, signed, and dated checklist(s) must be retained in the subject’s study file and the 
study’s Regulatory Binder or an electronic version completed within the subject’s medical record.   
The study coordinator, Stanford co-investigator, principal investigator, or treating physician, and 
a third reviewer must verify that the participant’s eligibility is accurate, complete, and legible in 
source records, as required by the CCTO SOP ‘Confirmation of Participant Eligibility in Clinical 
Trials’.  A description of the eligibility verification process should be included in the EPIC or other 
Electronic Medical Record progress note.   
The protocol-specific checklist is required by the SRC and must be approved by the IRB.   

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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3.1 
SCREENING PARTICIPANT ELIGIBILITY CHECKLIST 
Protocol Title: 
Phase I/Ib Clinical Trial of Autologous CD22 Chimeric Antigen Receptor 
(CAR) T cells in Adults with Recurrent or Refractory B Cell Malignancies 
Protocol Number: 
CCT5029 / IRB-50836 
Protocol Director: 
Matthew Frank, M.D., Ph.D. 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV.  Inclusion/Exclusion Criteria 
INCLUSION CRITERIA 
Yes 
No 
Supporting Documentation† 
1. Disease Status 
a. Disease Status of ALL 
• 
Must have chemotherapy refractory disease 
defined as progression or stable disease after 
a standard line of therapy, or relapsed disease 
after achieving CR. 
• 
Subjects with persistent or relapsed minimal 
residual disease (MRD) (by flow cytometry, 
PCR, FISH, or next generation sequencing) 
require verification of MRD on two 
occasions at least 2 weeks apart. 
• 
Subjects with Philadelphia Chromosome 
positive acute lymphoblastic leukemia 
(Ph+ALL) are eligible if they progressed 
after receiving a tyrosine kinase inhibitor 
(TKIs). 
• 
Subjects with recurrence of isolated CNS 
relapse after achieving complete remission 
(CR) are eligible. 
b. Disease Status of aggressive B-cell NHL 
• 
Histologically confirmed aggressive B cell 
NHL including the following types defined 
by WHO 2008:  
o DLBCL not otherwise specified; 
T cell/histiocyte rich large B cell 
lymphoma; DLBCL associated with 
chronic inflammation; Epstein-Barr virus 
(EBV)+ DLBCL of the elderly; OR  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 NA 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 NA 
      
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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INCLUSION CRITERIA 
Yes 
No 
Supporting Documentation† 
o primary mediastinal (thymic) large B cell 
lymphoma; OR  
o transformation of follicular lymphoma, 
marginal zone lymphoma or chronic 
lymphocytic leukemia/small lymphocytic 
lymphoma to DLBCL; OR  
o Follicular Lymphoma Grade 3B 
• 
Subjects with DLBCL, Follicular Lymphoma 
Grade 3B –or–   
Subjects with transformed FL, MZL, or 
CLL/SLL who HAVE NOT received 
chemotherapy prior to transformation: 
o Must have received an anthracycline 
regimen and an anti-CD20 monoclonal 
antibody (unless documented CD20-
negative) and be refractory or relapsed 
after second line of DLBCL treatment.  
Subjects with a partial response to second 
line therapy must be ineligible for 
autologous transplant.   
• 
Subjects with transformed FL, MZL, or 
CLL/SLL who HAVE received 
anthracycline-containing chemotherapy prior 
to transformation: 
o Must have progressed, had SD or recurred 
with transformed disease after initial 
treatment for DLBCL. 
2. Measureable Disease 
• 
Subjects with ALL: must have evaluable or 
measurable disease (MRD positive by flow 
cytometry, NGS, or PCR is acceptable). 
• 
Subjects with aggressive B-cell NHL: must 
have evaluable or measurable disease 
according to the revised IWG Response 
Criteria for Malignant Lymphoma[38].  
Lesions that have been previously irradiated 
will be considered measurable only if 
progression has been documented following 
completion of radiation therapy. 
 
 
 
 
 
 
      
 
      
3. CD22 expression  
• 
Subjects with ALL: CD22 positive 
expression on malignant cells is required and 
must be detected by immunohistochemistry 
or flow cytometry.  The choice of whether to 
use flow cytometry or immunohistochemistry 
will be determined by what is the most easily 
available tissue sample in each subject.   
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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INCLUSION CRITERIA 
Yes 
No 
Supporting Documentation† 
CD22 expression must be demonstrated 
subsequent to any anti-CD22 targeted therapy 
(e.g. Moxetumomab pasudotox or inotuzumab 
ogozamicin) in subjects with ALL. 
• 
Subjects with aggressive B-cell NHL:  CD22 
expression 
at 
any 
level, 
including 
undetectable, will be acceptable.  Subjects 
must have archival tissue available for 
analysis of CD22 expression or must be 
willing to undergo a biopsy of easily 
accessible disease.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
4. Prior Bone Marrow-Stem Cell Transplant  
Subjects who have undergone autologous SCT 
with disease progression or relapse following SCT 
are eligible.  Subjects who have undergone 
allogeneic SCT will be eligible if, in addition to 
meeting other eligibility criteria, they have no 
evidence of GVHD and have been without 
immunosuppressive agents for at least 30 days. 
 
 
      
5. Prior Therapy Wash-out 
At least 2 weeks or 5 half-lives, whichever is 
shorter, must have elapsed since any prior 
systemic therapy at the time the subject is 
planned for leukapheresis, except for systemic 
inhibitory/stimulatory immune checkpoint 
therapy, which requires 5 half-lives.   
Exceptions: 
a. There is no time restriction with regard to 
prior intrathecal chemotherapy provided there 
is complete recovery from any acute toxic 
effects of such; 
b. Subjects receiving hydroxyurea may be 
enrolled provided there has been no increase 
in dose for at least 2 weeks prior to starting 
apheresis; 
c. Subjects who are on standard ALL 
maintenance type chemotherapy (vincristine, 
6-mercaptopurine or oral methotrexate) may 
be enrolled provided that chemotherapy is 
discontinued at least 1 week or 5 half-lives, 
whichever is shorter, prior to apheresis. 
d. Subjects receiving steroid therapy at 
physiologic replacement doses only are 
allowed provided there has been no increase 
in dose for at least 2 weeks prior to starting 
apheresis; 
e. For radiation therapy: Radiation therapy must 
 
 
      

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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INCLUSION CRITERIA 
Yes 
No 
Supporting Documentation† 
have been completed at least 3 weeks prior to 
apheresis, with the exception that there is no 
time restriction if the volume of bone marrow 
treated is less than 10% and also the subject 
has measurable/evaluable disease outside the 
radiation port or the site of radiation has 
documented progression. 
6. Prior CAR Therapy 
Subjects who have undergone prior CAR therapy 
must be at least 30 days post CAR infusion and 
have < 5% of CD3+ cells express the previous 
CAR if a validated assay is available. 
 
 
      
7. Toxicities due to prior therapy must be stable or 
resolved (except for clinically non-significant 
toxicities such as alopecia or cytopenias covered 
in *footnote to #10) 
 
 
      
8. Age greater than or equal to 18 years of age  
 
 
      
9. Eastern cooperative oncology group (ECOG) 
performance status of 0, 1, or 2; or Karnofsky 
≥ 60% (See section 13.1, Appendix A)  
 
 
      
10. Normal Organ and Marrow Function (supportive 
care is allowed per institutional standards, i.e. 
filgrastim, transfusion) 
• 
ANC ≥ 750/uL*  
• 
Platelet count ≥ 50,000/uL*  
• 
Absolute lymphocyte count (ALC) ≥ 150/uL*  
Adequate renal, hepatic, pulmonary and cardiac 
function defined as:  
• 
Creatinine ≤ 2 mg/dL OR creatinine 
clearance ≥ 60 mL/min  
• 
Serum ALT/AST ≤ 10x Upper limit of 
normal (ULN)  
(Elevated ALT/AST related to leukemia 
involvement of the liver will not disqualify a 
subject).   
• 
Total bilirubin ≤ 1.5 mg/dL, except in 
subjects with Gilbert’s syndrome.   
• 
Cardiac ejection fraction ≥ 45%, no evidence 
of physiologically significant pericardial 
effusion as determined by an ECHO, MUGA 
or Cardiac MRI [performed within 180 days 
or after most recent anthracycline based 
treatment or mediastinal radiation 
therapy (whichever is most recent)] 
 
 
ANC 
Platelet 
ALC 
 
 
Creatinine 
 
AST/ALT 
 
 
Bilirubin 
 
LVEF 
 
 
 
 
 
      
 
      
      
      
 
 
      
 
               
 
 
      
 
      
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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INCLUSION CRITERIA 
Yes 
No 
Supporting Documentation† 
• 
No clinically significant ECG findings 
• 
No clinically significant pleural effusion 
• 
Baseline O2 saturation > 92% on room air 
* ALL subjects will not be excluded because of 
pancytopenia ≥ Grade 3 if it is felt by the investigator to be 
due to underlying leukemia. 
ECG 
Pleural 
SaO2 
 
      
      
      
11. CNS Status  
Subjects with CNS involvement are eligible as 
long as there are no overt signs or symptoms that 
in the evaluation of the investigator would mask or 
interfere with the neurological assessment of 
toxicity.   
 
 
      
12. Females of childbearing potential must have a 
negative serum or urine pregnancy test within 7 
days prior to leukapheresis (females who have 
undergone surgical sterilization or who have been 
postmenopausal for at least 2 years are not 
considered to be of childbearing potential) 
 
 
      
13. Contraception 
Subjects of child-bearing or child-fathering 
potential must be willing to practice birth control 
from the time of enrollment on this study and for 
four (4) months after receiving the preparative 
lymphodepletion regimen. 
 
 
 
 
      
 
14. Ability to give informed consent.   
Must be able to give informed consent.  Legal 
authorized representative (LAR) is permitted if 
subject is cognitively able to provide verbal 
assent. 
 
 
      
Subjects meeting any of the following criteria are not eligible for participation in the study: 
EXCLUSION CRITERIA 
Yes 
No 
Supporting Documentation† 
1. Recurrent or refractory ALL limited to isolated 
testicular disease. 
 
 
      
2. Hyperleukocytosis (≥ 50,000 blasts/μL) or 
rapidly progressive disease that in the estimation 
of the investigator and sponsor would 
compromise ability to complete study therapy. 
 
 
      
3. History of other malignancy, unless disease free 
for at least 3 years.  At the discretion of the 
Principal Investigator, subjects in remission for 
 
 
      

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EXCLUSION CRITERIA 
Yes 
No 
Supporting Documentation† 
1-2 years prior to enrollment may be deemed 
eligible after considering the nature of other 
malignancy, likelihood of recurrence during one 
year following CAR therapy, and impact of prior 
treatment on risk of CD22-CAR T cells. Subjects 
in remission <1 year are not eligible. 
• 
Exception: Nonmelanoma skin cancer or 
carcinoma in situ (e.g. cervix, bladder, 
breast) is eligible. 
• 
Hormonal therapy in subjects in 
remission > 1 year will be allowed. 
4. Presence of active fungal, bacterial, viral, or 
other infection requiring intravenous 
antimicrobials.  Simple UTI and uncomplicated 
bacterial pharyngitis are permitted if responding 
to active treatment.   
 
 
 
 
 
 
      
 
 
5. No knowledge of: 
• 
HIV, 
• 
Hepatitis B (HBsAg positive) or  
• 
Hepatitis C virus (anti-HCV positive) 
infection.   
A history of hepatitis B or hepatitis C is permitted 
if the viral load is undetectable per quantitative 
PCR and/or nucleic acid testing. 
 
HIV 
HBV 
HCV 
 
      
      
      
      
6. Presence of cerebrovascular ischemia / 
hemorrhage, dementia, cerebellar disease, or any 
autoimmune disease with CNS involvement that 
in the judgment of the investigator may impair 
the ability to evaluate neurotoxicity. 
 
 
      
7. History of myocardial infarction, cardiac 
angioplasty or stenting, unstable angina, or other 
clinically significant cardiac disease within 
12 months of enrollment. 
 
 
      
8. Any medical condition that in the judgement of 
the sponsor investigator is likely to interfere with 
assessment of safety or efficacy of study 
treatment. 
 
 
      
9. History of severe immediate hypersensitivity 
reaction to any of the agents used in this study. 
 
 
      
10. Women who are pregnant or breastfeeding.   
 
 
      
11. In the investigator’s judgment, the subject is 
unlikely to complete all protocol-required study 
 
 
      

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EXCLUSION CRITERIA 
Yes 
No 
Supporting Documentation† 
visits or procedures, including follow-up visits, 
or comply with the study requirements for 
participation.  
12. Primary immunodeficiency or history of 
autoimmune disease (e.g. Crohns, rheumatoid 
arthritis, systemic lupus) requiring systemic 
immunosuppression/systemic disease modifying 
agents within the last 2 years. 
 
 
      
†All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.   
 
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
Treating Physician Signature: 
Date: 
Printed Name: 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
Study Coordinator Signature: 
Date: 
Printed Name: 
 
 
 

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3.2 
INFORMED CONSENT PROCESS 
All participants must be provided a consent form (or in the event that two stages of enrollment are 
planned, two consent forms as outlined in Section 13.8, Appendix H) describing the study with 
sufficient information for participants to make an informed decision regarding their participation.  
The investigational nature and research objectives of this trial, the procedures and treatments 
involved and their attendant risks and discomforts and potential benefits, and alternative therapies 
will be carefully explained to the subject, and the subject/LAR asked to review the consent form 
and to ask questions prior to agreeing to participate in this protocol.  The subject is reassured that 
participation on trial is entirely voluntary and that he/she can withdraw or decide against treatment 
at any time without adverse consequences. 
The original signed copy of the consent document(s) must be retained in the research file and a 
copy placed in the medical record. 
3.3 
SUBJECT SCREENING ASSESSMENTS AND REGISTRATION 
3.3.1 General considerations for Subject Screening 
The screening period begins on the date the subject signs the IRB/APB approved consent form and 
continues through date of enrollment (the date triple review eligibility sign off is completed to 
verify that the participant’s eligibility is accurate, complete, and legible in source records).  
Informed consent must be obtained before completion of any non-standard of care study specific 
procedures.  Procedures that are part of standard of care are not considered study specific 
procedures and may be performed prior to obtaining consent and used to confirm eligibility.  
Confirmation of this data must occur within 28 days of enrollment, unless specified otherwise.  If 
the subject has received anti-CD22 targeted therapy (e.g. Moxetumomab pasudotox or inotuzumab 
ogozamicin), then CD22 expression must be demonstrated subsequent to this therapy in subjects 
with ALL.  Subjects with aggressive B-cell NHL must have archived tissue available for analysis 
or be willing to undergo biopsy prior to starting conditioning lymphodepletion regimen.   
After written informed consent has been obtained, subjects will be screened to confirm study 
eligibility and participation.  Only subjects who meet the eligibility criteria listed in the Eligibility 
Checklist Section 3.1 will be enrolled in the study.  If at any time prior to enrollment the subject 
fails to meet the eligibility criteria, the subject should be designated as a screen failure on the 
subject screening log with the reasons for failing screening. 
3.3.2 Study Enrollment 
Before enrollment of a subject into the study, the responsible physician must ensure the subject 
meets all eligibility criteria using the Study Screening Procedures outlined in Section 5.1.  
Eligibility criteria will be reviewed and confirmed by the Principal Investigator or designee prior 
to any subject being enrolled into the study.   
Enrollment will be defined as the date triple review eligibility sign off is completed to verify that 
the participant’s eligibility is accurate, complete, and legible in source records.  At time of 
enrollment, each subject will receive a unique subject identification number.  This number will be 
used to identify the subject throughout the study and must be used on all study documentation 
related to the subject.  Furthermore, the subject identification number must remain constant 
throughout the entire clinical study, it must not be changed after enrollment or if the subject is 

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rescreened or retreated. 
Screening and enrollment for subjects enrolling in two stages due to patient or manufacturing 
scheduling will be completed as above but appropriate screening evaluations will be completed 
for each stage of eligibility as outlined in Section 13.8, Appendix H; subject identification number 
will remain constant throughout both stages of the protocol. 
4 
TREATMENT PLAN 
4.1 
OVERVIEW 
This is a Phase I/Ib study in adult subjects with B cell malignancies, including ALL and aggressive 
B-cell NHL who have relapsed or refractory disease.  In light of the previous experience of 
CD22-CAR T cells in subjects with ALL, subjects with ALL will receive 1 x 106 cells/kg 
CD22-CAR transduced T-cells.  Simultaneously, a standard 3 + 3 dose escalation design will be 
tested in subjects with aggressive B-cell NHL to establish MTD/RP2D using 3 dose levels of 
CD22-CAR T-cells (see Table 3).  Autologous PBMC will be obtained by leukapheresis and 
transduced with CD22-CAR lentiviral vector.  Cryopreserved PBMC stored from participation in 
other institutional cell therapy or cell collection studies or standard of care may be used to generate 
the cellular product on this study as long as the cryopreserved cells meet the criteria established in 
this IND.   
Subjects will receive a lymphodepleting chemotherapy preparative regimen followed by infusion 
of CD22-CAR transduced T-cells.  The DLT assessment period is defined as 28 days.  Subjects 
will be evaluated sequentially after treatment for toxicity, antitumor effects and for persistence of 
CAR in blood samples and functionality of transduced T cells.  Safety evaluations will also be 
conducted in each disease group separately: subjects with ALL and subjects with aggressive B-
cell NHL.   
Although a secondary endpoint, efficacy will be important in determining if a Phase 2 study is 
warranted with this CAR T cell therapy.  Efficacy analysis will be conducted in each disease cohort 
and will be used to establish a preliminary assessment of clinical response, overall survival (OS), 
and progression-free survival (PFS) as described in Section 12.2.  Stopping rules are defined in 
Section 12.3. 
4.1.1 Treatment Plan for Adults with ALL 
Initially 10 subjects with ALL will receive 1 x 106 cell/kg (± 20%) of CD22-CAR transduced 
T-cells to explore safety of CD22-CAR T cells manufactured using the Miltenyi Biotech 
CliniMACS Prodigy® system.  Treatment will be staggered as follows: at least 21 days will elapse 
between cell infusion for each of the first 3 subjects with ALL, followed by a pause while the third 
ALL subject completes the 28-day DLT observation period.  If no DLTs have been observed in 
the first 3 subjects with ALL, no further treatment stagger is necessary.  If a DLT is observed in 
any of the first 3 subjects with ALL, the 21-day treatment stagger will continue for another 3 
subjects.  If Dose Level -1 or Dose Level 2 is explored in subjects with ALL, the same 21 day 
treatment stagger for the first 3 subjects will be followed. 
Given the expected toxicity rates associated with CAR T-cell therapies, the maximum acceptable 
rate for dose limiting toxicity (DLT) in the ALL group and the aggressive B-cell NHL group 

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treated is 30% for each disease group. The dose will be reduced if the observed rate for DLT meets 
the criteria described in Section 12.1.2.2, with DLT evaluations after 10 subjects with ALL 
complete the 28-day DLT observation period, then after every 5 subjects up to 28 subjects with 
ALL. 
Alternatively, if there are 15 subjects with ALL treated at Dose Level 1 without sufficient evidence 
of activity and the DLT rate <30% at Dose Level 1, the  Safety Monitoring Committee (SMC) may 
recommend dose escalation to Dose Level 2, as described in Section 10.3.3 and Section 12.2.2.   
4.1.2 Treatment Plan for Adults with Aggressive B-cell NHL 
This CD22-CAR has not been previously administered to subjects with aggressive B-cell NHL.  
Therefore subjects will be treated in a standard 3 + 3 dose escalation design using 3 dose levels of 
CD22-CAR T-cells, with a potential Dose Level -1, (see Table 3) to establish MTD/RP2D.  
Treatment will be staggered as follows for each dose level: at least 21 days will elapse between 
infusion of each subject during dose escalation.  The final subject with aggressive B-cell NHL in 
a dose cohort must complete the 28-day DLT observation period before the decision is made 
whether to treat additional subjects at the current dose level or to dose escalate (as per Table 6).  
The SMC will review and confirm any decision to escalate dose of CD22-CAR T cells to the next 
level, based on the dose escalation plan described in Section 5.4.4. 
The MTD is defined in Section 5.4.4.1.  Once the MTD/RP2D is established, and expansion cohort 
will enroll additional subjects to further evaluate this regimen in subjects treated at MTD/RP2D, 
for safety (described in Section 12.1.2.1) and initial efficacy (described in Section 12.2.1).  
Evaluation of subjects in the aggressive B-cell NHL at MTD/RP2D will include those from the 
dose escalation cohort treated at MTD/RP2D, for a total of up to 36 subjects.   
4.2 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
4.2.1 Infection Prophylaxis 
Any temperature of >38◦ C will require initiation of the fever work-up and treatment according to 
institutional standards.   
4.2.1.1 Viral Prophylaxis 
All subjects will be treated as high risk and will receive viral prophylaxis according to institutional 
standards.   
4.2.1.2 Fungal Prophylaxis 
All subjects will be treated as high risk and will receive fungal prophylaxis according to 
institutional standards. 
4.2.2 B-cell Depletion 
Since B cell antigen-targeted immunotherapy has been demonstrated in other studies to also 
eliminate normal B cells, serum IgG levels will be monitored before cell infusion and every 3-12 
weeks after infusion.  If IgG < 400, intravenous IgG (IVIG) will be administered with the 
appropriate premedications as per institutional guidelines at the discretion of the treating physician. 

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4.2.3 Blood Product Support for Anemia and Thrombocytopenia 
Using complete blood count (CBC) as a guide, the subject will receive platelets and packed red 
blood cells as needed.  Attempts will be made to keep hemoglobin (Hgb) > 7.0 gm/dl, and 
platelets > 10,000/mm3, or as per institution guidelines.  All blood products with the exception of 
the lymphocyte product will be irradiated.  Leukocyte filters will be utilized for all blood and 
platelet transfusions to decrease sensitization to transfused white blood cells (WBCs) and decrease 
the risk of cytomegalovirus (CMV) infection. 
In subjects with coagulopathy, attempts will be made to keep platelets > 50,000/mm3 and 
fibrinogen  100 mg/dL.   
4.2.4 Tumor Lysis Syndrome 
Subjects at risk for tumor lysis syndrome, as per the investigator’s discretion, will receive 
allopurinol and hydration prophylactically as per the institutional guidance/managing team’s 
determination. 
4.2.5 Anti-Neoplastic Therapy 
Subjects must have evaluable disease at the time of protocol enrollment or enrollment for Stage 2.  
Every effort will be made to initiate cell culture within 30 days of apheresis so minimal time 
transpires for a subject’s disease to progress significantly.  In the event that circumstances external 
to this study arise , subjects may receive disease-directed therapy (standard or investigational) prior 
to moving to the treatment phase of this study if the investigator determines there is at significant 
risk of disease progression during the delay.  Since the toxicity of CAR-based therapy is related to 
disease burden (more disease associated with more CAR-related toxicity) and because the time to 
initiation of conditioning lymphodepletion regimen may be delayed due to multiple reasons, our 
experience to date indicates that patients may have rapid progression of their disease in this interval 
risking increased toxicity from either CAR therapy or disease progression.  Treatment data and 
unresolved toxicities will be captured in baseline assessment case report forms (CRFs).   
Data related to anti-neoplastic bridging therapy administered to subjects after enrollment, will be 
captured on study CRFs including dates of therapy, the agent and doses administered, the dose and 
schedule of radiation therapy, and response to therapy (if assessed prior to start of lymphodepleting 
chemotherapy). 
In order to initiate the conditioning lymphodepletion regimen, subjects must meet criteria 
established in Section 5.3, or if enrolling in two stages, the eligibility criteria outlined in Section 
13.8, Appendix H. A disease evaluation (methodology per PI discretion) may be performed at the 
investigator’s discretion, based on the duration of time from initial screening to start of 
chemotherapy. 
4.2.6 Concurrent Therapy for Extramedullary Leukemia or CNS Leukemia 
Subjects may have CNS disease without overt evidence of signs and symptoms that may mask the 
development of neurotoxicity.  Concurrent craniospinal radiation will not be allowed.  Concurrent 
therapy or prophylaxis for CNS leukemia consisting of standard intrathecal chemotherapy will be 
allowed as clinically indicated in subjects with ALL at times of re-staging lumbar punctures.  
Intrathecal chemotherapy will NOT be given from Day 0 until at least Day 24 (i.e., during the first 

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re-staging evaluation performed at Day 28 +/- 4).  Subsequent intrathecal therapy will be given no 
more frequently than monthly.  Intrathecal chemotherapy will NOT be administered in any subject 
who develops CNS toxicity until at least 2 weeks after complete resolution of neurologic toxicity. 
4.2.7 Cytokine Release Syndrome 
Cytokine release syndrome, a toxicity associated with infusion of CAR T cell therapy, has been 
described in Section 2.4.4.  Grading and management of CRS in this protocol will follow the 
guidelines in Section 13.2, Appendix B[10], which includes diligent supportive care and search 
for infection, with immunosuppression using anti-IL6R mAbs (e.g. tocilizumab) and/or 
corticosteroids reserved for more severe cases. Use of anakinra, an IL-1 receptor antagonist, 
currently approved by the US Food and Drug Administration for the treatment of patients with 
rheumatoid arthritis and neonatal-onset multisystem inflammatory disease, has been used off label 
for the treatment of secondary hemophagocytic lymphohistiocytosis (HLH), a condition in the 
spectrum of CRS potentially associated with chimeric antigen receptor (CAR) T-cell 
therapy[120],[121].  Anakinra may be considered for management of CRS related toxicities, at the 
investigator’s discretion. Because understanding of the constellation of symptoms defining CRS 
is evolving, AE CRFs will capture both the syndrome and the individual symptomatology of CRS.  
Investigators should follow the protocol’s CRS management guidelines whenever possible, but 
deviation from the guidance will not be considered a protocol deviation as all toxicity management 
should be at the treating physician’s discretion. 
4.2.8 Neurotoxicity 
Neurotoxicity (e.g., encephalopathy, somnolence, aphasia) has been observed with CAR T cell 
therapies and will be scored using CTCAE 5.0 and the tools available in Appendix B, Section 
13.2, using a combination of the the ASBMT Immune effector Cell-Associated Neurotoxicity 
Syndrome (ICANS) Consensus Grading for Adults with the Immune effector Cell-associated 
Encephalopathy (ICE) assessment tool.  All subjects will receive levetiracetam (Keppra®) 500- 
twice a day (BID) or per institutional guidelines beginning the day before cell infusion.  For good 
clinical practice, clinicians and staff will evaluate the ICE score every shift (± 2 hours) after cell 
therapy while hospitalized or up to Day 14, whichever happens first.  The maximum ICE score for 
each day should be documented, and any drop in ICE score below 7 should be urgently 
communicated to attending physician.  Neurologic evaluations will be assessed daily up to Day 
14.  Evaluation of any new onset of neurotoxicity should consider recommended interventions in 
Appendix B (Section 13.2.3.2, ASBMT Immune effector Cell-Associated Neurotoxicity 
Syndrome (ICANS) Consensus Grading for Adults) 
These recommendations should serve as guidance for toxicity management, but deviation from the 
guidance will not be considered a protocol deviation, as all toxicity management should be at the 
treating physician’s discretion. 
Medications with sedative properties should be avoided if possible unless required to manage 
seizures, e.g. benzodiazepines.  Leukoencephalopathy has been observed on MRI in the setting of 
neurotoxicity.  Follow-up MRI is recommended to monitor the course of leukoencephalopathy to 
potential resolution. 
Subjects and their families/caregivers should be warned of the risk of late neurotoxicity through 
Day 28 and told to seek immediate medical attention for any new symptoms of neurotoxicity.  In 

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addition, subjects should be advised not to drive or operate heavy machinery for the first month 
after discharge and/or until 1 month after complete resolution of neurotoxicity symptoms. 
4.3 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
4.3.1 Criteria for removal prior to CD22-CAR T cell infusion 
Subjects will be taken off treatment and followed until effects of chemotherapy and all 
toxicities are resolved to Grade 1 or baseline for any of the following: 
✓ 
General or specific changes in the subject’s condition that render the subject 
unacceptable for cell infusion on this study in the judgment of the investigator, 
including inability to meet eligibility criteria for Stage 2: Lymphodepleting 
Chemotherapy and CD22-CAR T cell infusion, if enrolling in two stages. 
✓ 
Pregnancy in a female of child-bearing potential. 
✓ 
Cells do not meet release criteria. 
Once toxicities and effects of chemotherapy resolve, subjects who are unable to undergo cell 
infusion will be removed from this study. 
4.3.2 Criteria for removal from the option for a 2nd cell infusion 
Subjects will not be eligible for further therapy (2nd cell infusion) and will be followed until 
off-study criteria are met for the following: 
✓ 
Dose limiting toxicity (DLT) after first infusion.  The definition of DLT is in 
Section 5.4.7.1 
✓ 
Pregnancy in a female of child-bearing potential. 
✓ 
No cells available for re-treatment. 
4.3.3 Criteria for transition to Long Term Follow-up 
Subjects will move directly to Long Term Follow-up for gene therapy and followed until off study 
criteria are met for the following: 
✓ 
Did not respond to CD22-CAR treatment (did not achieve a CR or PR) or 
progresses following response, and is either not eligible or chooses not to pursue 
re-treatment 
✓ 
Proceeds to alternative therapy after CAR treatment 
Subjects on Long Term Follow-up will be followed for survival, subsequent therapy, long-term 
gene therapy follow up (including RCL blood sampling), as described in Section 5.5.5.  At the 
discretion of the investigator, subjects may continue correlative sample collection. 
4.3.4 Off-Study Criteria  
✓ 
Subject withdrawal of consent (in which case the reason will be documented, if 
possible).  Subjects who withdraw consent for additional procedures may still 
participate in long-term follow up.  
✓ 
Subject who meet any of the withdrawal criteria listed in Section 4.3.1 and who 

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have recovered from all study-induced toxicity. 
✓ 
Subject lost to follow-up.  Should a subject fail to return to the clinic for a scheduled 
protocol specific visit, site will need to make 2 attempts by a combination of 
telephone and mail to contact the subject.  Site must document both attempts to 
contact the subject.  If a subject does not respond within 1 month after the second 
contact the subject will be considered lost to follow-up and no additional contact 
will be required. 
✓ 
Death 
✓ 
Conclusion of the 15 years of follow up, or subject enrolls in a separate long-term 
follow up protocol for subjects receiving gene transfer. 
4.3.5 Off-Study Procedure 
Off study date and reason should be documented in the study CRFs.  For subjects withdrawing 
consent, the investigator should inquire whether the subject agrees to allow chart review of normal 
medical care procedures and/or long term follow-up of gene therapy research participants.  Cell 
products and biological samples from off-study subjects may continue to be used for process 
development and correlative studies, as outlined in the consent form. 
5 
SUBJECT STUDY PROCEDURES 
5.1 
SUBJECT SCREENING 
The screening period begins on the date the subject/LAR signs the IRB and APB approved consent 
form and continues through confirmation of enrollment.  Procedures that are to be performed as 
part of standard medical care, such as for diagnosis or treatment of a disease or medical condition, 
may be performed and the results subsequently used for determining study eligibility without first 
obtaining consent.  Informed consent must be obtained prior to initiation of any clinical procedures 
that are performed solely for the purpose of determining eligibility for research, e.g. withdrawal 
from medication (wash-out period).  Only subjects who meet the eligibility criteria listed in 
Section 3.1 will be enrolled in the study.   
All subjects will undergo the screening procedures, which include a comprehensive history and 
physical exam performed by a study physician as outlined below.  Imaging, bone marrow biopsy 
and aspiration, and organ specific studies will be performed as per institutional guidelines.  The 
following screening tests must be performed within 28 days prior to enrollment unless specified 
otherwise. 
If patient or manufacturing scheduling requires, screening may be completed in two stages: 1) for 
leukapheresis, and 2) for lymphodepleting chemotherapy and CD22-CAR T cell infusion, as 
outlined for each stage in Section 13.8, Appendix H.   
(a) CD22 expression  
For R/R ALL subjects:  Expression will be evaluated by immunohistochemistry or by flow 
cytometry in a CLIA approved laboratory and documentation at screening will be required 
(testing is permitted to be conducted at any time since diagnosis, unless subject has received 
anti-CD22 targeted therapy, such as Moxetumomab pasudotox or inotuzumab ozogamicin, in 

Protocol: CD22 CAR T-cell in Adults 
  
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which case the specimen must be collected after such therapy). 
For R/R aggressive B-cell NHL:  CD22 expression at any level, including undectable, will be 
acceptable.  Subjects must have archival tissue available for analysis of CD22 expression or 
must be willing to undergo a biopsy of easily accessible disease. 
(b) Medical history and concomitant medication 
The subject’s complete history through review of medical records and by interview will be 
collected and recorded.  Concurrent medical signs and symptoms must be documented to 
establish baseline severities.  A disease history, including the date of initial diagnosis and list 
of all prior treatment, responses, and duration of response to the prior treatment also will be 
recorded.  Most current disease status will be determined to include presence and location of 
current disease. Prior therapy washout periods will be calculated. History of known infection 
with HIV, hepatitis B and hepatitis C will be elicited, but viral testing is not necessary, as this 
will be performed standard of care prior to the leukapheresis procedure, as per institutional 
procedures. 
(c) Physical examination  
A complete physical examination will be performed.  The exam will include general 
appearance of the subject, height and weight, examination of the skin, eyes and ears, nose, 
throat, lungs, heart, abdomen, extremities, musculoskeletal system, and nervous system.   
(d) Vital signs, including blood pressure, heart rate, oxygen saturation and temperature  
(e) Performance status (ECOG or Karnofsky) see Appendix A, Section 13.1 
(f) Electrocardiogram (ECG)  
(g) ECHO, MUGA or Cardiac MRI for LVEF and pericardial effusion assessment [performed 
within 180 days or after most recent anthracycline based treatment or mediastinal 
radiation therapy (whichever is most recent)] 
(h) Creatinine clearance: A measured 24 hour urine creatinine clearance test may be performed 
if the serum creatinine is elevated, and the measured value will be recorded in the CRF and 
may be used to qualify the subject for study participation. 
(i) β-HCG pregnancy test on all women of child-bearing potential 
(j) Coagulation tests including prothrombin time (PT)/ partial thromboplastin time (PTT) 
(k) General Laboratory Tests: The following will be obtained during the screening process: 
o Chemistries: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, calcium, AST, ALT, alkaline phosphatase, bilirubin, albumin, 
total protein 
o Phosphorus and magnesium 
o CBC with differential  
o C-reactive protein (CRP), ferritin  
o Urinalysis 

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(l) Additional Tests:  
The investigator may order additional tests in some subjects if needed to fully assess clinical 
status and obtain baseline results.  Examples of such tests include: haptoglobin, soluble IL2R, 
immunoglobulin levels, and viral serology or PCR for cytomegalovirus (CMV), herpes simplex 
virus (HSV), varicella zoster virus (VZV), and Epstein-Barr virus (EBV). 
(m) Disease Evaluation (methods will be determined by investigator based on subjects’ location 
of disease, not all are required on all subjects) 
o Imaging Studies appropriate to sites relevant to subject’s disease: subjects with 
aggressive B-cell NHL will undergo PET/CT; other imaging studies (e.g. MRI of 
the brain) will be performed as determined by investigator 
o Bone marrow aspirate/biopsy: subjects with ALL will undergo bone marrow 
biopsy, subjects with bone marrow involvement prior to therapy or if new 
abnormalities in the peripheral blood counts or blood smear cause suspicion of bone 
marrow involvement will undergo bone marrow aspirate and biopsy 
o Lumbar puncture, if determined as clinically necessary by the investigator 
5.2 
LEUKAPHERESIS FOR CELL ACQUISITION:  
Leukapheresis (apheresis) will be performed according to institutional standards with the goal of 
obtaining a minimum of 1 x 108 CD3+ T cells for transduction.  If PBMCs have been 
cryopreserved for a different cell therapy or cell collection study or standard of care, they may be 
used to generate CD22-CAR T cells on this study if they meet criteria outlined in this IND. 
Target cell number will be based upon the expected expansion and planned cell doses of transduced 
T cells/kg.  The target will be 14-20 L apheresis in adults (target 2 x 109 mononuclear cells).  
Prophylactic intravenous CaCl2 and MgSO4 infusions may be administered by the apheresis 
clinical team per standard operating procedures.  Institutional guidelines will be followed for 
venous access and apheresis procedures.   
If the patient is unable to meet the required number of cells and is unable (by investigator’s 
discretion or scheduling constraints) to undergo further apheresis collections, the patient will be 
discontinued from the study.  If, after enrollment and leukapheresis, the decision is made to not 
proceed with CD22-CAR T cell manufacturing, the collected apheresis product will be made 
available to the subject for alternative CAR-T cell production, if requested. 
Eligibility criteria to undergo leukapheresis is as follows all subjects, unless undergoing two stage 
enrollment (see Section 13.8, Appendix H): 
• Subjects must have no evidence of a clinically significant uncontrolled infection prior to 
leukapheresis 
• Absolute lymphocyte count ≥ 150/uL within last 7 days (unless lower count attributed to 
disease status) 
• No new signs or symptoms of kidney or liver dysfunction outside eligibility criteria within 
last 7 days  
• Females of child-bearing potential must not be pregnant.   

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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Systemic Corticosteroid therapy at dose ≥ 5 mg/day of prednisone (or equivalent doses of 
other corticosteroids) and other short-acting cytotoxic/antiproliferative drugs drugs must be 
avoided for 3 days prior to leukapheresis. 
The following procedures/requirements will occur on the leukapheresis collection day (unless 
otherwise specified) and as outlined in the Section 9 Study Calendar: 
• Vital signs, including blood pressure, heart rate, respiratory rate, oxygen saturation, and 
temperature  
• Weight 
• Labs (need not be repeated if screening labs were performed within 7 days prior to 
leukapheresis)  
o Chemistry panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, AST, ALT, alkaline phosphatase, bilirubin, albumin, total 
protein) 
o Phosphorus and magnesium 
o CBC with differential  
o CRP 
o Pregnancy test (females of child-bearing potential only) 
• Leukapheresis  
• Correlative studies sample collection, as detailed in Appendix G, Section 13.7 
• Adverse/Serious Adverse Event reporting – record only unexpected serious adverse 
events considered related or possibly related to study procedures.  
• Concomitant medications documentation  
Subjects may receive disease-directed therapy (standard or investigational) prior to initiating 
conditioning lymphodepletion chemotherapy if the investigator determines there is at significant 
risk of disease progression if all treatment is stopped while waiting for cell manufacture (see 
Section 4.2.5).  
Any change to baseline toxicities (“Course Zero”) will be captured in baseline assessment CRFs, 
but adverse events related only to anti-neoplastic bridging therapy will not be collected in study 
CRFs (see Section 7.3). 
• , urea nitrogen, albumin, alkaline phosphatase, ALT and/or AST, total bilirubin). 
5.3 
CONDITIONING LYMPHODEPLETION CHEMOTHERAPY REGIMEN  
Subjects will receive a conditioning lymphodepletion chemotherapy regimen in order to induce 
lymphocyte depletion and create an optimal environment for expansion of CD22-CAR T cells in 
vivo.  Conditioning lymphodepletion chemotherapy regimen has been chosen based on the clinical 
site’s standards of practice and institutional procedures to minimize deviations and risks to 
subjects.  Routine anti-emetic prophylaxis and treatment should be employed.  Corticosteroids 
may not be used (except for physiologic replacement). 
5.3.1 Criteria for Initiating Conditioning Lymphodepletion Chemotherapy Regimen 
In order to initiate the conditioning lymphodepletion chemotherapy regimen, all subjects must 
meet the following criteria within 7 days prior to starting chemotherapy: 

Protocol: CD22 CAR T-cell in Adults 
  
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gene; following lymphodepleting chemotherapy 
 
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• There must be 14 days or more than five half-lives from the last dose of standard 
chemotherapy (7 days from ALL maintenance therapy), with the exclusion of steroids, 
which may be continued until starting conditioning lymphodepletion regimen.   
• No evidence of uncontrolled infection,  
• No clinically significant cardiac dysfunction,  
• Serum creatinine must be < 2 x ULN,  
• No acute neurological toxicity > Grade 1 (with the exception of peripheral sensory 
neuropathy), 
• Negative pregnancy test in child-bearing females within 7 days of starting chemotherapy. 
• Repeat disease evaluation, at the discretion of the investigator, if the subject received any 
antineoplastic therapy after enrollment (per Section 4.2.5), if greater than 28 days has 
elapsed between date of enrollment and start of conditioning lymphodepletion 
chemotherapy regimen, or if investigator believes disease may have significantly advanced 
since enrollment.   
Should an event exceed these criteria immediately prior to conditioning chemotherapy, 
conditioning chemotherapy must be delayed until the event resolves to ≤ Grade 1 or baseline.   
 
5.3.2 Conditioning Lymphodepletion Chemotherapy Regimen Procedures 
Subjects will initiate one of the conditioning chemotherapy regimens as listed in Table 4, at the 
discretion of the investigator.  The conditioning chemotherapy regimen may be administered in an 
outpatient setting per investigator’s discretion.  The dose calculation for the chemotherapy 
administration will be based on the height (measured within the past 30 days) and weight measured 
on Day -6 or -5 of the start of lymphodepletion.  At the investigator’s discretion, the timing of the 
start and ending of the regimen of conditioning lymphodepletion chemotherapy may be adjusted 
based on the best interest of the patient. 
The following procedures will be completed daily during chemotherapy, unless otherwise 
specified:  
• Height (taken within 30 days prior) and weight (Day -6 or Day -5 only) 
• Vital signs, including blood pressure, heart rate, respiratory rate, oxygen saturation, and 
temperature  
• Pregnancy test (females of child-bearing potential only), performed within 7 days prior to 
the start of chemotherapy 
• Labs  
o Chemistry Panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, calcium, AST, ALT, alkaline phosphatase, bilirubin, albumin, total 
protein) 
o Phosphorus, magnesium, and LDH, uric acid (on Day -5 or -6 only) 
o CBC with differential  
o CRP and ferritin (on Day -5 or -6 only) 
• Chemotherapy administration  
• Correlative studies sample collection, as detailed in Appendix G, Section 13.7 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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• Adverse/Serious Adverse Event reporting  
• Concomitant medications documentation  
• Hydration: Subjects will receive Home IV fluid infusion per institutional guidelines for the 
agents administered.   
Each subject will receive one of the lymphodepleting regimens, at the investigator’s discretion as 
follows: 
Table 4. Conditioning Lymphodepletion Chemotherapy Regimen 
Regimen #1 
Cyclophosphamide 
500 mg/m2 per day IV infusion over at 
least 60 minutes or as tolerated, on Day 
-5, -4 and -3 
-5, -4, -3 
Fludarabine 
30 mg/m2 per day IV infusion over at 
least 30 minutes or as tolerated, daily 
for 3 days. 
-5, -4, -3 
Regimen #2 
Cyclophosphamide 
500 mg/m2 per day IV infusion over at 
least 60 minutes or as tolerated, on Day 
-6 and -5 
-6, -5 
Clofarabine 
40 mg/m2 per day IV infusion over at 
least 2 hours or as tolerated, daily for 4 
days. 
(Reduce dose by 25% of the usual dose if CrCl 60-
80 mL/min; Reduce dose by 50% if CrCl 30-60 
mL/minute) 
-6, -5, -4, -
3 
Regimen #3 
Bendamustine 
90 mg/m2 per day IV infusion over 10 
minutes or as tolerated, daily for 2 days. 
(Adjust or hold dose for CrCl Less than 30 
mL/minute) 
-4, -3 
 
 
 
 
 
 
 
 
 
 
 
 
Hydration may be adjusted based on clinical need (e.g. over hydration or dehydration).  There will 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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be no dose adjustment of chemotherapy agents for weight considerations or abnormal lab values.  
If subjects are eligible for the trial, then the full dose of lymphodepletion agents will be 
administered. 
5.4 
INVESTIGATIONAL AGENT ADMINISTRATION AND RESEARCH PROCEDURES 
5.4.1 Cell Processing:  
Cellular Product: Autologous T cells; transduced with lentiviral vector (CD22.BB.Z) Chimeric 
Antigen Receptor (CD22-CAR); following Lymphodepleting Chemotherapy  
Autologous CD22-CAR T cells will be generated from fresh or cryopreserved PBMCs under GMP 
conditions in the manufacturing facility using Miltenyi CliniMACS Prodigy® system.  Apheresis 
products from participating subjects will be sent to the manufacturing facility through Stanford 
Bone Marrow Transplant Department’s Cellular Therapeutics Facility (CTF); final cell products 
will be received and final formulated product distributed by the CTF. 
Any prepared cells not required for the first infusion or for research or regulatory purposes 
(including sufficient QA retention vials for testing cryopreserved product stability at time of 
additional infusions) will be cryopreserved by standard techniques and will be made available 
should the subject be eligible for a second infusion as outlined in Section 5.6.  Additional product 
in excess of that needed for infusion may be utilized for research. 
Fresh or cryopreserved PBMCs (depending on the timing of apheresis relative to cell culture, 
subject condition, and scheduling availability) will be used for cell manufacturing.  Cells will be 
required to meet standard release criteria including transduction efficiency ≥ 10%, T cell content 
≥ 70%, sterility and minimum levels of lipopolysaccharides (LPS), as well as no evidence for 
replication competent lentivirus.  All procedures will take place using good manufacturing process 
guidelines. 
The release criteria will be based upon analyses of CD22-CAR lenti-transduced autologous PBL 
and will include:  
Table 5. CD22-CAR Product Rapid Release Criteria 
Test 
Criteria 
Cell viability1 
≥ 70%  
Total Cell Count1 
within 20% of planned dose 
level  
CD3+% 
≥ 70% 
CAR+ % 
≥ 10%  
Endotoxin1  
< 5 EU/kg  
Mycoplasma by PCR1  
Negative 
RCL2 
Negative  
Sterility testing3  
Negative  
1Performed on sample from final product, results available at the time of infusion. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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2Two samples will be sent to Indiana University GTTL: 1) Real-time PCR testing, results available at the time of infusion; 2) 
culture-based testing; results not available prior to infusion.  
3Gram stain is performed on final product prior to infusion and is available at the time of infusion; 14-Day cultures will be sent 
from the harvest (Day 7, or 11) drug product. Sample results collected from the final product will not be available before cells are 
infused into the subject.  Although cells will not be infused prior to a preliminary negative sterility reading from Day 3 to 5 of the 
culture. 
 
5.4.2 CD22-CAR T cell Infusion 
5.4.2.1 Cell Infusion Criteria 
Subjects will be hospitalized to receive treatment with CD22-CAR T cells, if not previously 
hospitalized, and will remain hospitalized for approximately 7 (±2) days.  Patients may be 
discharged once all AEs have resolved to Grade 1 or better, or at the discretion of the treating 
physician.  Subjects may be discharged with non-critical and clinically stable or slowly improving 
toxicities (e.g., renal insufficiency, cytopenias) even if > Grade 1, if deemed appropriate by the 
investigator.  Subjects must meet the following criteria in order for cells to be infused (based on 
labs obtained within 24 hrs of cell infusion): 
✓ CD22-CAR T cells must have met release criteria (section 5.4.1) 
✓ Subject has no evidence of hemodynamic instability 
✓ Subject has not developed a new requirement for supplemental oxygen therapy 
✓ Subject has not developed symptoms concerning for new, systemic infection or condition 
that in the opinion of the PI may pose an unacceptable risk to the subject 
✓ There is no evidence of clinically significant cardiac dysfunction, uncontrolled, significant 
tumor lysis syndrome, serum creatinine > 2 x ULN, and no acute neurological toxicity 
> Grade 1 (with the exception of peripheral sensory neuropathy).   
If these criteria are not met, measures will be taken to resolve the underlying condition(s) and the 
cell infusion must be delayed until the event resolves. Fresh, uncryopreserved CD22-CAR T cells 
should be infused within 72 hours of planned infusion or frozen for later use. If the CD22-CAR T 
cells infusion is delayed > 2 weeks, conditioning chemotherapy must be repeated, unless 
investigator deems this unnecessary.   
Corticosteroid therapy at a dose ≥ 5 mg/day of prednisone (or equivalent doses of other 
corticosteroids) and other short-acting cytotoxic/antiproliferative  drugs must be avoided for 
5 days prior to CD22-CAR T cell administration.   
5.4.2.2 Premedications  
Adult subjects will receive levetiracetam 500 mg orally twice a day as per institutional guidelines, 
at the physician’s discretion (maximum dose of 750 mg/dose) beginning the day before cell 
infusion (Day -1). 
Subjects at high risk of TLS, per investigator’s discretion, may receive allopurinol 300 mg orally 
once daily or at 100 mg/m2/dose TID beginning the day prior to cell infusion (Day -1) or at the 
time of the conditioning lymphodepletion chemotherapy regimen, as determined by investigator. 
Subjects will receive the following medications 30-120 minutes prior to cell infusion:  

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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1) Diphenhydramine:  25-50 mg/dose orally (PO) or IV; 
2) Acetaminophen:  650 mg/dose PO or IV 
5.4.2.3 Cell Infusion 
Cells are delivered to the subject care unit by a staff member from CTF.  Prior to infusion, the cell 
product identity label is double-checked by two authorized staff (MD or RN) and an identification 
of the product and documentation of administration are entered in the subject’s chart, as is done 
for blood banking protocols.  Cell products should NOT be infused unless the product 
identification matches the subject’s identification.   
Cells are to be infused intravenously (IV) over 10-30 minutes (or as tolerated based on volume 
and/or DMSO toxicity) via non-filtered tubing, gently agitating the bag during infusion to prevent 
cell clumping.  After infusing cells, rinse the infusion tubing and empty bag with a backflush of 
normal saline. Infuse the remaining cells using the backflush method.  Documentation in the 
medical record should include the volume of cell infusion, the thaw start/stop time (if cells are 
cryopreserved), and cell product infusion time start/stop times.   
5.4.3 Determination of Cell Dose 
Cell dose will be body weight-based; the dose of CD22-CAR transduced T cells will be calculated 
using actual body weight, capped at 100 kg, measured within 14 days of cell manufacture start 
date.   
If cell growth limitations preclude administration of the number of cells targeted for the assigned 
cohort level, the subject will receive as many cells as possible, as the efficacious dose is not yet 
known, and the subject will be evaluable for feasibility of manufacturing but will not be evaluable 
for safety in that dose cohort, although toxicities will be assessed and reported separately.  An 
additional three subjects per disease group may be enrolled due to cell growth limitations. 
If cell growth limitations preclude administration of the number of cells targeted for the assigned 
cohort level in 3 subjects (out of 6), manufacturing of the cell product will be considered not 
feasible as there will be inadequate number of subjects to evaluate safety at the targeted dose level. 
5.4.4 Dose Escalation in Subjects with Relapsed/Refractory Aggressive B-cell NHL 
There will be a Phase 1 dose-escalation design with three dose cohorts in subjects with aggressive 
B-cell NHL to determine the MTD/RP2D (see Table 3).  Each dose cohort will initially include a 
minimum of 3 subjects.  Treatment will be staggered as follows for each dose level: at least 21 
days will elapse between infusion of each subject during dose escalation.  The final subject with 
aggressive B-cell NHL in a dose cohort must complete the 28-day DLT observation period before 
the decision is made whether to treat additional subjects at the current dose level or to dose escalate 
to allow for safety assessment of DLTs (as defined in Section 5.4.7.1) as per Table 6.  If Dose 
Level 3 is completed without DLTs, an MTD may not be determined.  This will be considered the 
‘highest cell dose’ studied, and will be the dose level that will be studied further in the expansion 
cohort or recommended phase 2 dose (RP2D). 
Dose escalation will follow the rules outlined in the Table below. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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Table 6. Dose Escalation Rules for Subjects with Aggressive B-cell NHL 
Number of Subjects with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 subjects at the next dose level.  If 0 out 
of 3 occur, dose may escalate.   
1 out of 3 
If DLT develops in one of first 3 subjects at a Dose 
Level, the cohort will be expanded to 6 subjects.   If 
no additional subjects develop DLT, MTD will not 
have been exceeded and the next dose level can be 
administered after the four week safety assessment 
period of the last subject at this dose level. 
If DLT develops in any subject at Dose Level -1, 
accrual will be temporarily stopped while consultation 
with the IRB and FDA occurs.   
2 out of 6 
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose (highest 
dose administered).  Up to three (3) additional subjects 
will be entered at the next lowest dose level if only 3 
subjects were treated previously at that dose. 
<1 out of 6 at highest dose level 
below the maximally 
administered dose 
This is the MTD and is generally the RP2D.  At least 
6 subjects must be entered at this dose level. 
5.4.4.1 Definition of Maximal Tolerated Dose (MTD) 
The maximum tolerated dose (MTD) will be evaluated and reported separately in each disease 
group (ALL and aggressive B-cell NHL).  During dose escalation of subjects with aggressive B-
cell NHL, MTD is defined as the dose level below that at which 2/6 subjects develop DLTs.  
Subjects with ALL treated at the established dose of 1 x 106 transduced T cells/kg and subjects 
with aggressive B-cell NHL treated at the MTD/RP2D, the maximum acceptable rate of DLTs for 
each group is 30%.   
5.4.5 Dose Expansion Cohort for Subjects with Aggressive B-cell NHL 
After the MTD/RP2D is established for aggressive B-cell NHL subjects, a dose-expansion cohort 
will enroll up to 33 evaluable subjects (for a total of 36 evaluable subjects treated at the final 
MTD/RP2D) to monitor safety and indicate efficacy.  The sample size for the aggressive B-cell 
NHL dose-expansion cohort is determined to indicate efficacy (see Section 12.2.1 for more 
details). 
The trial will continue to evaluate safety after the first 11 (or 14) subjects in the dose-expansion 
cohort, corresponding to a total of 17 evaluable subjects treated at the MTD/RP2D with either 6 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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(or 3) subjects from the dose-escalation cohort(s), and every 5 subjects thereafter (see Section 
12.1.2.1).  If de-escalation occurs, new safety boundaries will be generated based on the number 
of currently enrolled subjects and will take place after every 5 additional subjects.  If Dose Level -1 
is found to be unsafe, the trial will stop enrollment for this disease population. 
5.4.6 Dose De-escalation Subjects with Relapsed/Refractory ALL 
Subjects with relapsed/refractory ALL will be treated at Dose Level 1 (1 x 106 transduced T 
cells/kg), as previous clinical studies support this dose level.  The dose will de-escalate to Dose 
Level -1 if the safety boundaries for the number of DLTs presented in Section 12.1.2.2 are met. 
5.4.7 Safety Assessment in Both Populations: in Subjects with Relapsed/Refractory B-cell 
ALL and Subjects with Relapsed/Refractory Aggressive B-cell NHL  
Dose limiting toxicities (DLTs) will be evaluated in each disease group (ALL and aggressive B-
cell NHL) and reported separately.  The period of observation to determine DLT is 28 days after 
cell infusion.  Only adverse events (AEs) assessed by investigator to be possibly, probably or 
definitely related to pre-infusion chemotherapy and/or CD22-CAR T cells (any component of the 
treatment regimen) will be used in the definition of DLT (See Section 7.2.2 for definition of 
‘suspected’ adverse reaction).  Toxicities occurring after initiation of the conditioning 
lymphodepletion chemotherapy regimen but prior to CD22-CAR T cell infusion will primarily be 
attributable to the chemotherapy administration or disease, if not extraneous causes.  After cell 
infusion, toxicities will be evaluated for temporal and causal relationship to chemotherapy versus 
cell infusion.  Some symptoms may overlap and attribution will not be clearly definable, in which 
case, toxicities will be attributed as possibly related to both preparative regimen and cell infusion.  
Toxicities will be attributed to the T cells if: 1) they were NOT present before T cell infusion; OR 
2) they increase in grade in temporal association with the T cell infusion; AND 3) they are not 
clearly explained by other factors. 
Subjects who are fully assessable for DLT are those that have completed the conditioning 
lymphodepletion chemotherapy regimen and received the CD22-CAR T cell infusion.  
Chemotherapy-related toxicities experienced by subjects who are unable to receive CD22-CAR T 
cells will not be considered in the definition of DLT.   
5.4.7.1 Definition of DLT 
Adverse events that are at least possibly related to the treatment regimen (conditioning 
lymphodepletion chemotherapy regimen and/or CD22-CAR T cells) with onset within the first 28 
days following CD22-CAR T cell infusion will be considered DLTs as follows:  
o Hematologic toxicity will not be considered DLTs, as these are common after CAR 
T therapy and have been successfully managed with standard supportive therapies. 
• Grade 4 CRS (of any duration) or Grade 3 CRS that lasts greater than 7 days. 
• Grade 4 neurotoxicity (of any duration) or Grade 3 neurotoxicity that lasts >72 hours 
(severity as defined in Appendix B, Section 13.2.3.). 
o Infusion reactions ≥ Grade 2 in severity lasting more than 24 hours despite standard 
supportive care. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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• Any other Grade 3 or greater, non-hematological toxicity will be considered a DLT with 
the following exceptions: 
o Tumor lysis syndrome, including associated abnormalities (e.g., electrolytes, uric 
acid, renal function); 
o Grade 3 diarrhea that resolves to  ≤ Grade 2 within 4 days; 
o Grade 3 low electrolyte levels that are correctable and asymptomatic, Grade 3 
hypoalbuminemia;  
▪ Hypocalcemia toxicity grade should be assigned based on the calcium level 
corrected for degree of hypoalbuminemia according to the following (or 
comparable) formula: For every albumin decrease of 1 gm/dL a total 
calcium increase of 0.2 mmol/L is to be made; 
o Abnormal coagulation parameters in subjects on anticoagulant therapy or with pre-
existing coagulopathy; 
o Grade 3 transaminase, alkaline phosphatase, bilirubin or other liver function test 
elevation, provided there is resolution to ≤ Grade 2 or baseline within 14 days.  
Grade 4 transaminitis lasting < 72 hours will also not be considered DLT;Grade 3 
nausea and/or anorexia.Grade 3 or 4 fever lasting ≤ 14 days, as this is common and 
expected with CAR therapy and may be a biomarker for an effective 
immunotherapeutic regimen; 
o Grade 3 or 4 infection or neutropenic fever unless subjects have normal blood 
counts at baseline, and infection is not considered likely related to lymphodepleting 
chemotherapy and relationship to CD22-CAR T cells is suspected (Note: Grade 4 
infection uncontrolled for > 7 days will be considered DLT.); 
• 
Toxicities occurring within 24 hours post cell infusion related to cell 
infusion, (including Grade 3 and 4 allergic reaction) that are reversible to a 
grade 2 or less within 8 hours with up to two doses of acetaminophen 15 
mg/kg/dose (to a max adult dose of 650 mg) or up to two doses of 
diphenhydramine 1 mg/kg up (to a max adult dose of 50 mg); 
• In patients with history of prior SCT, any histologically proven acute GVHD grade 3 or 
higher within 30 days of receiving the CD22-CAR T cells will be considered DLT. 
Adverse events will be graded according to NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE v5.0).  As noted in Section 2.4.4 CRS will be graded according to a revised 
grading system (See Appendix B, Section 13.2.1).  Adverse events attributed to CRS will be 
mapped to the overall CRS grading assessment for the determination of DLT. 
5.5 
EVALUATIONS AND FOLLOW UP 
Subjects will be hospitalized prior to receipt of CD22-CAR T cells, if not before administration of 
conditioning lymphodepletion chemotherapy regimen, and may remain in the hospital for 
approximately 7 (±2) days.  Subjects should remain hospitalized for ongoing cell-related fever, 
hypotension, hypoxia, or ongoing central neurological toxicity > Grade 1, or if deemed necessary 
by the treating investigator.  Subjects may be discharged with non-critical and clinically stable or 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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slowly improving toxicities (e.g., renal insufficiency) even if > Grade 1, if deemed appropriate by 
the investigator. 
Given the possibility that a subject could develop CRS or neurotoxicity after discharge from the 
hospital, subjects will be asked to remain within commuting distance to the clinic for the first 28 
days post cell infusion, and subjects and their family members/caregivers will be educated on 
potential symptoms such as fever, dyspnea, confusion, aphasia, dysphasia, somnolence, 
encephalopathy, ataxia, or tremor.  If subjects develop these symptoms, they will be instructed to 
immediately contact the investigator or seek immediate medical attention.   
During this post cell infusion period, the following procedures will be completed at the time points 
outlined in the Section 9 Study Calendar:  
5.5.1 Evaluation Prior to Cell infusion 
Prior to cell infusion subjects will undergo safety evaluations with general laboratory tests, 
physical exam, neurologic exam, vital signs, adverse event collection, concomitant medication 
monitoring, and correlative sample collection. 
Thyroid stimulating hormone (TSH) levels should be measured once within 28 days prior to cell 
infusion. 
Once, any time between enrollment and start of cell infusion, a blood sample for replication 
competent lentivirus (RCL) testing will be collected and sent to Indiana Gene Therapy Testing 
Laboratory (IU GTTL), as described in Section 13.4. 
Please refer to the Section 9 Study Calendar for a list of all procedures. 
5.5.2 Monitoring During and Immediately After Cell Infusion 
Monitoring will include vital signs (blood pressure, heart rate, respiratory rate, oxygen saturation, 
and temperature) prior to infusion, at the conclusion of cell infusion (± 10 min), and at 60 (± 10 
min), and as clinically indicated. 
✓ Supplemental oxygen will be available at the bedside.   
If an allergic or other acute reaction occurs, studies appropriate for investigation of a transfusion 
reaction will be performed (e.g., urinalysis, CBC, Coomb’s test).  Acute reactions will be treated 
according to institutional standards of care. 
 
5.5.3 Evaluations Post Treatment Assessment Period Day 0 to Month 3 
After completing CD22-CAR T cell infusion all subjects will be followed in the post treatment 
assessment period.  Counting from Day 0 (CD22-CAR T cell infusion), subjects will undergo the 
following evaluations (during hospitalization or will return to the clinic): 
• From Day 0 to Day 14, evaluations 5 times per week, with no more than 48 hours between 
evaluations  
• From Day 15 to Day 27, evaluations twice per week (± 4 days) 
• Day 28 (± 4 days) 
• Month 2 (± 2 weeks) 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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• Month 3 (± 2 weeks) 
Please refer to the Section 9 Study Calendar for a list of all procedures at each visit. 
Procedures will include safety evaluations with general laboratory tests, targeted physical exams 
(as clinically indicated), neurologic exams, adverse event collection, concomitant medication 
monitoring, and correlative sample collection. Vital signs monitoring (including blood pressure, 
heart rate, oxygen saturation, respiratory rate, and temperature) should be performed every shift 
(± 2 hours) during hospitalization and with each visit after discharge. Neurotoxicity evaluations in 
the form of ICE score/ CAPD evaluations should be performed every shift (± 2 hours) and with 
any change in neurologic functioning during the initial hospitalization for cell infusion. 
Monitoring of CRP, ferritin, and LDH (only if LDH is elevated at baseline) levels may assist with 
the diagnosis and define the clinical course in regards to CRS/neurotoxicity.  It is therefore, 
recommended that CRP and LDH (if elevated at baseline) be monitored when lab specimens are 
drawn starting at Day 0 and continuing through hospitalization.  In addition, lactate can be 
monitored as clinically indicated. 
Day 28 (± 4 days) will be the first disease evaluation post cell infusion. This is the primary efficacy 
endpoint for subjects with ALL, but subjects with lymphoma will also undergo disease evaluation 
at Day 28 (± 4 days).  Evaluations will include general laboratory tests, full physical exam, 
neurologic exam, performance status, weight, vital signs, adverse event collection, concomitant 
medication monitoring, disease evaluation, and correlative sample collection. Quantitative 
immunoglobulins should be measured every 3 to 12 weeks post infusion until Month 3 (± 2 weeks) 
to monitor IgG levels. It is recommended to measure T and B cell lymphocyte subsets monthly 
starting at Day 28 to monitor for return of B cells, a possible indictor of loss of CAR T cell 
persistence. 
The second disease evaluation will occur at the Month 3 visit (± 2 weeks). This is the primary 
efficacy endpoint for subjects with lymphoma. Evaluations will include general laboratory tests, 
full physical exam, neurologic exam, performance status, weight, vital signs, targeted adverse 
event and concomitant medication collection, disease evaluation, and correlative sample 
collection.  Evaluations may be performed by local physician/medical provider in the event 
circumstances prevent the subject from returning to Stanford clinic, if all source documents are 
transmitted to the research team for inclusion in the medical record/research record. 
5.5.3.1 Disease Evaluation Post Cell Infusion 
Disease evaluation methods will be determined by the investigator based on subjects’ location of 
disease; not all are required on all subjects, but methods should remain consistent while on study:  
o Imaging Studies appropriate to sites relevant to subject’s disease: subject with bulky 
disease will undergo PET/CT, other imaging studies  (e.g. MRI of the brain) will be 
performed as determined by investigator 
o Bone marrow aspirate: subjects with bone marrow involvement prior to therapy or if 
new abnormalities in the peripheral blood counts or blood smear cause suspicion of 
bone marrow involvement will undergo bone marrow aspirate, with biopsy if needed  
o Lumbar puncture, for subjects with known or suspected CNS involvement only 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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o Lymph node biopsy in subjects with lymphoma only, if feasible, once between Day 7 
and Day 28 (during peak CAR activity) for correlative studies 
5.5.3.2 Small Volume Apheresis for Research 
Subjects may undergo a small volume apheresis (approximately one to two blood volumes) to 
obtain peripheral lymphocytes for correlative studies.  Every attempt will be made to use an 
indwelling catheter or peripheral lines for the small volume apheresis.  If this is not feasible and 
an apheresis specimen cannot be collected, peripheral blood should be collected into the 
appropriate tubes for correlative samples.  
A small volume apheresis for research will be considered at the following time points: 
• Day 28 (± 7 days) 
• Month 3 (± 1 month) 
• Month 6 (± 1 month) 
• Month 9 (± 1 month) 
• Month 12 (± 2 months) 
5.5.3.3 Targeted Adverse/Serious Adverse Event reporting  
After Day 30 and for 24 months or until disease progression (whichever occurs first), targeted AE 
collection of neurological, hematological (Grade 3 or higher), infections, autoimmune disorders, 
and secondary malignancies will be performed if attributed as possibly, probably or definitely 
related to CD22-CAR.  Targeted SAE collection will occur as described in Section 7.3. 
5.5.3.4 Targeted Concomitant Medication Documentation  
After Day 28 visit and for 24 months or until disease progression (whichever occurs first), targeted 
concomitant medication collection of gammaglobulins, immunosuppressive drugs, anti infectives, 
and vaccinations will be performed. 
5.5.3.5 RCL Testing 
The US Food and Drug Administration requires monitoring for replication competent lentivirus in 
all human subjects receiving lentiviral gene therapy.  Even if a subject withdraws from other study 
evaluations, permission to continue RCL testing and annual gene therapy questionnaires will be 
requested. Blood collection for RCL testing will be performed at the following time points and 
sent to IU GTTL as described in Section 13.4 
• Month 3 (± 1 month) 
• Month 6 (± 1 month) 
• Month 12 (± 2 months) 
If all tested samples are negative for RCL through Month 12, blood samples will be collected 
and archived annually until Year 5 (± 2 months). 
5.5.4 Evaluations Post Treatment Assessment Period (After Month 3)  
Subjects who received CD22-CAR T cells will return to the clinic at the following intervals, unless 
there is no clinical response, documented disease progression or alternative disease therapy is 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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started, at which time the subject will proceed to long term gene therapy follow up (see Section 
5.5.5).  Correlative sample collection and post treatment assessments may be performed by the 
local medical care team or via TeleHealth if in the best interest of the patient, but results, progress 
notes and scans should be sent to the research team for inclusion in the medical record/research 
record. 
5.5.4.1 Post Treatment Assessment Schedule 
Subjects who received CD22-CAR T cells will be evaluated at the following timepoints (additional 
evaluations may be performed as clinically indicated): 
• Month 6 (± 4 weeks) 
• Month 9 (± 4 weeks) 
• Month 12 (± 4 weeks) 
• Every 6-12 months until 5 years post cell infusion 
• Annually Year 6 to Year 15 (± 3 months) 
5.5.4.2 Post Treatment Assessments: 
Please refer to the Section 9 Study Calendar for a list of all procedures at each visit. 
Evaluations of disease status in subjects who have not progressed after CD22-CAR T cells will be 
conducted at Stanford for the first 24 months, when feasible.  If not feasible, disease evaluations 
may be performed virtually or by referring physician or outside medical facility as long as 
documentation is forwarded to the study Principal Investigator/research team. If subject’s disease 
has not progressed by Month 24, disease assessments will continue to be performed per standard 
of care.  
Should a subject fail to return to the clinic for a scheduled protocol specific visit, sites will need to 
make 2 attempts by a combination of telephone and mail to contact the subject. Sites must 
document both attempts to contact the subject. If a subject does not respond within 1 month after 
the second contact the subject will be considered lost to follow-up and no additional contact will 
be required. 
Evaluations will include general laboratory tests (as clinically indicated), physical exam, 
neurologic exam, performance status, weight, vital signs, targeted adverse event and concomitant 
medication collection, disease evaluation, RCL testing, and correlative sample collection. A small 
volume apheresis for research will be considered at Month 6 (± 1 month), Month 9 (± 1 month), 
and Month 12 (± 2 months). 
A PBMC sample (for CD22-CAR T cells, etc) should be collected at the time of progression 
or at time prior to starting any subsequent anticancer therapy without progression. 
5.5.4.3 Gene Therapy Safety Monitoring (Month 6 to Year 5) 
• Evaluations will be performed as per Section 5.5.5.2 regardless of disease status or 
alternative therapies. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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5.5.4.4 Annual Gene Therapy Questionnaire (Year 6 to 15) 
• Evaluations will be performed as per Section 5.5.5.2 regardless of disease status or 
alternative therapies.  
 
After year 5, the subject will be contacted (in clinic or via phone or written questionnaire) to 
evaluate for development of delayed adverse events (See questionnaire in Section 13.5, Appendix 
E:  Draft Letter and Questionnaire to Subjects for Long Term Follow-up for Delayed Adverse 
Events).    
• If vector modified cells were detected in the blood during the previous visit, then blood for 
persistence of vector modified cells will be collected and tested until negative.   
• Subjects are requested to inform the study research team of any changes to e-mail (if 
consented to use e-mail), phone, and address.  E-mails will be sent to subjects via the 
Secure Email to ensure securely and confidentially over an SSL/encrypted connection. 
• Distribution and collection of questionnaires 
o A draft letter to subject’s primary doctor is provided in Section 13.6, Appendix F.  This 
letter should be sent to the local health care provider via mail, fax or e-mail at the time 
the subject is referred back to the care of the local physician or with any change in 
primary doctors.  E-mails will be sent to subjects via the Secure Email to ensure 
securely and confidentially over an SSL/encrypted connection. 
o Subjects will be sent a request for information (Section 13.5, Appendix E:  Draft Letter 
and Questionnaire to Subjects for Long Term Follow-up for Delayed Adverse Events) 
and questionnaire annually. 
▪ If there is no response within 1 month, the study coordinator will follow up with 
a telephone call to request the information.  The questionnaire may be 
completed with the subject responses over the phone at this time. 
▪ If there is no response to the telephone call, the letter and questionnaire (Section 
13.5) should be sent to the subject via FedEx, signature required.   
▪ Each attempt to contact the subject and outcome must be documented in the 
medical record. 
5.5.5 Long Term Gene Therapy Follow-up  
At any time during the post treatment assessment period, the subject will proceed directly to the 
Long Term Gene Therapy Follow Up if he/she: 
1. Did not respond to treatment (i.e., did not achieve a CR or PR), or  
2. progresses following a response and is either not eligible for re-treatment or chooses not to 
pursue re-treatment, or  
3. proceeds to alternative disease directed therapy,  
The subject will subsequently be followed for survival, subsequent therapy, and long term gene 
therapy safety including RCL sampling. Correlative tests sampling may continue as per protocol 
at the discretion of the investigator.  Long-term follow up laboratory evaluations and blood 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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collections may be completed by the outside medical facility/care provider.   
Should a subject fail to return to the clinic or respond to contact for a scheduled protocol specific 
visit/contact, sites will need to make 2 attempts by a combination of telephone and mail to contact 
the subject. Sites must document both attempts to contact the subject. If a subject does not respond 
within 1 month after the second contact the subject will be considered lost to follow-up and no 
additional contact will be required. 
5.5.5.1 Long Term Gene Therapy Follow-up Schedule 
• Month 6 (± 1 month), Month 12 (± 2 months) after CD22-CAR T cell infusion 
• Every 12 months (± 2 months) for 5 years 
• Beginning with year 6 (± 3 months), subjects will return to the clinic or be contacted by 
phone, e-mail or mail one time annually for up to 15 years after cell infusion.  
5.5.5.2 Long Term Gene Therapy Follow-up Evaluations 
The following procedures will be completed for all subjects who are enrolled and received 
CD22-CAR T cells at each Long Term Gene Therapy Follow Up visit: 
• Physical exam, vital signs and performance status for year 1 through 5 (may be 
performed by the local physician) 
• Gene Therapy Safety Monitoring to specifically document: 
o  any new malignancies,  
o new incidence or exacerbation of a pre-existing neurologic disorder,  
o new incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder,  
o new incidence of a hematologic disorder; and  
o other factors that may be relevant to the feasibility and scientific value of the 
long-term follow up observations for gene therapy toxicities (i.e. exposure to other 
cancer causing agents). 
• RCL testing as described in Section 13.4 
• Annual Gene Therapy Questionnaire (see Section 13.5) for year 6 through 15 
• Laboratory evaluations as clinically indicated 
5.5.6 Evaluations of Subjects Who Do NOT Receive CD22-CAR T cells 
The following procedures/assessments will be completed for subjects who are enrolled but do 
not receive CD22-CAR T cells, at the time points outlined in the Section 9 Study Calendar until 
disease progression and/or toxicities attributable to the study participation resolve to ≤ Grade 1 
or stabilize:  
• Disease assessment per standard of care  
• Adverse/Serious Adverse Event reporting and concomitant medication documentation 
until 30 days after last study treatment (e.g., leukapheresis, conditioning chemotherapy).   

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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Should the subject fail to return to the clinic for a scheduled protocol specific visit, sites will need 
to make 2 attempts by a combination of telephone and mail to contact the subject.  Sites must 
document both attempts to contact the subject.  If a subject does not respond within 1 month after 
the second contact the subject will be considered lost to follow-up and no additional contact will 
be required. 
5.6 
OPTION FOR ADDITIONAL DOSE(S) OF CD22-CAR T CELLS 
On the day cells are infused, remaining cells that have been produced above and beyond the 
number of cells needed for a subject’s dose level will be cryopreserved using standard techniques.  
Cells will be reserved for 1-2 additional doses with corresponding QA retention vials, and 
remaining cells will be released for research.   
Subjects will have the option for additional infusions of CD22-CAR T cells (including preparative 
chemotherapy regimen, toxicity assessment and research blood sampling) if the following criteria 
are met: 
5.6.1 Eligibility Criteria for subsequent cell infusions: 
✓ Cell infusion of CD22-CAR T cells has been deemed safe.  Dose escalation cohort for 
subjects with aggressive B-cell NHL has been completed without 2 subjects in a disease 
group experiencing DLTs.  At least 3 subjects with ALL have completed the 28-day DLT 
observation period at the proposed dose level with DLT rate ≤30%. 
✓ Response to previous infusion.  Subjects who had a PR or SD with clinical benefit may 
elect to receive another infusion of cells.  Subjects that initially had a CR may only receive 
a second dose if evaluable disease recurs.  Clinical benefit is indicated by an improvement 
in the subject’s health status (e.g., decreased transfusion requirement, improved 
cytopenias, decrease in number of blasts not sufficient to reach a PR, improved 
performance status or quality of life, etc.).   
✓ At least 60 days have passed since the previous cell infusion. 
✓ Circulating levels of CD22-CAR T cells must be < 5% by flow cytometry. 
✓ Any toxicity (regardless of causality) after the previous CD22-CAR T cell infusion must 
resolve such that subjects meet all the initial eligibility criteria for major organ function 
and therapy washout as outlined in Section 3.1.   
✓ An adequate number of cryopreserved CD22-CAR T cells and QA retention vials or an 
adequate number of apheresis product sufficient to generate an additional dose of 
CD22-CAR T cells must be available. 
The cell dose (based on CAR transduced cells) for the second infusion shall not be greater than 
the current dose level completed or the safe dose if this has been determined. 
As a rule, subjects who incurred DLT after receiving the first cell infusion will not be eligible to 
receive additional cell infusions unless IRB, APB and FDA approval is granted on a case by case 
basis. 
5.6.2 Procedures for Additional Doses 
Subjects may receive additional antineoplastic and lymphodepleting chemotherapy prior to the 
second infusion of CD22-CAR T cells. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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Subjects must meet the eligibility criteria as described in Section 5.4.2.1.  The subject’s cell 
product will be tested for cell viability to confirm it still meets the IND product release criterion 
prior to the subject starting lymphodepletion chemotherapy.  The lymphodepletion chemotherapy 
dosing used for lymphodepletion prior to additional doses may differ from the first infusion, at 
investigator’s discretion. Cell infusion and evaluations after an additional dose of CD22-CAR will 
be the same as described above for the initial dose. 
Any subject who receives subsequent doses of CD22-CAR T cells will NOT be evaluable for 
toxicity purposes of this study as they will be beyond the 28 day observation period for DLTs after 
their first cell infusion.  However post-infusion monitoring will be the same as for the 1st infusion 
and all toxicities, including secondary reactions, will be recorded and reported.  If two or more 
subjects develop Grade 4 toxicity at any time following the second CD22-CAR T cell infusion that 
is felt to be possibly, probably or likely related to the CD22-CAR T cells, then second infusions 
will be paused pending discussion with the FDA, IRB and APB regarding continuing second 
infusions as part of the experimental regimen. 
5.6.2.1 Gene Therapy Follow Up After Additional Doses 
If a subject receives more than one infusion of CD22-CAR T cells, the timing of gene therapy long 
term evaluations is restarted with each subsequent gene therapy administration.  For example, a 
subject receives gene therapy and has undergone long term follow up for 1.5 years, develops 
progressive disease and is treated with a second gene therapy product.  That subject will begin the 
blood sample collection at 3, 6 and 12 months (± 1 month) post cell administration and continue 
for a total of 15 years of follow up from the LAST gene therapy administration.  The most recent 
RCL blood evaluation after the previous dose of CD22-CAR T cells will serve as the baseline RCL 
for the second dose; therefore, a second baseline RCL does not need to be repeated prior to 
additional doses of CD22-CAR T cells. 
6 
INVESTIGATIONAL AGENT AND COMMERCIAL DRUG INFORMATION 
6.1 
AUTOLOGOUS T CELLS TRANSDUCED WITH LENTIVIRAL VECTOR (CD22.BB.Z) CHIMERIC 
ANTIGEN RECEPTOR (CD22-CAR); FOLLOWING LYMPHODEPLETING CHEMOTHERAPY  
6.1.1 Description 
Cell therapy production will be conducted according to the appropriate manufacturing facility’s 
SOPs and must meet the requirements for a GMP facility.  The CD22-CAR replication 
incompetent lentiviral vector has been manufactured by Lentigen Technology Incorporated.  All 
procedures will take place using good manufacturing process guidelines. 
6.1.2 Stability 
Stability testing is ongoing. 
6.1.3 Administration 
Guidance on administration of CD22-CAR T cells is specified in section 5.4.2. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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6.1.4 Toxicities 
In addition to standard transfusion types of reactions (chills, fever, rigors), the toxicities specific 
to CAR T cell therapy are described in detail in section 2.4.  Every effort will be made to mitigate 
the risk of these toxicities with the intensive monitoring plans outlined in section 5 and the 
supportive care measures outlined in section 4.2.  With growing experience with CAR therapy 
world-wide, the risk of severe neurotoxicity is increasingly better recognized—most notable with 
the recent occurrences of fatal neurotoxicity.  With the incorporation of mandatory anti-seizure 
prophylaxis and prospective monitoring of neurologic function, we plan to rigorously monitor and 
evaluate for any neurotoxicity, with a plan to treat more severe neurotoxicity with steroids to 
mitigate the symptoms. 
6.2 
FLUDARABINE 
(Refer to FDA-approved package insert for complete product information) 
6.2.1 Description 
Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic nucleosides 
in that the sugar moiety is arabinose instead of ribose or deoxyribose.  Fludarabine is a purine 
antagonist antimetabolite.   
6.2.2 How Supplied  
Fludarabine will be obtained from commercially available sources by the Stanford Health Care 
Pharmacy Department.  Drug is supplied in a 50 mg vial as a fludarabine phosphate powder in the 
form of a white, lyophilized solid cake.   
6.2.3 Stability  
Following reconstitution with 2 mL of sterile water for injection to a concentration of 25 mg/ml, 
the solution has a pH of 7.7.  The fludarabine powder is stable for at least 18 months at 2-80C; 
when reconstituted, fludarabine is stable for at least 16 days at room temperature.  Because no 
preservative is present, reconstituted fludarabine will typically be administered within 8 hours.  
Specialized references should be consulted for specific compatibility information.  Fludarabine is 
dephosphorylated in serum, transported intracellularly and converted to the nucleotide fludarabine 
triphosphate; this 2-fluoro-ara-ATP molecule is thought to be required for the drug’s cytotoxic 
effects.  Fludarabine inhibits DNA polymerase, ribonucleotide reductase, DNA primase, and may 
interfere with chain elongation, and RNA and protein synthesis. 
6.2.4 Storage  
Intact vials should be stored refrigerated (2-8C). 
6.2.5 Administration  
Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes as 
described in Section 5.3. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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6.2.6 Toxicities  
The primary side effect is myelosuppression; however, thrombocytopenia is responsible for most 
cases of severe and life-threatening hematologic toxicity.  Serious opportunistic infections have 
occurred in subjects treated with fludarabine.  Hemolytic anemia has been reported after one or 
more courses of fludarabine with or without a prior history of a positive Coomb’s test; fatal 
hemolytic anemia has been reported.  In addition, bone marrow fibrosis has been observed after 
fludarabine therapy.  Other common adverse effects include malaise, fever, chills, fatigue, 
anorexia, nausea and vomiting, and weakness.  Irreversible and potentially fatal central nervous 
system toxicity in the form of progressive encephalopathy, blindness, and coma is only rarely 
observed at the currently administered doses of fludarabine.  More common neurologic side effects 
at the current doses of fludarabine include weakness, pain, malaise, fatigue, paresthesia, visual or 
hearing disturbances, and sleep disorders.  Adverse respiratory effects of fludarabine include 
cough, dyspnea, allergic or idiopathic interstitial pneumonitis.  Tumor lysis syndrome has been 
rarely observed in fludarabine treatment of CLL.   
6.3 
 CYCLOPHOSPHAMIDE  
(Refer to FDA-approved package insert for complete product information) 
6.3.1 Description  
Cyclophosphamide is a nitrogen mustard-derivative alkylating agent.  Following conversion to 
active metabolites in the liver, cyclophosphamide functions as an alkyating agent; the drug also 
possesses potent immunosuppressive activity.  The serum half-life after IV administration ranges 
from 3-12 hours; the drug and/or its metabolites can be detected in the serum for up to 72 hours 
after administration.   
6.3.2 How Supplied  
Cyclophosphamide will be obtained from commercially available sources by the Stanford Health 
Care Pharmacy Department.   
6.3.3 Stability  
Following reconstitution as directed with sterile water for injection, cyclophosphamide is stable 
for 24 hours at room temperature or 6 days when kept at 2-80C.   
6.3.4 Administration  
It will be diluted in an appropriate solution and infused as described in Section 5.3. 
6.3.5 Toxicities  
Hematologic toxicity occurring with cyclophosphamide usually includes leukopenia and 
thrombocytopenia.  Anorexia, nausea and vomiting, rash and alopecia occur, especially after 
high-dose cyclophosphamide; diarrhea, hemorrhagic colitis, infertility, and mucosal and oral 
ulceration have been reported.  Sterile hemorrhagic cystitis occurs in about 20% of subjects; 
severity can range from microscopic hematuria to extensive cystitis with bladder fibrosis.  
Although the incidence of hemorrhagic cystitis associated with cyclophosphamide appears to be 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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lower than that associated with ifosfamide, mesna (sodium 2-mercaptoethanesulfonate) has been 
used prophylactically as a uroprotective agent in subjects receiving cyclophosphamide.  
Prophylactic mesna is not effective in preventing hemorrhagic cystitis in all subjects.  Subjects 
who receive high dose cyclophosphamide may develop interstitial pulmonary fibrosis, which can 
be fatal.  Hyperuricemia due to rapid cellular destruction may occur, particularly in subjects with 
hematologic malignancy.  Hyperuricemia may be minimized by adequate hydration, alkalinization 
of the urine, and/or administration of allopurinol.  If allopurinol is administered, subjects should 
be watched closely for cyclophosphamide toxicity (due to allopurinal induction of hepatic 
microsomal enzymes).  At high doses, cyclophosphamide can result in a syndrome of inappropriate 
antidiuretic hormone secretion; hyponatremia with progressive weight gain without edema occurs.  
At high doses, cyclophosphamide can result in cardiotoxicity.  Deaths have occurred from diffuse 
hemorrhagic myocardial necrosis and from a syndrome of acute myopericarditis; in such cases, 
congestive heart failure may occur within a few days of the first dose.  Other consequences of 
cyclophosphamide cardiotoxicity include arrhythmias, potentially irreversible cardiomyopathy, 
and pericarditis.  Other reported adverse effects of cyclophosphamide include headache, dizziness, 
and myxedema; faintness, facial flushing, and diaphoresis have occurred following IV 
administration.  Mesna (sodium 2-mercaptoethanesulphonate; given by IV injection) is a synthetic 
sulfhydryl compound that can chemically interact with urotoxic metabolites of cyclophosphamide 
(acrolein and 4-hydroxycyclophosphamide) to decrease the incidence and severity of hemorrhagic 
cystitis, but is not a required premedication for this study.   
6.4 CLOFARABINE INJECTION (CLOLAR ®) 
(Refer to FDA-approved package insert for complete product information) 
6.4.1 Description:  
Clolar (clofarabine) injection is a purine nucleoside metabolic inhibitor indicated for the treatment 
of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia 
after at least two prior regimens. The terminal half-life after IV administration was 5.2 hours.  
6.4.2 How Supplied:  
Clofarabine will be obtained from commercially available sources by the institution’s Pharmacy 
Department. Clofarabine is supplied in single-use flint vials containing 20 mg of clofarabine in 
20mL of solution. 
6.4.3 Stability:  
Vials containing undiluted clofarabine should be stored at 25°C (77°F); excursions permitted to 
15-30°C (59-86°F). Following reconstitution as directed clofarabine should be infused with 24 
hours of preparation.  
6.4.4 Administration:  
Clofarabine should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% 
Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to IV infusion to a final 
concentration between 0.15 mg/mL and 0.4 mg/mL.  

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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6.4.5 Toxicities 
Clofarabine causes myelosuppression which may be severe and prolonged. Febrile neutropenia 
occurred in 55% and non-febrile neutropenia in an additional 10% of pediatric patients in clinical 
trials, increasing the risks of hemorrhage and infections. In addition hyperuricemia (tumor lysis), 
systemic inflammatory response syndrome (SIRS) and capillary leak syndrome, as well as venous 
occlusive disease of the liver (VOD) had been described. Additional toxicities are summarized in 
Section 2.3. 
6.5 
BENDAMUSTINE HYDROCHLORIDE FOR INJECTION (BENDEKA ®) 
(Refer to FDA-approved package insert for complete product information) 
Bendamustine is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and 
anaphylactoid reactions) to bendamustine or mannitol. 
6.5.1 Description:  
Bendamustine is an alkylating drug which is FDA approved for treatment of patients with CLL 
and NHL that has progressed during or within six months of treatment with rituximab or rituximab-
containing regimen. The mean terminal elimination t1/2 of M3 and M4 are approximately 3 hours 
and 30 minutes respectively.  
6.5.2 How Supplied:  
Bendamustine will be obtained from commercially available sources by the institution’s Pharmacy 
Department. Bendamustine for Injection is supplied in individual cartons of 5 mL clear multiple-
dose vials containing 100 mg of Bendamustine hydrochloride as a clear, and colorless to yellow 
ready-to-dilute solution.  
Dilute with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium 
Chloride Injection, USP, or 5% Dextrose Injection, USP. The resulting final concentration of 
bendamustine hydrochloride in the infusion bag should be within 0.49 mg/mL to 5.6 mg/mL. After 
transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear, and 
colorless to yellow solution. 
6.5.3 Stability:  
Bendmustine Injection should be stored in the refrigerator 2°C – 8°C (36°F - 46°F). Retain in 
original package until time of use to protect from light. 
BENDEKA is supplied in a multiple-dose vial. Although it does not contain any antimicrobial 
preservative, BENDEKA is bacteriostatic. The partially used vials are stable for up to 28 days 
when stored in its original carton under refrigeration (2°C to 8°C or 36°F to 46°F). Each vial is not 
recommended for more than a total of six (6) dose withdrawals. After first use, store the partially 
used vial in the refrigerator in the original carton at 2°C to 8°C or 36°F to 46°F and then discard 
after 28 days Administration:  
6.5.4 Toxicities 
Bendamustine causes myelosuppression which may be severe. In two NHL studies, 98% of 

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patients had Grade 3-4 myelosuppression; 3 patients died from myelosuppression-related adverse 
reactions- one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 
thrombocytopenia and pneumonia from an opportunistic infection (CMV). Infusion reactions 
occurred commonly and included fever, chills, pruritus and rash. Anaphylaxis occurred rarely, 
particularly in second or subsequent cycles of therapy. Tumor lysis syndrome and other skin 
reactions have also been reported. Additional toxicities are summarized in Section 2.3. 
6.6 
PRE-MEDICATIONS 
6.6.1 Acetaminophen (Tylenol)  
Will be given as a pre-medication.  This agent will be provided by the institution’s pharmacy.  
Please refer to the package insert for complete pharmaceutical information on this product. 
6.6.2 Diphenhydramine (Benadryl)  
Will be given as a pre-medication IV or orally.  This agent will be provided by the institution’s 
Pharmacy Department.  Please refer to the package insert for complete pharmaceutical information 
on this product. 
6.6.3 Antimicrobial Prophylaxis 
Subjects will receive appropriate antimicrobial prophylaxis (e.g., Bactrim for PCP and acyclovir 
for HSV and VZV prophylaxis) during lymphodepleting chemotherapy and following treatment 
as per institutional guidelines.  This agent will be provided by the institution’s Pharmacy 
Department.  Please refer to the package insert for complete pharmaceutical information on this 
product. 
6.6.4 Levetiracetam (Keppra) 
Adult subjects will receive levetiracetam 500 mg orally twice a day (maximum dose of 
750 mg/dose) or as per institutional guidelines at the discretion of the treating physician beginning 
the day before cell infusion (Day -1).  This dose may be adjusted based on symptoms of 
neurotoxicity and/or with recommendations of neurologic consult.  Levetiracetam should continue 
through Day 28 once neurotoxicity develops.  This agent will be provided by the institution’s 
Pharmacy Department.  Please refer to the package insert for complete pharmaceutical information 
on this product. 
6.6.5 Allopurinol 
Subjects with high disease burden at risk for tumor lysis may be given allopurinol as per standard 
supportive care as per the investigator’s discretion.  Allopurinol will be administered at 300 mg 
orally once daily, starting at the time of initiation of the conditioning lymphodepletion 
chemotherapy regimen.  This agent will be provided by the institution’s pharmacy.  Please refer to 
the package insert for complete pharmaceutical information on this product. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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7 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
POTENTIAL ADVERSE EVENTS 
7.1.1 CD22-CAR T cells 
Because these cells have been previously administered in only a small number of humans, there 
may be unanticipated adverse events.   
Section 2.4 and Section 6.1 discuss the potential risks of this investigational therapy based on 
previous studies with this or similar preparative regimens or cell products, including the risks of 
chemotherapy, risk of autoimmunity, risk of neurotoxicity, risk of the gene therapy component, 
and risk of cytokine storm.  Transient, reversible mild effects have been observed with the 
administration of fresh cells, including chills, fever, rigors, diaphoresis, anorexia, nausea, diarrhea, 
headache and myalgias.  General guidance for treatment of the most common toxicities are 
included in Section 4.2. 
7.1.2 Risk of Apheresis:  
Apheresis is a safe procedure that is routinely performed in healthy adults.  Participants will be 
closely monitored and procedures to minimize risks and prevent side effects are incorporated into 
all aspects of the protocol.  The institutions have broad expertise to adequately manage side effects.  
The potential risks of apheresis in this trial are as follows: 
a.   The most common side effects of apheresis are pain and bruising at IV sites.  A central 
venous catheter may be required.  Possible side effects include pain, bleeding, bruising, 
infection, thrombosis, vascular perforation. 
b.   During apheresis, mild side effects from citrate anticoagulant are common and include 
chills, numbness and tingling ("pins and needles"), anxiety, muscle cramps, and nausea.  
More serious side effects due to citrate-induced hypocalcemia are uncommon and 
include low blood pressure, seizures, weakness, and tetany.  Citrate reactions rapidly 
resolve when the collection is slowed down or stopped.  Prophylactic IV CaCl2 and 
MgSO4 infusions may be administered to subjects deemed to be at high risk of citrate 
toxicity.  Risks of parenteral calcium and magnesium include extravasation necrosis 
and cardiovascular effects including bradycardia and blood pressure changes.  
However, side effects are unlikely given the low rate of infusion and use of large bore 
catheters for apheresis. 
c.   Transient mild thrombocytopenia is common after apheresis, but bleeding is unlikely. 
d.   Dilutional anemia occurs during apheresis, but this is unlikely to be clinically 
significant.   
e.   Side effects of blood draws include pain and bruising, lightheadedness, and rarely, 
fainting.   

Protocol: CD22 CAR T-cell in Adults 
  
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7.2 
ADVERSE EVENT DEFINITIONS 
7.2.1 Adverse Event 
An adverse event (AE) is defined as any reaction, side effect, or untoward event that occurs during 
the course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant.  For this study, AEs will include 
events reported by the subject, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation.  A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All adverse events will be graded according to NCI CTCAE v5.0. 
If a subject requires additional disease directed therapy after completing apheresis but before the 
start of lymphodepletion chemotherapy, these toxicities will not be considered study related 
adverse events and will NOT be collected or reported.  Toxicities present at the initiation of 
lymphodepletion chemotherapy will be considered baseline conditions. 
An abnormal laboratory value will be considered a reportable, recordable AE if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study therapy 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention, except for Grade 1 electrolyte 
changes or prophylactic therapies 
• 
Is associated with death or another serious adverse event, including hospitalization.   
• 
Is judged by the Investigator to be of significant clinical impact 
• 
Is a hematologic abnormality, including WBCs, hemoglobin, neutrophils, and platelets that 
constitutes a change in grade or attribution from baseline (e.g. worsens from baseline Grade 1 
to Grade 2) during the first 28 days, or Grade 3 or 4 greater than 28 days post CD22-CAR T 
infusion. 
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action(s) taken and about the subject’s outcome. 
7.2.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the investigational therapy caused the adverse event.  For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
investigational therapy and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused by a 
drug. 
7.2.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
protocol or informed consent documents or is not listed at the specificity or severity that has been 
observed; or is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application.  "Unexpected” also refers to adverse events or 
suspected adverse reactions that are mentioned in the protocol or informed consent documents as 

Protocol: CD22 CAR T-cell in Adults 
  
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occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under investigation. 
7.2.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.2.5 Serious Adverse Event 
An AE or suspected adverse reaction is considered serious if in the view of the investigator or the 
sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
In-patient hospitalization or prolongation of existing hospitalization  
o Note: Hospitalizations related to monitoring of expected CRS symptoms, scheduling 
issues (e.g. evening or weekend evaluations), and convenience considerations do not 
constitute a serious adverse event. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the subject or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
Deaths occurring after the 30 day window due to disease progression or causes unrelated to study 
interventions will not be recorded as an SAE, but will be documented as a study outcome as per 
Section 12.1.2. 
7.2.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.2.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the subject or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that had it occurred in a more severe form, might have caused death. 
7.2.8 Protocol Deviation  
Any change, divergence, or departure from the IRB and APB-approved research protocol.   
7.2.9 Non-compliance  
The failure to comply with applicable IRB requirements, FDA or other regulatory requirements 
for the protection of human research subjects. 

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7.2.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document, or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.3 
ADVERSE EVENT REPORTING 
Both Serious and Non-Serious Adverse Events will be clearly noted in source documentation and 
listed on study specific AE logs.  The Principal Investigator or designee will assess each AE to 
determine whether it is unexpected according to the Informed Consent, Protocol Document, or 
related to the investigation.  All AEs will be tracked until resolution or until 30 days after the last 
study treatment, whichever is later.   
All adverse events (as defined in Section 7.2.1) will be recorded and reported from the start of 
lymphodepletion chemotherapy and conclude 30 days after the last study treatment.  Prior to the 
start of lymphodepletion chemotherapy, only unexpected serious adverse events related to study 
procedures will be collected.  In the event that a subject requires disease directed therapy after 
undergoing leukapheresis but prior to commencing lymphodepletion chemotherapy, these adverse 
events and any adverse events unrelated to participation in this study will not be collected or 
reported. 
Serious adverse events that occur more than 30 days after the last administration of study treatment 
and have an attribution of at least possibly related to the agent/intervention should be recorded and 
reported in the AE log. 
In addition, any suspected adverse events that occur after 30 days, during the initial 5 years of 
follow up, will also be recorded and reported (section 5.5.5).  Suspected adverse events occurring 
in subjects who received cell therapy that are potentially related to the gene therapy nature of this 
study will be reported at the time of the investigator notification of their occurrence during 15 year 
follow up (Section 5.5.5.2). 
After Day 30 and for 24 months or until disease progression (whichever occurs first), targeted AE 
collection of neurological, hematological (Grade 3 or higher), infections, autoimmune disorders, 
and secondary malignancies will be performed if attributed as possibly, probably or definitely 
related to CD22-CAR. 
7.3.1 Stanford Reporting 
Serious Adverse Events (SAEs) (as defined in section 7.2.4) Grade 3 and above, and all subsequent 
follow-up reports will be reported to the Stanford Cancer Institute Data and Safety Monitoring 
Committee (DSMC), regardless of the event’s relatedness to the investigation, for institutional 

Protocol: CD22 CAR T-cell in Adults 
  
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gene; following lymphodepleting chemotherapy 
 
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reporting purposes.   
All SAEs Grade 3 and above attributed possibly, probably or definitely related to CD22-CAR T 
cells, and unexpected, will be reported to the APB using eProtocol within 10 working days of 
determination, or within 5 working days for deaths or life-threatening experiences.  Any positive 
sterility results during manufacture, including prior to final product formulation, will be reported 
to the APB using eProtocol within 5 working days.   
Events meeting the IRB definition of ‘Unanticipated Problem’ (as determined by the Principal 
Investigator) will be reported to the IRB using eProtocol within 10 working days of determination, 
or within 5 working days for deaths or life-threatening experiences. 
APB and IRB will be notified via an expedited safety report if any stopping rules are triggered, as 
described in Section 12.3. 
All adverse events will be reported to IRB and APB at annual continuing review. 
7.3.2 IND Sponsor Reporting Criteria  
The Principal Investigator must immediately (within 24 hours of knowledge of event) report to 
the IND Sponsor, using the study-specific form or MedWatch form, any serious adverse event, 
whether or not considered drug related or expected.  The investigator must include an assessment 
of whether there is a reasonable possibility that the CD22-CAR T cells caused the event.  The 
Principal Investigator is responsible for promptly providing the Sponsor with any information 
needed to determine whether the SAE requires submission of an IND Safety Report. 
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between the 
study therapy and the event (e.g. death from anaphylaxis).  In that case, the investigator must 
immediately report the death to the sponsor. 
Non-serious adverse events must be recorded in a timely manner and reported to Sponsor at IRB 
continuing review and in IND Annual Reports. 
Events will be submitted to Sponsor’s Medical Representative, at: 
David Miklos, M.D., PhD   
Associate Professor of Medicine (Blood and Marrow Transplantation) 
Clinical Director Cancer Cell Therapy 
Medical Director of Stanford Cellular Therapeutics and Transplantation Laboratory  
269 West Campus Dr, CCSR 2205,  M/C 5623 
Stanford, California, 94305-5623 
650-452-8155 
7.3.3 Reporting Pregnancy  
✓ Maternal exposure 
If a female subject becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy reported to the Sponsor and the Stanford regulatory 
authorities (IRB, APB, DSMC).  The potential risk of exposure of the fetus to the investigational 
agent(s) or chemotherapy agents (s) should be documented in box B5 of the MedWatch form 

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“Describe Event or Problem”. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment under 
study may have interfered with the effectiveness of a contraceptive medication.  However, as 
subjects who become pregnant on study risk intrauterine exposure of the fetus to agents which may 
be teratogenic, the Sponsor is requesting that pregnancy occurring while subject still has detectable 
CD22-CAR T cells in peripheral blood should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other (pregnancy)” under the Pregnancy, 
puerperium and perinatal conditions.   
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
If any pregnancy occurs within 4 months of last dose of lymphodepletion chemotherapy or while 
CD22-CAR T cells are detectable in peripheral blood, then the investigator should inform the 
Sponsor immediately (within 24 hours of knowledge of event). 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies.  The same timelines apply when outcome information is available. 
✓ Paternal exposure 
Male subjects should refrain from fathering a child or donating sperm for 4 months after the last 
dose of lymphodepletion chemotherapy and while CD22-CAR T cells are detectable in peripheral 
blood. 
Pregnancy of the subject’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring during the reporting period should, if possible, be followed up 
and documented. 
7.4 
FDA REPORTING CRITERIA 
7.4.1 IND Safety Reports to the FDA (Refer to 21 CFR 312.32) 
The Sponsor will be responsible for reporting to the FDA any unexpected fatal or life-threatening 
suspected adverse reactions as soon as possible but no later than 7 calendar days of initial receipt 
of the information using the MedWatch Form 3500a.   
 
7.4.2 FDA Annual Reports (Refer to 21 CFR 312.33) 
The Sponsor will submit the Annual Report to the FDA according to 21CFR§312.33, and any 
associated FDA correspondences regarding the IND annual report.   
7.4.3 Serious Adverse Event Reporting on Cell Therapy Products to the FDA 
A sample from all products that are non-conforming or do not meet release specifications will be 

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used to conduct an out of specification investigation and the remainder either disposed of 
according to our facility biohazardous material disposal SOP or the FDA will be contacted by the 
manufacturing team to determine whether the product is suitable for infusion.  The manufacturing 
facility will report all products manufactured including those that did not meet release criteria or 
were otherwise not infused in the annual IND report to the FDA. 
All HCT/P deviations involving 351 cell products will be reported using MedWatch Form 3500a 
according to FDA publication “Guidance for Industry: MedWatch Form FDA 3500A: Mandatory 
Reporting of Adverse Reactions Related to Human Cells, Tissues, and Cellular and Tissue-Based 
Products (HCT/Ps) available at:  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/Tissue/ucm074000.htm. 
7.4.4 Action Plan for Positive Results on Cell Product Safety Testing:  
In the unlikely event that a positive sterility test or mycoplasma test result is obtained after 
distribution of a cell product that has been administered, or after administration of the product to 
the subject, the following steps will be initiated IMMEDIATELY: 
a. Clinical Laboratory personnel will notify Director of Manufacturing and Process 
Development of the test results. 
b. Director of Manufacturing and Process Development will notify the Principal Investigator 
who will be updated with any substantive changes, including the final report on the 
identification and sensitivity from the positive sterility test.  The manufacturer’s QS Director 
or designee will determine the need for quality improvement based on the nature and extent 
of the incident.   
c. If Director of Manufacturing is unable to reach Principal Investigator within 15 minutes, 
contact inpatient attending physician caring for the subject on the hospital service via 
hospital page with direct communication.  NOTE:  The Principal Investigator and/or 
designee will contact the attending physician, who will determine the extent of the work-up 
of a positive culture in consultation with appropriate infectious disease consultants, as well as 
determine an appropriate action treatment plan.   
d. The Principal Investigator and/or attending physician will discuss the positive results with the 
subject, and specify the clinical therapy, antibiotic regimen and/or monitoring plan.   
e. A contaminated sample of a product that has been administered to a subject will be handled 
in the same fashion as a Grade 4/5 toxicity.  The Principal Investigator will be responsible for 
notifying the IRB and APB via an Unanticipated Problem (UP) report within 5 working days, 
and the Sponsor will notify the FDA via an expedited 7-day IND Safety Report.   
In addition to the above, appropriate Safety reporting will be done as per the manufacturing 
facility’s SOP for Sterility Testing .  A sample of each product is retained by Quality Systems and 
will be sent to the Microbiology Laboratory for repeat testing and speciation.  An 
Out-of-Specification (OOS) Investigation will be conducted by the Quality Systems staff of the 
manufacturing laboratory including root cause analysis, review of viable environmental 
monitoring results collected at the time of manufacturing on personnel, equipment and reagents.  
Whether or not attribution is established, a formal Corrective and Preventive Action plan will be 
issued by the manufacturing facility and appropriate remediation will be performed including 

Protocol: CD22 CAR T-cell in Adults 
  
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gene; following lymphodepleting chemotherapy 
 
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retraining of manufacturing personnel, elimination of any contaminated reagents and re-cleaning 
of the production facility followed by viable microbiological monitoring to establish effectiveness 
of cleaning. 
8 
CORRELATIVE/SPECIAL STUDIES  
CAR T cell therapy targeting a single tumor associated antigen has mediated striking remissions 
in B cell leukemia and aggressive B-cell NHL; however, the complex interplay of tumor, T cell 
and intrinsic CAR properties that influence these outcomes are not well understood.  The clinical 
experience to date has demonstrated variable patterns of tumor remission and CAR T cell efficacy 
and persistence.  We aim to utilize this study as an opportunity to collect correlative data that will 
permit extensive study of both the B cell and T cell compartment prior to and following CAR 
T cell therapy.  We aim to integrate multi-dimensional technologies to permit complex analyses 
of the apheresis product, the CAR T cell product pre-infusion and in vivo expanded CAR T cells 
following antigen encounter.  We additionally aim to investigate properties of B cell tumors that 
render them susceptible to CAR T cell cytotoxicity and study physiologic and malignant B cell 
remodeling under the pressure of multi-targeted CAR therapy. 
Overall goal of study correlatives:  
• Explore the T cell and tumor properties that influence CAR T cell efficacy and persistence 
and permit disease relapse 
Specific Aims: 
• 
Assess the impact of T cell subset composition as delineated using flow cytometry, mass 
cytometry and ATAC-Seq on CAR T cell expansion and persistence  
• 
Where possible, use TCR sequencing to fate map cells contained in the apheresis of 
manufactured product to persistent CD22-CAR T cells as an exploratory aim to identify 
subsets with a greater likelihood of T cell persistence in the setting of adoptive cell therapy.   
• 
Characterize antigen expression on relapsed B-ALL or aggressive B-cell NHL following 
CAR-mediated targeting 
• 
Utilize the CAR-mediated arrest of B cell maturation to gain insight on physiologic and 
pathophysiologic B cell development, maturation arrest and alternative survival pathways in 
normal and malignant B cells.   
• 
Explore the level CD22 surface expression and CD22 site density on leukemic blasts, and 
malignant lymphoma cells when feasible and correlate with clinical response to CAR T cells. 
• 
To establish the utility of chromatin structure and epigenomic technology to characterize 
CAR T cell therapies. 
8.1 
CORRELATIVE STUDIES 
8.1.1 Sample Collection Schedule 
The samples to be collected and schedule for sample collection is detailed in Section 13.7 
Appendix G: Correlative Sample Schedule .  Every effort will be made to collect correlative 
samples as described in Appendix G, but changes in tests, schedules, sample volume limitations 
and/or conduct of apheresis, and conflicts with schedules or patient conditions may result in missed 
or altered sample collection.  These variations will be noted but will NOT constitute a protocol 

Protocol: CD22 CAR T-cell in Adults 
  
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deviation given the exploratory nature of correlative testing. At the discretion of the principal 
investigator, correlative samples may be omitted if not applicable to the subject’s disease or not in 
the best interest of the subject. Omitted correlative samples for these reasons should not be 
considered a protocol deviation. 
8.1.2 Blood Drawing Limits for Research Purposes  
The maximum amount of blood that may be drawn per day from adult subjects is 2.5% of total 
blood volume (192-200 mL).  The volume to be drawn per day for research purposes will comply 
with institutional policy.  Subjects may undergo a small volume apheresis (approx. one to two 
blood volumes) in lieu of standard blood draw to obtain peripheral blood lymphocytes for 
correlative studies including Day 28 (± 1 week), and Month 3 (± 2 weeks), 6 (± 1 month), 9 (± 1 
month), and 12 (± 2 months). 
8.2 
MONITORING GENE THERAPY TRIALS: PERSISTENCE, AND RCL, AND TOXICITY 
8.2.1 Monitoring Persistence 
Due to the nature of these studies, it is possible that expansion of specific T-cell clones will be 
observed as tumor reactive T-cells proliferate in response to tumor antigens.  Therefore, care will 
be taken to track T-cell persistence both immunologically and molecularly by flow cytometry 
using anti-CD22 anti-idiotype antibody at the time points listed in Section 13.7.   
8.2.1.1 Persistence of genetically engineered transduced cells 
If any subject has more than 5% persistence of gene transduced cells at Month 6, samples will be 
subjected to flow cytometry using anti-CD22 anti-idiotype antibody that would allow the 
identification of clonality of persisting gene transduced cells.  Such techniques may include 
analysis of BV chain expression, T cell cloning or LAM-PCR.  If a predominant or monoclonal 
T cell clone derived from gene transduced cells is identified during the follow-up, the integration 
site and sequence will be identified and subsequently analyzed against human genome database to 
determine whether the sequences are associated with any known human cancers.  If a predominant 
integration site is observed, the T cell cloning or LAM-PCR test will be used at an interval of no 
more than 3 months after the first observation to see if the clone persists or is transient.  In all 
instances where monoclonality is persistent and particularly in instances where there is expansion 
of the clone, regardless of whether or not the sequence is known to be associated with a known 
human cancer, the subject should be monitored closely for signs of malignancy, so that treatment, 
if available, may be initiated early. 
8.2.2 Safety Assessment Testing for Replication Competent Lentivirus in Lentiviral Vector 
Based Gene Therapy Products during Subject Follow up 
In compliance with OSP and FDA’s Guidance for Industry: Gene Therapy Clinical Trials – 
Observing Participants for Delayed Adverse Events (2006), subjects who have received at least 
one dose of a genetically engineered cellular therapy will be evaluated for long term safety and 
occurrence of adverse events according to the requirements established by FDA guidance and the 
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules 
(NIH Guidelines) (2016). 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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8.2.2.1 Replication-competent Lentivirus Evaluations 
Blood samples will undergo analysis at Indiana University Gene Therapy Testing Laboratory (IU 
GTTL) for detection of RCL by detection of p24 antigen and reverse transcriptase activity (Product 
Enhanced Reverse Transcriptase [PERT]) at the following time points: 
• prior to cell infusion (at baseline)  
• at Month 3 (±1 month),  
• at Month 6 (± 1 month), and  
• at Month 12 (± 2 months) post cell administration.   
Samples sent to IU GTTL MUST be drawn on Monday, Tuesday, Wednesday or Thursday, and 
shipped on ice priority overnight.  The lab cannot accept samples on the weekends (see Section 
13.4).  If all samples in the first year are negative, annual blood samples will be archived for the 
next 4 years (± 2 months) (for a total of 5 years after cellular therapy) with a brief clinical history 
conducted annually.  If any post-treatment samples are positive, further analysis of the RCL and 
more extensive subject follow-up will be undertaken, in consultation with the FDA.     
If a subject dies or develops neoplasms during this follow up, efforts will be made to assay a biopsy 
sample for RCL.  Subjects who receive additional CD22-CAR T cell infusions will re-start RCL 
testing based on the new infusion date. 
  

Protocol: CD22 CAR T-cell in Adults 
  
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9 
STUDY CALENDAR 
 
 
 
Preparative Regimen 
and Cell Infusion 
Post Treatment Assessment 
Long Term Follow-Upl 
 
Procedure 
Screeninga 
(≤ 28 days of 
enrollment, 
unless 
specified) 
Apheresisd 
Day -5, 
Day -4, 
Day -3 
Prior to 
cell 
infusion 
(< 24 h) 
Day 0 
Day 1 to 
Day 14i  
(± 2 d) 
Twice 
weekly, 
Day 15 to 
Day 27 
(± 4 d) 
Day 28 
(± 4 d) 
Monthly, 
Month 2-3 
(±2  weeks) 
Month 6 (±1 mo) 
 9, (±1  mo)  
12 (±2 mo) 
q6-12 months to 
5 years 
Annually, 
Year 6 to 15 
(±3 mo) 
At Disease 
Progression 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
X 
X 
Xi 
Xi 
X 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
Xf 
Xf 
Xf 
X 
X 
X 
 
 
Neurologic exam 
 
 
 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
 
 
Performance Status 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
Height 
X 
 
Xr 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
 
 
 
X  
X 
 
 
 
Labsc 
• CBC with diff 
X 
Xd 
X 
X 
X 
Xi 
Xi 
X 
X 
X 
 
 
• PT/PTT  
X 
 
 
 
 
 
 
 
 
 
 
 
• Chemistriesb 
X 
Xd 
X 
X 
X 
Xi 
Xi 
X 
X 
 
 
 
• Phosphorus 
X 
Xd 
Xr 
 
X 
Xt 
Xt 
 
 
 
 
 
• Magnesium 
X 
Xd 
Xr  
X 
X 
Xt 
Xt 
 
 
 
 
 
• CRP 
X 
Xd 
Xr 
X 
X 
Xt 
Xt 
X 
 
 
 
 
• Ferritin 
X 
 
Xr 
 
 
Xt 
Xt 
X 
 
 
 
 
• Uric acid and LDH 
 
 
Xr 
 
Xt 
Xt 
Xt 
 
 
 
 
 
• CD22 staining by IHC 
or flow cytometry  
Xp 
 
 
 
 
 
 
 
 
 
 
 
• Quantitative IgG 
immunoglobulins 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
 
• Urine analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
• β-HCG pregnancy test 
on all females of 
child-bearing potential 
X 
Xc 
Xc 
 
 
 
 
 
 
 
 
 
• RCL blood sample 
 
 
 
Xn 
 
 
 
 
Xn 
Xn 
 
 
ECG  
X 
 
 
 
 
 
 
 
 
 
 
 
ECHO, MUGA or cardiac 
MRI 
Xq 
 
 
 
 
 
 
 
 
 
 
 
Correlative Research 
Studies  
Correlative samples outlined in Section 13.7, Appendix G 
• 
Leukapheresis  
 
X 
 
 
 
 
 
Xj 
Xj 
Xj 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
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Preparative Regimen 
and Cell Infusion 
Post Treatment Assessment 
Long Term Follow-Upl 
 
Procedure 
Screeninga 
(≤ 28 days of 
enrollment, 
unless 
specified) 
Apheresisd 
Day -5, 
Day -4, 
Day -3 
Prior to 
cell 
infusion 
(< 24 h) 
Day 0 
Day 1 to 
Day 14i  
(± 2 d) 
Twice 
weekly, 
Day 15 to 
Day 27 
(± 4 d) 
Day 28 
(± 4 d) 
Monthly, 
Month 2-3 
(±2  weeks) 
Month 6 (±1 mo) 
 9, (±1  mo)  
12 (±2 mo) 
q6-12 months to 
5 years 
Annually, 
Year 6 to 15 
(±3 mo) 
At Disease 
Progression 
Disease Evaluation  
• PET/CT 
chest/abdomen/pelvis, 
brain MRI (or other 
appropriate imaging) 
Xk 
 
Xk 
 
 
 
 
Xk 
Xk 
Xk 
 
 
• Lumbar puncture 
Xk 
 
 
 
 
 
 
Xk 
Xk 
Xk 
 
 
• Bone marrow aspirate  
Xk 
 
Xk 
 
 
 
 
Xk 
Xk 
Xk 
 
X 
• MRD blood sample 
(Subjects with ALL only) 
 
 
Xk 
 
 
 
 
Xk 
Xk 
Xk 
 
 
• Lymph node biopsy 
Xs 
 
 
 
 
Xs 
Xs 
 
 
 
Xs 
Treatment Regimen 
•  
 
 
 
 
 
 
 
 
 
 
 
 
• Lymphodepleting 
chemotherapy 
 
 
Xe 
 
 
 
 
 
 
 
 
 
• CD22-CAR T cells 
infusion 
 
 
 
 
Xg 
 
 
 
 
 
 
 
Response Evaluationk,l 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Adverse Eventsv 
 
X 
 
 
 
 
 
X 
Xo 
Xo 
 
Xo 
Concomitant Medications 
X 
 
 
 
 
 
 
X 
Xo 
Xo 
 
Xo 
Long term follow up 
questionnaires 
 
 
 
 
 
 
 
 
 
 
Xu 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
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a. 
Within 28 days prior to enrollment, unless otherwise specified. 
b. 
Laboratory evaluation to include; Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Urea nitrogen (BUN), Creatinine, Glucose, Calcium (Ca) 
total, ALT/GPT, AST/GOT, Alkaline Phosphatase, Bilirubin, Albumin, Total Protein); creatinine clearance may be performed if the serum creatinine is elevated.  The PI may 
order additional tests in some subjects if needed to fully assess clinical status and obtain baseline results.  Examples of such tests include: haptoglobin, soluble IL2R, 
immunoglobulin levels, and viral serology or PCR for cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), and Epstein-Barr virus (EBV). 
c. 
Within 7 days prior to leukapheresis procedure and Day -5. 
d. 
For cell acquisition for product development.  Visit may be skipped if subject has cryopreserved cells that meet IND criteria. Labs required within 7 days prior to leukapheresis. 
e. 
Subjects will receive hydration and prophylactic medications according to institutional standard practice prior to, during and after lymphodepletion chemotherapy.  
f. 
Vital signs (blood pressure, heart rate, respiratory rate, pulse oximetry, temperature) collected on Day 0: prior to infusion, at the conclusion of the infusion (±10 min), 60  (±10 
min) minutes after infusion, and as clinically indicated; then Day 1-28: every shift (± 2 hrs) during hospitalization, and with each visit after discharge.   
g. 
Premedications will be provided as described in protocol Section 6.6.  Subject may be offered additional CAR T cell treatments if enough cells were manufactured from the 
initial preparation, the subject experienced at least partial response to the first infusion, and the subject meets all eligibility criteria.  Subsequent infusions will follow the same 
procedures as the first. 
h. 
Neurologic exam daily and ICE score every shift (± 2 hrs) during hospitalization, then neurologic exam with each visit after discharge. After Day 28, continue until end of 
neurotoxicity or at investigator discretion. 
i. 
Five (5) times per week from Day 1 to  Day 14 (± 2 days) (unless otherwise indicated) with visits no more than 48 hours apart, and then twice weekly until Day 28 (± 4 days).   
j. 
Subjects may undergo a small volume apheresis (approx. one to two blood volumes) in lieu of standard blood draw to obtain peripheral blood lymphocytes for correlative 
studies including Day 28 (±7 days), and 3 (± 2 weeks) , 6 (± 1 month) , 9 (± 1 month) , and 12 (± 2 months) months. 
k. 
Subjects with leukemia will undergo bone marrow biopsy and patients with aggressive B-cell NHL will undergo PET/CT (or PET at investigator discretion) at screening, Day 28 
(±4 days) and Month 3  (± 1 month), 6  (± 1 month), then per standard of care frequency.  Disease evaluations may be repeated if >28 days passes between enrollment and start 
of lymphodepletion chemotherapy or if bridging anti-neoplastic therapy is used post-enrollment (per Section 4.2.5).  Other methodologies including lumbar puncture, x-rays, 
MRI, MRD evaluation, lymphocyte subsets, etc determined by investigator based on sites and type of disease may be used; consistency throughout protocol evaluations is 
necessary.  Day 28  will be considered the response evaluation for subjects with ALL.  Month 3 will be considered the response evaluation for subjects with aggressive B-cell 
NHL.   
l. 
Subject will be monitored by physical exams, disease evaluations, vitals, CBC with diff, Chemistries, and IgG levels until relapse or subject proceeds to other therapies at 
investigator’s discretion; at which time Long-Term Gene Therapy follow-up will proceed as per Section 5.5.5 
m. Every 3-12 weeks (±2 weeks) post infusion until Month 3. 
n. 
RCL samples collected and sent to IU GTTL: prior to cell infusion; and at 3 (± 1 month), 6 (± 1 month), and 12 months (± 2 months) post cell infusion.  Subsequent RCL blood 
samples may be stored annually for 4 additional years if all RCL in first year negative. 
o. 
Targeted adverse/serious adverse event reporting and concomitant medication collection until Month 24, disease progression, or start of alternate therapy (whichever occurs 
first).   
p. 
For R/R ALL: CD22 expression can be any time since diagnosis, but must be re-demonstrated if patient has received targeted anti-CD22 therapy. For R/R aggressive B-cell 
NHL:  CD22 expression is not required.  Subjects must have archival tissue available or must be willing to undergo a biopsy of easily accessible disease. 
q. 
Testing performed within 180 days or after most recent anthracycline based treatment or mediastinal radiation therapy may be used for confirmation of eligibility 
r. 
Height within 30 days prior to Day -5. Others collected once, Day-5 or Day -6 only. 
s. 
If feasible and easily accessible, lymph node biopsy will be obtained from subjects with lymphoma at baseline, and once between Day 7 and Day 28.  A PBMC sample (for 
CAR T cells, etc) and lymph node biopsy may be collected at the time of progression, prior to starting any subsequent anticancer therapy, if clinically feasible.   
t. 
 LDH testing only required if elevated at baseline (prior to lymphodepletion chemotherapy). Uric acid only at baseline (Day -5 or -6). Phosphorus, magnesium, CRP, Ferritin, 
and LDH daily while hospitalized during initial hospitalization, then Day 14 (± 3 days) and Day 21 (± 3 days).  
u. 
After 5 years, health status data will be obtained from surviving subjects via telephone contact or mailed questionnaires.  The long term follow up period for lentiviral vectors is 
15 years.   
v. 
All adverse events will be recorded and reported from the start of lymphodepletion chemotherapy and conclude 30 days after the last study treatment.  Prior to the start of 
lymphodepletion chemotherapy, only unexpected serious adverse events related to study procedures will be collected (see Section 7.3.1). 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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10 MEASUREMENTS AND MONITORING 
10.1 PRIMARY AND SECONDARY ENDPOINTS  
10.1.1 Primary Endpoints:   
The primary endpoint for feasibility is defined by the rate of successful manufacture of the 
CD22-CAR T cells produced with the Miltenyi CliniMACS Prodigy® system to satisfy the 
targeted dose level and meet the required release specifications within 7 or 10 days of 
manufacturing initiation. 
In patients with relapsed/refractory aggressive B-cell NHL, a primary endpoint for safety is the 
maximum tolerated dose (MTD).  The MTD is defined as the dose level with 0 DLTs out of 3 
feasible patients or 1 DLT out of 6 feasible patients; in this study, the recommended phase 2 dose 
(RP2D) may not be the MTD as defined above.  If the MTD is not found to be feasible, the dose 
below that is found to be safe and feasible will be the RP2D. 
For both disease populations, primary endpoints for safety of CD22-CAR T cells as evidenced by 
the incidence and severity of dose limiting toxicities (DLT), adverse events, serious adverse 
events, laboratory abnormalities, changes in vital signs, and changes in physical examination 
following infusion of CD22-CAR T cells, recorded and graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0.  
10.1.2 Secondary Endpoints  
The secondary endpoints are the overall response rates per response criteria in adults with 
relapsed/refractory CD22 expressing B-cell ALL and adults with relapsed/refractory aggressive 
B-cell NHL (see below for response criteria for each disease population). 
10.1.2.1 Response Criteria  
➢ The response rate as measured by Response Criteria for ALL (Refer to Section 13.3.1 
Response Criteria for ALL)(*Modified from: Cheson BD, et al.) 
- Complete Response (CR)  
- Partial Response (PR) 
− - Hematological Activity 
- Stable Disease (SD) 
-Progressive Disease (PD) 
 
➢ The response rate as measured by Response Criteria for Lymphoma (Refer to Section 13.3.2 
Response Criteria for Lymphoma): 
- Complete Response (CR)  
- Partial Response (PR) 
- No Response or Stable Disease (SD) 
- Progressive Disease (PD) 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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10.2 INSTITUTIONAL REVIEW OF PROTOCOL 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB, APB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any 
changes made to the protocol will be submitted as a modification and will be approved by the IRB 
and APB prior to implementation.  The Protocol Director will disseminate the protocol amendment 
information to all participating investigators. 
10.3 DATA AND SAFETY MONITORING PLAN 
10.3.1 Clinical Team  
The clinical research team will meet on a regular basis during dose escalation and when subjects 
are being actively treated on the trial to discuss cell manufacturing, toxicities, eligibility questions, 
trial accrual, and treatment needs.  Decisions about dose level enrollment and dose de-escalation 
if applicable will be made based on the toxicity data from prior subjects in each disease group.  
Members from cell processing facilities will join as needed.   
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator.  Adverse events will be reported as required above.  Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or protocol 
deviations will be immediately reported to the IRB, DSMC, APB and to the Sponsor.   
The principal investigator will review adverse event and response data on each subject to ensure 
safety and data accuracy.  The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.   
10.3.2 Data Safety Monitoring Committee  
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for the clinical study.  The DSMC members include at least four physicians, one 
oncology nurse, one oncology data manager and one biostatistician, and are selected in 
consultation with Stanford Cancer Institute leadership to cover expertise in areas such as medical 
oncology, radiation oncology, hematology, blood and marrow transplantation, and pediatric 
oncology.  Members with additional expertise may be appointed on an ad hoc basis.  The DSMC 
will audit study-related activities to determine whether the study has been conducted in accordance 
with the protocol, local standard operating procedures, FDA regulations, and Good Clinical 
Practice (GCP).  The DSMC will review monthly any serious adverse events (Grade ≥3) and 
protocol deviations, and annually audit regulatory binders, patient eligibility, data entry, IRB 
compliance and all serious adverse events and adverse events associated with the research to ensure 
the protection of human subjects.  Results of the DSMC audit will be communicated to the IRB 
and APB and the appropriate regulatory authorities at the time of continuing review, or in an 
expedited fashion, as needed. 
10.3.3 Safety Monitoring Committee  
The clinical team has assembled an independent SMC consisting of Stanford and external 
academic investigators who are independent of the clinical trials under review and who are 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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knowledgeable in cellular therapies to review all serious adverse events (SAEs), subject 
deviations, and internal and external audit/monitoring reports on a more frequent basis.  The SMC 
will confirm dose escalation decisions based on available AEs and dose limiting toxicity (DLT) 
determinations for each dose cohort, and determine whether the study needs to be halted based on 
protocol specified safety rules (Section 12.3). 
10.4 DATA MANAGEMENT PLAN 
Study data will be collected on paper or electronic case report forms (CRFs).  This study will 
utilize a Medrio electronic clinical database for eCRFs.  If there is a gap between study open to 
enrollment and Medrio database activation, paper CRFs will be utilized until the Medrio eCRFs 
are available.  CRFs should summarize the clinical findings and observations necessary to ensure 
safety of participants on the study, and to document the study outcomes.  All data will be kept 
secure.  Paper study files will be kept in a locked, secure location.  Electronic study data will be 
stored in encrypted, backed-up, password protected computers.  Personal identifiers will not be 
used when collecting and storing data.  An enrollment log will be maintained in the regulatory 
binder/file which is the only location of personal identifiers with unique subject identification 
number.  
11 COLLABORATIVE AGREEMENTS  
In order to track cell product throughout manufacture and back to the bedside for infusion, the cell 
manufacturer will be provided selected protected health information.  This collaborative agreement 
is disclosed in the informed consent document.  
A collaborative research agreement exists with Adaptive Biosciences, Inc. to exchange data and 
biospecimens for correlative studies on circulating tumor DNA.  
Additionally, a collaboration with Syncopation Life Sciences will share clinical and manufacturing 
data as well as biospecimens. 
12 STATISTICAL CONSIDERATIONS 
The aims of this clinical trial are three-fold:  
1. To evaluate the feasibility of manufacturing CD22-CAR T cellular products in the Miltenyi 
CliniMACS Prodigy® system across both diseases, ALL and aggressive B-cell non-
Hodgkin lymphoma.  The CliniMACS Prodigy® represents the next generation in 
automated cell processing, combining and streamlining cell processing workflows into one 
closed system.   
2. To establish safety in two adult disease populations.  CD22-CAR T cells have not been 
previously administered to subjects with aggressive B-cell non-Hodgkin lymphoma, and 
we will establish the maximum tolerated dose (MTD) or recommended Phase 2 dose 
(RP2D) of CD22-CAR T cells in this patient population.  Simultaneously, we will seek to 
expand the prior pediatric and young adult experience with this CD22-CAR T cell agent in 
adults with CD22+ expressing B-cell ALL at the established dose of 1x106 transduced T 
cells/kg.  Once MTD/RP2D is determined in subjects with aggressive B-cell non-Hodgkin 
lymphoma, this disease population will undergo the same safety evaluation. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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3. To evaluate in a preliminary fashion efficacy of CD22-CAR T cells in two disease 
populations, subjects with relapsed/refractory ALL and subjects with relapsed/refractory 
aggressive B-cell non-Hodgkin lymphoma. 
The precedent for conducting clinical trials of this scope was established by the ongoing clinical 
trials CCT5001/IRB-41382 and CCT5007/IRB-41383 conducted by Stanford Center for Cancer 
Cell Therapy. 
A formal statistical analysis plan (SAP) will be prepared and finalized before database lock for the 
final analysis for the study report.  The SAP will provide details regarding the definition of analysis 
subjects (populations), analysis variables, and analysis methodology to meet all study objectives. 
The principle and key elements of the SAP are provided as follows: 
• In general, safety and efficacy data will be summarized for each disease group with 
descriptive statistics, including means, standard deviations, medians, minimums and 
maximums for continuous variables, the number of subjects and percent in each category 
for categorical variables. 
• Data from each individual will be tabulated as appropriate.  Efficacy and safety endpoints 
will be tabulated by dose cohort and time point. 
12.1 PRIMARY OUTCOMES: 
o Feasibility rate of successful manufacturing of CD22-CAR T cells for the designated 
dosage in each disease population, using the Miltenyi CliniMACS Prodigy® system. 
o DLT rate and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of 
CD22-CAR T cells in adults with relapsed/refractory aggressive B-cell NHL. 
o DLT rate of an established dose of CD22-CAR T cells in adults with relapsed/refractory 
CD22 expressing B-cell ALL  
12.1.1 Feasibility  
Feasibility will be defined as the successful manufacturing of CD22-CAR T cells that meet 
established release criteria to satisfy the targeted dose level.  Although we anticipate reaching the 
targeted cell dose during manufacture, feasibility of manufacturing cells remains a primary 
objective in this subject population.   
The study will have one interim evaluation for feasibility in each disease population.  Feasibility 
for patients with R/R aggressive B-cell NHL will be evaluated after the first 6 subjects’ cell 
production.  Feasibility for patients with R/R ALL will be evaluated after the first 10 subjects’ cell 
production.  If the targeted number of cells cannot be produced in at least 3 of the first 6 patients 
with aggressive B-cell NHL or at least 5 of the first 10 patients with ALL on this trial that meet 
the established release criteria, further enrollment in that disease population will be paused pending 
evaluation of the manufacturing process.  The Protocol Director, in collaboration with the Cancer 
Cell Therapy (CCT) Manufacturing team, the CCT Clinical Research Operations & Procedures 
team, representatives from the manufacturing facilities, and IND Sponsor’s authorized 
representatives, would work to modify the manufacturing process to improve rate of successful 
manufacture.  Any changes to the protocol or IND will be submitted to FDA, and APB and IRB 
approval will be obtained prior to continuing enrollment.  Based on previous experience, the 
probability of successful manufacturing of cells is 95%.  Thus, the probability of suspending the 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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trial for lack of feasibility is negligible (p < 0.001).  
If cell growth limitations preclude administration of the targeted cohort cell dose, the subject will 
receive as many cells as possible, and be considered evaluable for feasibility, but not evaluable for 
toxicity.  If a minimum of 1.0 x 105 CD22-CAR-transduced T cells per kg cannot be obtained for 
infusion, the subject may be treated but will not be evaluable for toxicity or response, but will be 
considered a feasibility failure.  The study has a goal of 80% feasibility to warrant further 
investigation of the experimental therapy.  Subsequently, contingent upon meeting the first 
feasibility rule after 6 R/R aggressive B-cell NHL subjects, the study will allow for a total of 10 
R/R aggressive B-cell NHL subjects (maximum of 4 subjects to be replaced during dose-
escalation) to be replaced for safety and efficacy evaluations due to inability to achieve the target 
cell product.  Similarly, contingent upon meeting the first feasibility rule after 10 R/R ALL 
subjects, the study will allow for a total of 6 R/R ALL subjects to be replaced for safety and 
efficacy evaluations.   
12.1.2 Safety  
The safety and tolerability of CD22-CAR T cell regimen will be assessed in each disease group 
by: 
• Suspected adverse events, and 
• Suspected serious adverse events 
As evidenced by: 
o Changes in clinical laboratory tests (clinical chemistry, hematology, etc). 
o Changes in vital signs (blood pressure, pulse, respiratory rate and body 
temperature). 
o Changes in physical exams.  Signs and symptoms assessed may require additional 
testing as clinically indicated such as ECG, PFT, radiographic studies, etc. 
o Subject reported signs and symptoms 
Safety data will be analyzed per standard methods and interpreted descriptively for each disease 
group (ALL and aggressive B-cell NHL).  Safety data will be summarized for each disease group 
separately and for the dose cohorts of subjects with aggressive B-cell NHL, if needed.  Adverse 
events will be assessed using the CTCAE version 5.0 for type and severity of event.  Serious 
Adverse Events will be summarized for the targeted dose level of a disease group.  Reasons for 
discontinuation of study therapy will be tabulated. 
Laboratory testing includes hematology, serology, serum chemistry, and urinalysis.  Baseline 
laboratory testing will be those results obtained prior to initiating the conditioning 
lymphodepletion chemotherapy regimen.  The study will utilize local lab for all clinical laboratory 
testing.  Laboratory data will be tabulated based on the following result class. 
• 
Normal: result is within the local lab normal range 
• Abnormal: result is either higher or lower than the normal range 
All abnormal values will be assessed for clinical significance and investigator determination noted 
in source documents.   
Vital signs collected immediately prior to receiving study drug will be the baseline vital signs.  

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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Observed vital sign values and change from baseline in vital signs at each visit will be summarized 
without formal statistical testing. 
Vital sign result may also be tabulated based on the following result class. 
• Normal: result is within the normal range 
• Abnormal: result is either higher or lower than the normal range 
All abnormal values will be assessed for clinical significance; clinical significance will be captured 
in the case report form.  Number and percent of subjects within each result class will be tabulated 
by time point for each vital sign. 
Findings of physical examinations will be tabulated by dose cohorts without formal statistical 
analysis. 
12.1.2.1 Safety Evaluation for Subjects with Aggressive B-cell NHL 
To evaluate the safety of administering escalating doses of autologous CD22-CAR engineered 
T cells that can be feasibly produced to meet established release specifications in adults with 
aggressive B-cell NHL, defined as DLBCL, PMBCL, and tDLBCL, following a lymphodepleting 
conditioning regimen, the following dose levels will be used: 
▪ Dose Level 1:     1 x 106 transduced T cells/kg (± 20%) 
▪ Dose Level 2:     3 x 106 transduced T cells/kg (± 20%) 
▪ Dose Level 3:     1 x 107 transduced T cells/kg (± 20%) 
A dose limiting toxicity (DLT) as defined in Section 5.4.7.1.  Based on preliminary data, the 
probability of a DLT is less than 20%.  In this study, the maximum acceptable DLT rate is 30%. 
The MTD/RP2D for patients with R/R aggressive B-cell NHL will be determined using a ‘3+3’ 
dose escalation design.  The first cohort of 3 patients will be treated at dose level 1 and escalation 
will proceed based on the number of DLTs in each cohort and constrained by the feasibility of 
producing the current dose level.  The MTD/RP2D is defined as the feasible dose level achieving 
0 DLT out of 3 evaluable subjects or 1 (or fewer due to feasibility) DLT out of 6 evaluable subjects.  
The maximum number of subjects to be enrolled in the ‘3+3’ dose-escalation is 19 R/R aggressive 
B-cell NHL subjects (max 15 subjects required by ‘3+3’ plus max 4 subjects replaced for 
feasibility).  Ignoring feasibility, basic operating characteristics of the dose-escalation design are 
presented in the table below. 
True MTD 
True DLT 
probability at each 
dose 
Average* 
Number of 
patients 
enrolled 
Average* 
Number of 
DLTs 
Probability* 
correct dose 
declared MTD 
Probability* 
all doses 
found toxic 
Dose level 1 
30% 
40% 
50% 
8 
3 
34% 
50% 
Dose level 2 
15% 
30% 
50% 
10 
3 
34% 
17% 
Dose level 3 
10% 
20% 
30% 
11 
2 
35% 
9% 
*From 1000 simulations using ssim3p3( ) function in R package: ‘UBCRM’ 
After the MTD/RP2D is established, a dose-expansion cohort will enroll up to 33 evaluable 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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subjects (for a total of 36 evaluable subjects treated at the final MTD/RP2D) to monitor safety and 
indicate efficacy.  The sample size for the aggressive B-cell NHL dose-expansion cohort is 
determined to indicate efficacy (see Section 12.2.1 for more details). 
The trial will continue to evaluate safety after the first 11 (or 14) subjects in the dose-expansion 
cohort, corresponding to a total of 17 evaluable subjects treated at the MTD/RP2D with either 6 
(or 3) subjects from the dose-escalation cohort(s), and every 5 subjects thereafter.  Safety 
boundaries will be used to monitor a DLT rate of 30%; however, given the expected toxicity rate 
we do not anticipate crossing these boundaries.  If the number of DLTs reported in the table below 
is met, the MTD/RP2D dose level will be de-escalated by one dose level and the dose expansion 
cohort will complete enrollment with the updated RP2D dose level, to further assess safety at this 
dose level and gather preliminary evidence for efficacy.  If de-escalation occurs, new safety 
boundaries will be generated based on the number of currently enrolled subjects and will take place 
after every 5 additional subjects.  If Dose Level -1 is found to be unsafe, the trial will stop 
enrollment for this disease population. 
Table 7. Maximum DLTs during Dose Expansion in Subjects with Aggressive B-cell NHL 
Total number of evaluable 
patients treated at 
MTD/RP2D 
Stop and De-escalate if 
Number of DLTs reached 
17 
8+ 
23 
9+ 
28 
11+ 
The toxicity boundaries correspond to Pocock boundaries with a 10% significance level used for 
all looks and are calculated using the function toxbdry( ) in the R package ‘clinfun’ assuming a 
DLT rate of 25% is acceptable.   
12.1.2.2 Safety Evaluation in Subjects with ALL  
Safety evaluations will occur after the first 10 R/R CD22-positive ALL subjects are evaluable for 
safety assessment and every 5 subjects thereafter.  After 15 evaluable subjects, both safety and 
futility evaluations will be implemented simultaneously.  If the tabulated threshold of DLTs in the 
table below is met, the established CD22-CAR T-cell dose will be decreased by one dose level (as 
defined in Section 5.4.6) for subjects with R/R ALL.  If de-escalation occurs, new safety 
boundaries will be generated based on the number of currently enrolled patients.  The cohort will 
complete enrollment up to a maximum of 28 evaluable patients with safety assessments after every 
5 patients treated at the updated dose level.  If dose level -1 is found to be unsafe, the trial will stop 
enrollment for this disease population. 
Table 8. Maximum DLTs during Dose Expansion in Subjects with ALL 
Total number of evaluable 
patients treated at 
MTD/RP2D 
Stop and De-escalate if 
Number of DLTs reached 
10 
5+ 
15 
7+ 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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20 
9+ 
The toxicity boundaries correspond to Pocock boundaries with a 10% significance level used for 
all looks and are calculated using the function toxbdry( ) in the R package ‘clinfun’ assuming a 
DLT rate of 25% is acceptable.   
12.2 SECONDARY OUTCOMES 
Although a secondary outcome, efficacy as measured by overall response rate will be important in 
determining if a Phase 2 study is warranted in either disease group.  The clinical responses in each 
disease group will be evaluated at Day 28, 3 months, and every 3 months up to 1 year, as per 
Section 9, until disease progression at which time, subjects will be followed as per Section 5.5 
until off-study criteria are met. 
Overall survival (OS) and progression-free survival (PFS) will be assessed in each disease group.  
Progression-free survival (PFS) will be measured from the start of the lymphodepleting 
chemotherapy preparative regimen until the documentation of disease progression or death due to 
any cause, whichever occurs first.  Overall survival (OS) will be determined as the time from the 
start of the lymphodepleting chemotherapy preparative regimen until death.   
12.2.1 Efficacy Evaluation for Subjects with Aggressive B-cell NHL 
An overall response rate (CR or PR) of 25% at 3 months is determined to be sufficient activity 
worthy of further investigation.  A futility analysis will be conducted when 17 evaluable subjects 
have been treated at the MTD/RP2D [with 3 (or 6) from the dose-escalation cohort(s) and 14 (or 
11) from the dose-expansion cohort] and have reached the Month 3 PET imaging assessment.  If 
4 or fewer out of 17 evaluable R/R aggressive B-cell NHL subjects have a CR or PR at 3 months, 
further enrollment to this disease population will stop and the therapy at the MTD/RP2D will be 
declared inactive. 
Assuming no futility stopping, dose level -1 is not found unsafe, and no failure of manufacturing 
the required doses, the study will enroll for a maximum sample size of 36 evaluable aggressive 
B-cell NHL subjects treated at the MTD/RP2D.  This corresponds to a dose-expansion cohort size 
of 33 (or 30) evaluable subjects depending on how many subjects were used to establish the 
MTD/RP2D in the dose-escalation.  With 36 subjects, the Minimax Simon two-stage design has 
80% power at a 5% significance level to test the null hypothesis that the ORR  25%, assuming a 
target ORR of 45%.  If 14 or more respond at 3 months out of the total of up to 36 evaluable R/R 
aggressive B-cell NHL subjects treated at the MTD/RP2D, the therapy will be declared active and 
worthy of further investigation. 
12.2.2 Efficacy Evaluation for Subjects with ALL 
A futility analysis will be conducted when 15 evaluable subjects have been treated at the 
established dose and have reached Day 28 bone marrow assessment.  If 7 or fewer out of 15 
evaluable R/R ALL subjects have a CR, further enrollment to the cohort at this dose level will stop 
for futility; however, upon review by principal investigators, further enrollment to the cohort may 
continue at dose level 2 if DLT rate at dose level 1 is sufficiently safe.  Assuming no futility 
stopping, dose level -1 is not found unsafe, and no failure of manufacturing the required doses, the 
study will enroll a maximum sample size of 28 evaluable ALL subjects treated at the established 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
dose.  If 18 or more respond at Day 28 out of the total 28 evaluable subjects, the therapy will be 
declared sufficiently active for efficacy and worthy of further investigation.  With 28 evaluable 
patients, the Minimax Simon two-stage design has 80% power at a 10% significance level to test 
the null hypothesis that the ORR  50%, assuming a target ORR of 70%. 
12.3 PROTOCOL STOPPING RULES 
To summarize, the study will be halted pending discussions with the FDA, IRB and APB if any of 
the following conditions are met: 
• DLT stopping rule for a maximum acceptable DLT rate of 30% triggered at Dose Level -1 
for either disease group cohort (ALL or aggressive B-cell NHL). 
• Development of EBV lymphoma or polyclonal lymphoproliferative disease (PLPD) in any 
subject. 
• Any Grade 5 event at least possibly related to the research regimen. 
• If the targeted number of cells cannot be produced in at least 3 of the first 6 subjects with 
aggressive B-cell NHL or at least 5 of the first 10 patients with ALL on this trial, further 
enrollment will be paused pending evaluation of the manufacturing process regardless of 
the safety evaluation. 
• If more than 10 aggressive B-cell NHL subjects (max 4 during dose-escalation) or more 
than 6 ALL subjects need to be replaced for the safety evaluation due to inability to achieve 
the target cell product, further enrollment to that disease population will stop. 
• If 7 or fewer subjects out of the first 15 evaluable ALL subjects have a response (CR) at 
Day 28, accrual will stop after evaluation of the safety objectives. Similarly if 4 or fewer 
subjects out of the first 17 evaluable aggressive B-cell NHL subjects treated at MTD/RP2D 
have a response (CR or PR) at Month 3, accrual will stop after evaluation of the safety 
objectives. 
12.4 SAMPLE SIZE 
12.4.1 Accrual estimates 
Given the number of subjects seeking out adoptive cell therapy trials the rate limiting factor at this 
time is the time and labor intensive nature of manufacturing the CD22-CAR T cells.  We anticipate 
enrollment of 1-2 subjects per month per each disease group, given the number of subjects with 
B-ALL and aggressive B-cell NHL treated in Stanford Cancer Therapy Clinics.  The recruitment 
period for this study is expected to be 2-3.5 years.  Subjects will be followed for a total of 15 years 
post treatment.  The total duration of this study is expected to be 7-8.5 years of active treatment 
and short term follow up, and a total of 15 years of long term follow up after the last subject 
completes study therapy. 
12.4.2 Sample size justification 
The primary objectives of this study are safety and feasibility.  The ‘3+3’ design will be used for 
dose-escalation in R/R aggressive B-cell NHL subjects across three possible dose levels of 
CD22-CAR T-cells under investigation.  We will perform an interim analysis for feasibility after 
the 6 subjects and will continue to enroll if 3 or more subjects are successful in feasibility of 
manufacturing cells.  A minimum of 9 subjects and maximum of 22 subjects (max of 18 evaluable 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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from dose-escalation and max of 4 additional from feasibility) may be required to establish the 
MTD/RP2D for R/R aggressive B-cell NHL subjects. After the MTD/RP2D is established in this 
disease population, the trial will expand to enroll a dose-expansion cohort at the established dose 
to monitor safety and indicate efficacy.  The dose-expansion cohort will have three interim 
evaluation time points for safety and one interim evaluation for futility.  The first interim analysis 
will evaluate both safety and futility after 17 evaluable subjects have been treated at the established 
MTD/RP2D (including subjects from both dose-escalation and dose-expansion).  If 5 or more 
subjects respond (CR or PR) at 3 months and 8 or fewer subjects experience a DLT, the trial will 
continue to enroll and evaluate safety after 23 and 28 evaluable subjects have been treated at the 
established dose level.  To indicate efficacy, a Minimax Simon two-stage design was used to 
motivate the maximum sample size for the dose-expansion cohort.  With a total of 36 evaluable 
subjects (using both dose-escalation and dose-expansion cohorts treated at established dose), the 
Minimax Simon two-stage design has 80% power at a 5% significance level to test the null 
hypothesis that the ORR  25%, assuming a target ORR of 45%, where ORR is measured by CR 
or PR.  The study has a feasibility goal of 80% and will allow for an additional 10 subjects to be 
replaced for safety and efficacy evaluations due to inability to achieve the target cell product (max 
of 4 subjects during dose-escalation).  For relapsed/refractory aggressive B-cell NHL subjects, 
a maximum of 18+10+33 = 61 patients may be required to establish safety and feasibility, 
and indicate sufficient efficacy.  
Simultaneously, a minimum of 10 patients with relapse/refractory ALL may be enrolled at the 
established dose (1 x 106 transduced T cells/kg ± 20%).  We will perform an interim analysis for 
feasibility after first 10 patients and will continue to enroll if 5 or more patients are successful in 
feasibility of manufacturing cells.  We will perform a safety evaluation for possible dose de-
escalation after 10 evaluable patients have been observed for the 28 day DLT assessment period, 
and additional safety evaluations every 5 patients thereafter.  After 15 evaluable patients have been 
observed, we will perform safety and futility evaluations.  If 8 or more patients respond (CR only) 
and 7 or fewer patients experience a DLT at 28 days, the trial will continue at the established dose. 
With a total of 28 evaluable patients, the Minimax Simon two-stage design has 80% power at a 
10% significance level to test the null hypothesis that the ORR  50%, assuming a target ORR of 
70%, where ORR is measured by CR only.  The study has a feasibility goal of 80% and will allow 
for an additional 6 relapse/refractory ALL patients to be replaced for safety and efficacy 
evaluations due to inability to achieve the target cell product.  For relapse/refractory ALL 
patients, a maximum of 28+6= 34 patients may be required to establish safety and feasibility, 
and indicate sufficient efficacy.  
Table 9. Enrollment Table by Objective 
Objective 
Subjects with Aggressive 
B-cell NHL 
Subjects with ALL 
Manufacturing Feasibility 
Evaluated in first 6 subjects 
Evaluated in first 10 subjects 
Safety – Preliminary (MTD) 
Up to 18 (6 + 6 +6) subjects 
10 evaluable subjects 
Safety – Secondary (Dose Expansion) 
After 17 evaluable subjects 
at MTD/RP2D, 
 then every 5 subjects 
After 15 evaluable subjects 
at target dose, 
 then every 5 subjects 
Efficacy – Preliminary Futility 
17 evaluable subjects at 
MTD/RP2D 
15 evaluable subjects at 
target dose 
Efficacy – Full Analysis 
Up to 36 evaluable subjects 
Up to 28 evaluable subjects 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) 
gene; following lymphodepleting chemotherapy 
 
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at MTD/RP2D 
at target dose 
Number of Replacements allowed 
Up to 10 
Up to 6 
Total number of subjects 
18 + 33 + 10 = 61 
10 + 18+ 6 = 34 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
111 of 150 
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13 APPENDICES 
13.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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13.2 APPENDIX B:  GUIDELINES TOXICITY ASSESSMENT AND MANAGEMENT 
13.2.1 Guidelines for Grading Suspected Cytokine Release Syndrome according to ASBMT CRS 
Consensus Grading# 
CRS 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever† 
Temperature ≥ 38° C 
Temperature ≥ 38° C 
Temperature ≥ 38° C 
Temperature ≥ 38° C 
With either: 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring one 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors (excluding 
vasopressin) 
And/or§: 
Hypoxia 
None 
Requiring low-flow 
nasal cannula^ or blow-
by 
Requiring high-flow 
nasal cannula, 
facemask, non-
rebreather mask, or 
Venturi mask 
Requiring positive 
pressure (e.g.: CPAP, 
BiPAP, intubation and 
mechanical ventilation 
CPAP: Continuous positive airway pressure; BiPAP: Bilevel positive airway pressure 
# Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS 
grading. 
†  Fever is defined as temperature ≥ 38° C not attributable to any other cause. In patients who have CRS then receive 
anti-pyretics or anti-cytokine therapy such as tocilizumab,  steroids or anakinra, fever is no longer required to grade 
subsequent CRS severity.  In this case, CRS grading is driven by hypotension and/or hypoxia. 
§ CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with a temperature of 39.5 ° C, hypotension requiring one vasopressor and hypoxia requiring low-
flow nasal cannula is classified as having Grade 3 CRS. 
^ Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 liters/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics.  High-flow nasal cannula is defined as oxygen delivered at > 6 liters/minute. 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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13.2.2 Guidelines for Managing Suspected Cytokine Release Syndrome 
Grade 1 
Temperature > 38°C 
WITH 
no 
hypotension 
AND/OR 
no 
hypoxia 
Symptoms are not life threatening and require symptomatic treatment only  
Treatment:   
➢ Supportive Care 
➢ VS Q4-6 hr (incl orthostatic BP) and prn, monitor for progression 
➢ Assess for infection, pan-culture with CSR, treat febrile neutropenia if present 
➢ Acetaminophen, NSAIDS and cooling blanket PRN  
Grade 2 
Temperature > 38°C 
WITH hypotension 
not 
requiring 
pressors 
AND/OR 
requires 
nasal 
cannula oxygen to 
maintain SpO2 > 
92% 
Symptoms require and respond to moderate intervention   
Treatment:   
➢ Notify ICU if not improving 
First ONSET only : 
➢ Tocilizumab 8 mg/kg IV X 1 
➢ Dexamethasone 10 mg IV X 1 
➢ If orthostatic, give bolus and reassess. 
➢ If ongoing orthostatic or re-occurs > 24 hrs, treat as grade 2 
Grade 2 recurrent (recurs after > 24 hrs of toci) or refractory /ongoing (not responding > 24 hrs) : 
✓ Anakinra 100 mg SQ q6h X 3 days 
✓ Dexamethasone 10 mg IV q6h 
✓ Taper dex when ≤ gr 1. 
✓ Monitor organ function closely (incl. cardiac, respiratory, renal, neurologic, liver) : VS q2-
4h and prn, telemetry and continuous O2, anticipate transfer if worsening symptoms. 
➢ Be vigilant for HLH, trend DIC screen and ferritin 
Grade 3 
Temperature > 38°C 
WITH hypotension 
requiring 1 pressor 
+/- 
vasopressin 
AND/OR 
requires 
facemask or high-
flow 
oxygen 
to 
maintain SpO2 > 
92% 
Symptoms require and respond to aggressive intervention  
Treatment:   
➢ Transfer to ICU 
➢ Tocilizumab 8 mg/kg IV X 1 (even if given previously) 
➢ Anakinra 100 mg SQ q6h X 3 days 
➢ Dexamethasone 10 mg/IV q6h 
➢ Manage hypotension and hypoxia with ICU support 
 
➢ Be vigilant for HLH, trend DIC screen and ferritin 
Grade 4 
Temperature > 38°C 
WITH hypotension 
requiring > 1 pressor 
(not 
including 
vasopressin) 
AND/OR 
requires 
intubation or NIPPV 
Life-threatening symptoms 
Treatment:  ABC’s, stabilize, transfer or treat in ICU 
➢ Tocilizumab 8 mg/kg IV X 1 (even if given previously) 
➢ Anakinra 100 mg SQ q6h X 3 days 
➢ Solumedrol X 3 days then taper 
➢ Manage hypotension and hypoxia with ICU support 
 
➢ Be vigilant for HLH, trend DIC screen and ferritin 
 
 
 
 
   
 
Echocardiogram as needed 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
114 of 150 
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13.2.3 Encephalopathy assessment tools for grading Immune effector Cell-Associated Neurotoxicity 
Syndrome (ICANS) 
13.2.3.1 Immune Effector Cell-associated Encephalopathy (ICE) Assessment 
Directions: Answer whether each task was performed correctly (Not Done/Yes/No).  If you answer YES 
put 1 in the Score column; If you answer NO (or Not Done) put 0 in the Score column. 
 
Tasks 
Performed 
correctly? 
Score 
Orientation 
 
 
1. What is the current year? 
 
0 
2. What is the current month? 
 
0 
3. What is the current city? 
 
0 
4. What hospital are you in? 
 
0 
Naming 
 
 
5. Name this object (point to an object in the room) 
 
0 
6. Name this object (point to an object in the room) 
 
0 
7. Name this object (point to an object in the room) 
 
0 
Following commands 
 
 
8. Show me (insert object, e.g. 2 fingers) or Close your eyes and 
stick out your tongue. 
 
0 
Writing 
 
 
9. Write a simple sentence (provide paper and pencil) 
 
0 
Attention 
 
 
10. Count backwards from 100 in 10's. 
 
0 
Total Score 
 
 
  
 
Scoring ICE 
No impairment: Score 10 
Grade 1 ICANS: Score 7-9 
Grade 2 ICANS: Score 3-6 
Grade 3 ICANS: Score 0-2 
Grade 4 ICANS: Score 0 due to subject unarousable and  unable to perform ICE assessment. 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
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13.2.3.2 ASBMT Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) Consensus Grading for Adults 
Neurotoxicity 
Domain 
Grade 1 
 (Some or all of the following: 
spontaneous awakening, mild 
confusion, word-finding 
difficulty, +/- new tremor, no 
clinical seizures) 
Grade 2 
(Some or all of the following: 
awakening to voice, moderate 
confusion, expressive aphasia, 
perseveration, no clinical 
seizures) 
Grade 3 
(Some or all of the following: 
awakening to tactile stimulus, 
global aphasia, myoclonus, clinical 
seizure, brief electrographic 
seizures) 
Grade 4 
(Some or all of the following: 
coma/posturing, focal weakness, status 
epilepticus, pupillary/CN abnormalities, 
diffuse cerebral edema) 
ICE Score^ 
7-9 
3-6 
0-2 
0 (unarousable, unable to perform ICE) 
Depressed level of 
consciousness⁑ 
Awakens spontaneously 
Awakens to voice 
Awakens only to tactile stimulus 
Patient is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse.  Stupor or 
coma 
Seizure 
N/A 
N/A 
Any clinical seizure focal or 
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 findings§ 
N/A 
N/A 
N/A 
Deep focal motor weakness such as 
hemiparesis or paraparesis 
Raised ICP / 
Cerebral edema 
N/A 
N/A 
Focal/local edema on neuroimaging# 
Diffuse cerebral edema on neuroimaging; 
Decerebrate or decorticate posturing; or  
Cranial nerve VI palsy; or 
Papilledema; or  
Cushing’s triad 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) not attributable to any 
other cause.  For example, a patient with and ICE score of 3 who has a generalized seizure is classified as having a Grade 3 ICANS. 
^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 a 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 hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading.  It may be graded 
according to CTCAE v5.0. 
ICE: Immune effector Cell-associated Encephalopathy; ICP: Intracranial pressure; EEG: electroencephalogram 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
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13.2.3.3 Neurologic Recommended Treatments by Grade 
Neurotoxicity Grade 
Grade 1 
 (Some or all of the following: 
spontaneous awakening, mild 
confusion, word-finding 
difficulty, +/- new tremor, no 
clinical seizures) 
Grade 2 
(Some or all of the following: 
awakening to voice, moderate 
confusion, expressive aphasia, 
perseveration, no clinical 
seizures) 
Grade 3 
(Some or all of the following: 
awakening to tactile stimulus, 
global aphasia, myoclonus, clinical 
seizure, brief electrographic 
seizures) 
Grade 4 
(Some or all of the following: 
coma/posturing, focal weakness, status 
epilepticus, pupillary/CN abnormalities, 
diffuse cerebral edema) 
Recommended 
Interventions by 
Grade 
Neuro chks q4h, with ICE q12 or 
as clinically indicated.  Cont 
Keppra 500 mg BID, reconcile 
meds to identify contributors  
Consult Neurology, neuro chks 
q2h X 6 hrs, then q4h if stable, 
telemetry and continuous O2, CT 
of the head, consider EEG, 
Consider incr Keppra to 1000 mg 
BID, tocilizumab 8 mg/kg if 
concurrent CRS and no prior toci.  
 
Notify Neuro consult, discuss 
imaging with neurology, neuro chks 
q2h X 12-24 hours, Discuss with 
MICU. ICE score q 4 X 12-24 hrs. 
telemetry and continuous O2 
consider empiric increase in AED, 
Consider possibility of diffuse 
cerebral edema, continue Keppra 
1000 mg BID, add Vimpat 100 mg 
BID, Dexamethasone 10 mg IV 
q6h, Tocilizumab per CRS pathway, 
not to exceed 3 doses in 24 hrs. 
ABC’s, stabilize patient, transfer to MICU, 
emergent CT head when stabilized, neuro 
chks q1h with ICE scores and pupillometry, 
Adjust antiepileptic drugs based on EEG and 
discussion with NCC, Methylprednisolone 
1g IV daily; reassess daily, taper when able • 
Tocilizumab per CRS pathway, not to exceed 
3 doses in 24 hours, Consider Anakinra 
100mg SQ every 6 hrs x 3 days 
 
. 
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
117 of 150 
Amd 3, Version 2022-0722 
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
118 of 150 
Amd 3, Version 2022-0722 
 
13.3 APPENDIX C:   RESPONSE CRITERIA 
13.3.1 Response Criteria for ALL 
13.3.1.1 Introduction  
This document provides the working definitions and specifications for a consistent and efficient 
analysis of efficacy, assessing clinical activity in acute lymphoblastic leukemia (ALL). The current 
document is written primarily for the relapse and refractory disease setting. Modifications may be 
indicated for earlier disease settings. This document is based on the standardized response criteria 
defined by National Comprehensive Cancer Network (NCCN) Guidelines (NCCN 2013 v1) and further 
supported by the workshop report on acute leukemia from American Society of Hematology 
(ASH)[122] (Appelbaum et al 2007) and the International Working Group (IWG) guideline for acute 
myeloid leukemia (AML)[123] (Cheson et al 2003). The Cheson IWG guideline and Appelbaum ASH 
report were used in recent drug approvals (e.g. Marqibo) in ALL, prior to the NCCN guideline 
availability. The NCCN guidance is a more recently published United States based guideline for ALL.  
The objectives of this document are to:  
• Ensure that the definitions of responses in the clinical study protocol correctly reflect the above 
mentioned guidelines.  
• Provide guidance for the response assessment and clinical monitoring to ensure consistency in 
applying the guidelines.  
13.3.1.2 Types of Efficacy Assessments 
Disease characterization at baseline and evaluation of response rely on the following:  
• Bone marrow assessment  
•  Peripheral blood assessment  
• Extramedullary disease assessment, including  
o CNS disease  
o Other extramedullary sites  
• Minimal residual disease (MRD) assessment of bone marrow 
Response Criteria 
Response Category 
Definition 
Complete 
remission 
(CR) 
All the following criteria are met: 
Bone Marrow 
• 
< 5% blasts 
Peripheral Blood  
• 
Neutrophils > 1.0 X 106/L, and 
• 
Platelets > 100 X 106/L, and 
• 
Circulating blasts < 1% 
Extramedullary disease 
• 
No clinical evidence of extramedullary disease (by physical exam and CNS symptom 
assessment), and 
• 
If additional assessments (e.g. CSF assessment by LP, CNS imaging, bipsy, etc.) are 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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performed, results must show remission status. 
Transfusion independency 
• 
No platelet and/or neutrophil transfusions less than or equal to 7 days before the date 
of the peripheral blood sample for disease assessment. 
Complete 
remission 
with incomplete blood 
count recovery (CRi) 
All criteria for CR as defined above are met, except that the following exist: 
• 
Neutrophils > 1.0 X 106/L, and/or 
• 
Platelets > 100 X 106/L, and/or 
• 
Platelet and/or neutrophil transfusions less than or equal to 7 days before the date of 
the peripheral blood sample for disease assessment. 
No response 
Failure to attain the criteria needed for any response categories or relapse 
Relapsed Disease 
Only in patients who achieved a CR or Cri and who have:  
• 
Reappearance of blasts in the blood (> 1%), or 
• 
Reappearance of blasts in the bone marrow (> 5%), or 
• 
(Re-) appearance of any extramedullary disease after CR or CRi 
Unknown 
“Unknown” is assigned in case the baseline assessment or the response assessment is not 
done, incomplete, indeterminate, or not performed within the respective time frame.  If there 
is evidence of relapse, the overall response will be assessed as “relapsed disease” with the 
relapsed component alone. 
In order for the best overall disease response to be categorized as CR or CRi, there must be no clinical 
evidence of relapse as assessed by peripheral blood and extramedullary disease assessment (physical exam 
and CNS symptom assessment) at a minimum of 4 weeks (28 days) after the initial achievement of CR or 
CRi. Please note, if additional assessments (e.g. bone marrow, CSF assessment by LP, CNS imaging, 
biopsy, etc.) are performed in the same evaluation for disease response evaluation purposes, they will also 
need to show remission status. 
 
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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13.3.2 Response Criteria for Lymphoma 
Response Criteria Lymphoma (From: Cheson BD, et al : Recommendations for Initial Evaluation, Staging, 
and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.  J Clin 
Oncol 2014 ; 32 :3059-3067) 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
121 of 150 
Amd 3, Version 2022-0722 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
13.4 APPENDIX D: MONITORING GENE THERAPY TRIALS: REPLICATION COMPETENT LENTIVIRUS 
(RCL) 
Subject Testing for RCL PCR 
Subject blood samples will be obtained at the following time points: 
1. Prior to cell infusion 
2. 3 months(± 1 month) 
3. 6 months (± 1 month) 
4. 12 months (±2 months) 
All Samples are scheduled from the most recent cell infusion, and should proceed even after disease 
progression. If any post-treatment samples are positive, further RCL testing and subject work-up 
should be undertaken. 
Procedures: 
Samples will be collected from subjects returning to clinic or, at investigator discretion, may be 
collected by a local medical provider.  Samples will be shipped directly to Indiana University GTTL, 
as described in Stanford Center for Cancer Cell Therapy SOP ‘Remote RCR/RCL Collection’.  
Procedures in brief include: 
1. 4 mL blood sample collected in EDTA tube (lavender/purple top).  If necessary, sample may 
be collected as 2 x 2 mL EDTA tubes. 
2. Sample will be packaged according to biohazardous shipping regulation (UN 3373, 
‘Diagnostic Specimens’) and shipped on ice priority overnight to Indiana University GTTL. 
Attn: Lisa Duffy 
IU GTTL 
980 West Walnut St, R3-C668 
Indianapolis, IN 46202-5188 
Phone: 317-274-0323 
a. ‘NGVB Sample Submission Form’ and ‘Sample Submission Form Master 
Agreements’ must accompany sample for proper processing 
b. Sample shipment must occur Monday-Thursday, as IU GTTL is unable to accept 
samples over the weekend or holidays 
3. Notify IU GTTL representatives by email when sample delivery is expected. 
Document Retention 
1. RCL Reports from Indiana University will be sent to the Sponsor Investigator or designated 
representative; who will distribute the results.  Groups requesting RCL results notification 
include: 
a.  Principal Investigator and co-investigators 
b. IND Sponsor, or delegated representative 
c. CCT-Clinical Research Operations & Procedures (CCT-CROP) [regulatory support] 
d. CCT Manufacturing team 
2. Hard copies will be retained in the subject’s research record or other suitable study file in a 
locked file cabinet. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
13.5 APPENDIX E:  DRAFT LETTER AND QUESTIONNAIRE TO SUBJECTS FOR LONG TERM 
FOLLOW-UP FOR DELAYED ADVERSE EVENTS  
[date] 
[name and address] 
Dear [subject name], 
You have participated in a clinical research study that requires that the study doctors and nurses 
monitor your health for 15 years.  In addition to the annual visits you will be attending, we would like 
for you to report certain events listed below to your study doctor or nurse if they occur: 
1. Your doctor tells you that you have been diagnosed with any new type of cancer, including blood 
disorders such as leukemia or lymphoma (this would be separate from your cancer diagnosis). 
2. You develop loss of feeling in any part of your body, especially hands and feet; you develop a 
loss of control of any body part (arms, legs…); you have a seizure; you experience memory loss.  
In addition, if you experience a worsening of any of the symptoms listed, please contact your 
study nurse or doctor.  These types of symptoms are called neurological disorders.  If your 
primary doctor or specialist tells you that you have developed neurological symptoms, contact 
your study doctor or nurse. 
3. You develop arthritis or autoimmune disease, or worsening of any previously experienced 
arthritis or autoimmune disease which you were experiencing prior to participation in the study.  
If you are experiencing symptoms of arthritis or have been told by your doctor that you have an 
autoimmune disease, contact your study doctor or nurse. 
Please complete the attached questionnaire and return it in the Fed-Ex envelope to the study 
coordinator. 
If you experience any of the events listed above during the upcoming year, please contact your 
study physician or the study nurse listed below as soon as you can.  They may ask you questions 
about your health and will record your symptoms/disease and then monitor your health if they decide 
that it is necessary.  When you call, please mention that you participated in a gene therapy clinical trial 
at the < put your institution here> .  Your subject identification number under this protocol is (#XXX). 
Study Coordinator:  
 
 
 
 
Name  
 
 
 
Address 
 
 
 
 
Phone 
Email 
If you have any questions about this letter or the follow up procedures for the study itself, please do 
not hesitate to contact the above study nurse. 
Thank you for your continued participation in our clinical research study.  Best regards, 
[study coordinator]  

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
Questionnaire to Subjects for Long Term Follow-up for Delayed Adverse Events 
Subject Identification [put subject study number here] 
Within the past year, have you: 
1. Had any problems with your health?  
 
 
YES    
 
NO 
If Yes, please explain:    
 
2. Required any hospitalizations? 
  
 
 
YES    
 
NO 
If Yes, please describe when and the reason:    
 
 
3. Seen any healthcare provider? 
  
 
 
YES    
 
NO 
If Yes, please describe when and the reason:    
 
 
4. Started on any new medications?   
 
 
YES    
 
NO 
If Yes, please list:    
 
5. Developed any new conditions or illnesses?  
 
YES    
 
NO 
If Yes, please describe:    
 
Please share any other new health concerns or problems: 
 
 
When you have completed this questionnaire, please return it to: 
Study Coordinator:  
 
 
 
 
Name  
 
 
 
Address 
 
 
 
 
Phone 
Fax 
Email 
A pre-addressed stamped envelope has been enclosed for your convenience, if you choose to mail this 
questionnaire.  We will also accept faxed or e-mailed completed questionnaires as well. 
Thank you very much for your participation. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
13.6 APPENDIX F:  PHYSICIAN (LOCAL MEDICAL PROVIDER) LETTER 
 [date] 
[name and address] 
Dear [physician name], 
Your subject [subject name] has participated in a clinical research study that requires 15 year 
monitoring for adverse events.  To aid in reporting adverse events that are possible related to the 
clinical research study, we are asking the subjects on our research study to designate a primary care or 
infectious disease physician that may help in the monitoring and reporting of adverse events.  Your 
subject has designated you.  If upon any of your visits with your subject, any of the following 
events are reported or discovered, please contact the study nurse or physician as soon as 
possible:  
1. New malignancies 
2. New incidence of exacerbation of a pre-existing neurologic disorder 
3. New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder 
4. New incidence of a hematologic disorder. 
If your subject experiences any of these events, please contact the study coordinator below as 
soon as you can so that they can record the event and then monitor your subject’s health if necessary.  
When you call, please mention that the subject has participated in a gene therapy clinical trial in the 
< designate location, institution and sponsor investigator> . 
Study Coordinator   
 
 
 
Name  
 
 
 
 
 
Address 
Phone  
 
 
 
 
  
Email  
 
 
 
 
  
 
If you have any questions about this letter or the study itself, please do not hesitate to contact the above 
study nurse. 
Thank you for your support in helping us to monitor for delayed adverse events.  Best regards, 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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13.7 APPENDIX G: CORRELATIVE SAMPLE SCHEDULE 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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13.8 APPENDIX H: ENROLLMENT 
USING TWO STAGES: 1) LEUKAPHERESIS 
AND 2) 
LYMPHODEPLETION CHEMOTHERAPY AND CELL INFUSION 
If patient or manufacturing scheduling requires, consenting and screening may be completed in two 
stages: 1) for leukapheresis, and 2) for lymphodepleting chemotherapy and CD22-CAR T cell 
infusion, as outlined with the following checklists. In addition the screening evaluations and Study 
Calendar are outlined using this two stage sequence for clarity.  All other applicable aspects of the 
clinical protocol apply to all patients. 
13.8.1 Screening Participant Eligibility Checklist: Two Stages for Screening/Enrollment 
I. 
Screening and Enrollment for Leukapheresis 
Protocol Title: 
Phase I/Ib Clinical Trial of Autologous CD22 Chimeric Antigen Receptor (CAR) 
T cells in Adults with Recurrent or Refractory B Cell Malignancies 
Protocol Number: 
CCT5029 / IRB-50836 
Protocol Director: 
Matthew Frank, M.D., Ph.D. 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV.  Inclusion/Exclusion Criteria for Stage 1: Leukapheresis 
INCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
1. Disease Status 
a. Disease Status of ALL 
• 
Must have chemotherapy refractory disease defined as 
progression or stable disease after a standard line of therapy, 
or relapsed disease after achieving CR. 
• 
Subjects with persistent or relapsed minimal residual 
disease (MRD) (by flow cytometry, PCR, FISH, or next 
generation sequencing) require verification of MRD on two 
occasions at least 2 weeks apart. 
• 
Subjects with Philadelphia Chromosome positive acute 
lymphoblastic leukemia (Ph+ALL) are eligible if they 
progressed after receiving a tyrosine kinase inhibitor (TKIs). 
• 
Subjects with recurrence of isolated CNS relapse after 
achieving complete remission (CR) are eligible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 NA 
      
 
 
 
 
 
 
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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INCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
b. Disease Status of aggressive B-cell NHL 
• 
Histologically confirmed aggressive B cell NHL including 
the following types defined by WHO 2008:  
o DLBCL not otherwise specified; T cell/histiocyte rich large B 
cell lymphoma; DLBCL associated with chronic 
inflammation; Epstein-Barr virus (EBV)+ DLBCL of the 
elderly; OR  
o primary mediastinal (thymic) large B cell lymphoma; OR 
transformation of follicular lymphoma, marginal zone 
lymphoma or chronic lymphocytic leukemia/small 
lymphocytic lymphoma to DLBCL  
o Follicular Lymphoma Grade 3B 
o Subjects with DLBCL , Follicular Lymphoma Grade 3B –or–   
Subjects with transformed FL, MZL, or CLL/SLL who 
HAVE NOT received chemotherapy prior to transformation:  
Must have received an anthracycline regimen and an 
anti-CD20 monoclonal antibody (unless documented CD20-
negative) and be refractory or relapsed after second line of 
DLBCL treatment.  Subjects with a partial response to second 
line therapy must be ineligible for autologous transplant.   
o Subjects with transformed FL, MZL, or CLL/SLL who 
HAVE received anthracycline-containing chemotherapy prior 
to transformation:  
Must have progressed, had SD or recurred with transformed 
disease after initial treatment for DLBCL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 NA 
      
 
2. CD22 expression  
• 
Subjects with ALL: CD22 positive expression on malignant 
cells is required and must be detected by 
immunohistochemistry or flow cytometry.  The choice of 
whether to use flow cytometry or immunohistochemistry will 
be determined by what is the most easily available tissue 
sample in each subject.   
CD22 expression must be demonstrated subsequent to any 
anti-CD22 targeted therapy (e.g. Moxetumomab pasudotox or 
inotuzumab ogozamicin) in subjects with ALL. 
• 
Subjects with aggressive B-cell NHL:  CD22 expression at any 
level, including undetectable, will be acceptable.  Subjects 
must have archival tissue available for analysis of CD22 
expression or must be willing to undergo a biopsy of easily 
accessible disease.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
      
3. Prior Bone Marrow-Stem Cell Transplant  
Subjects who have undergone autologous SCT with disease 
progression or relapse following SCT are eligible.  Subjects who 
have undergone allogeneic SCT will be eligible if, in addition to 
meeting other eligibility criteria, they have no evidence of GVHD 
 
 
      

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
INCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
and have been without immunosuppressive agents for at least 30 
days. 
4. Prior Therapy Wash-out 
At least 2 weeks or 5 half-lives, whichever is shorter, must have 
elapsed since any prior systemic therapy at the time the subject is 
planned for leukapheresis, except for systemic 
inhibitory/stimulatory immune checkpoint therapy, which 
requires 5 half-lives.   
Exceptions: 
a. There is no time restriction with regard to prior intrathecal 
chemotherapy provided there is complete recovery from any 
acute toxic effects of such; 
b. Subjects receiving hydroxyurea may be enrolled provided 
there has been no increase in dose for at least 2 weeks prior to 
starting apheresis; 
c. Subjects who are on standard ALL maintenance type 
chemotherapy (vincristine, 6-mercaptopurine or oral 
methotrexate) may be enrolled provided that chemotherapy is 
discontinued at least 1 week or 5 half-lives, whichever is 
shorter, prior to apheresis. 
d. Subjects receiving steroid therapy at physiologic replacement 
doses only are allowed provided there has been no increase in 
dose for at least 2 weeks prior to starting apheresis. 
e. For radiation therapy: Radiation therapy must have been 
completed at least 3 weeks prior to enrollment for apheresis, 
with the exception that there is no time restriction if the 
volume of bone marrow treated is less than 10% and also the 
subject has measurable/evaluable disease outside the radiation 
port or the site of radiation has documented progression. 
 
 
      
5. Prior CAR Therapy 
Subjects who have undergone prior CAR therapy will be eligible if 
< 5% of circulating levels of CD3+ cells express the previous CAR 
if a qualified assay exists; 30 days must have elapsed post CAR 
infusion prior to apheresis. 
 
 
      
6. Age greater than or equal to 18 years of age  
 
 
      
7. Eastern cooperative oncology group (ECOG) performance status 
of 0, 1, or 2; or Karnofsky ≥ 60% (See section 13.1, Appendix 
A)  
 
 
      
8. Normal Organ and Marrow Function (supportive care is allowed 
per institutional standards, i.e. filgrastim, transfusion) 
• 
ANC ≥ 750/uL*  
• 
Platelet count ≥ 50,000/uL*  
• 
Absolute lymphocyte count (ALC) ≥ 150/uL*  
 
ANC 
Platelet 
ALC 
 
      
      
      
      

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
INCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
Adequate renal and hepatic function defined as:  
• 
Creatinine ≤ 2 mg/dL OR creatinine clearance (as estimated 
by Cockcroft Gault Equation) ≥ 60 mL/min  
• 
Serum ALT/AST ≤ 10x Upper limit of normal (ULN)  
(Elevated ALT/AST related to leukemia involvement of the liver 
will not disqualify a subject).   
• 
Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert’s 
syndrome.   
* ALL subjects will not be excluded because of pancytopenia ≥ Grade 3 if it 
is felt by the investigator to be due to underlying leukemia. 
 
 
Creatinine 
AST/ALT 
 
Bilirubin 
 
 
 
      
               
      
 
 
9. CNS Status  
Subjects with CNS involvement are eligible as long as there are no 
overt signs or symptoms that in the evaluation of the investigator 
would mask or interfere with the neurological assessment of 
toxicity.   
 
 
      
10. Females of childbearing potential must have a negative serum or 
urine pregnancy test within 7 days prior to leukapheresis (females 
who have undergone surgical sterilization or who have been 
postmenopausal for at least 2 years are not considered to be of 
childbearing potential) 
 
 
      
11. Ability to give informed consent.   
Must be able to give informed consent.  Legal authorized 
representative (LAR) is permitted if subject is cognitively able to 
provide verbal assent. 
 
 
      
Subjects meeting any of the following criteria are not eligible for participation in Stage 1 
(Leukapheresis) of the study: 
EXCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
1. Recurrent or refractory ALL limited to isolated testicular disease. 
 
 
      
2. History of other malignancy, unless disease free for at least 3 
years.  At the discretion of the Principal Investigator, subjects in 
remission for 1-2 years prior to enrollment may be deemed 
eligible after considering the nature of other malignancy, 
likelihood of recurrence during one year following CAR therapy, 
and impact of prior treatment on risk of CD22-CAR T cells. 
Subjects in remission <1 year are not eligible. 
• 
Exception: Nonmelanoma skin cancer or carcinoma in 
situ (e.g. cervix, bladder, breast) is eligible. 
 
 
      

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
EXCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
• 
Hormonal therapy in subjects in remission > 1 year will 
be allowed. 
3. Presence of active fungal, bacterial, viral, or other infection that 
is uncontrolled requiring intravenous antimicrobials.  Simple UTI 
and uncomplicated bacterial pharyngitis are permitted if 
responding to active treatment.   
 
 
 
 
      
 
4. Current knowledge of infection with: 
• 
HIV, 
• 
Hepatitis B (HBsAg positive) or  
• 
Hepatitis C virus (anti-HCV positive).   
A history of hepatitis B or hepatitis C is permitted if the viral load 
is undetectable per quantitative PCR and/or nucleic acid testing. 
 
 
 
      
 
5. CNS disorder such as cerebrovascular ischemia/hemorrhage, 
dementia, cerebellar disease, or any autoimmune disease with 
CNS involvement that in the judgment of the investigator may 
impair the ability to evaluate neurotoxicity. 
 
 
      
6. History of myocardial infarction, cardiac angioplasty or stenting, 
unstable angina, or other clinically significant cardiac disease 
within 12 months of enrollment. 
 
 
      
7. History of severe immediate hypersensitivity reaction to any of 
the agents used in this study. 
 
 
      
8. Women who are pregnant or breastfeeding.   
 
 
      
9. In the investigator’s judgment, the subject is unlikely to complete 
all protocol-required study visits or procedures, including 
follow-up visits, or comply with the study requirements for 
participation.  
 
 
      
10. Primary immunodeficiency or history of autoimmune disease 
(e.g. Crohns, rheumatoid arthritis, systemic lupus) requiring 
systemic immunosuppression/systemic disease modifying agents 
within the last 2 years. 
 
 
      
†All subject files must include supporting documentation to confirm subject eligibility.  The method of confirmation 
can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record 
review.   
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in Stage 1: Leukapheresis on the study.  This study is approved by the Stanford Cancer 
Institute Scientific Review Committee, the Stanford IRB, and has finalized financial and contractual 
agreements as required by Stanford School of Medicine’s Research Management Group.   

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
132 of 150 
Amd 3, Version 2022-0722 
Treating Physician Signature: 
Date: 
Printed Name: 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
Study Coordinator Signature: 
Date: 
Printed Name: 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
I. 
Screening and Enrollment for Lymphodepleting Chemotherapy and CD22-CAR T cell 
infusion 
Protocol Title: 
Phase I/Ib Clinical Trial of Autologous CD22 Chimeric Antigen Receptor 
(CAR) T cells in Adults with Recurrent or Refractory B Cell Malignancies 
Protocol Number: 
CCT5029 / IRB-50836 
Protocol Director: 
Matthew Frank, MD, PhD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
 
IV. Inclusion/Exclusion Criteria for Stage 2: Lymphodepleting Chemotherapy and CD22-CAR 
T cell infusion 
INCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
1. Measurable Disease 
• 
Subjects with ALL: must have evaluable or measurable 
disease (MRD positive by flow cytometry, NGS, or PCR 
is acceptable). 
• 
Subjects with aggressive B-cell NHL: must have 
evaluable or measurable disease according to the revised 
IWG Response Criteria for Malignant Lymphoma[38].  
Lesions that have been previously irradiated will be 
considered measurable only if progression has been 
documented following completion of radiation therapy. 
 
 
 
 
 
 
      
 
      
2. Toxicities due to prior therapy must be stable or resolved 
(except for clinically non-significant toxicities such as 
alopecia or cytopenias) 
 
 
      
• 
 
Adequate renal, hepatic, pulmonary and cardiac function 
defined as:  
• 
Creatinine ≤ 2 mg/dL 
• 
Cardiac ejection fraction ≥ 45%, no evidence of 
physiologically significant pericardial effusion as 
determined by an ECHO, MUGA or Cardiac MRI 
[performed within 180 days or after most recent 
anthracycline based treatment or mediastinal 
 
ANC 
Platelet 
 
 
 
Creatinine 
 
      
      
      
 
 
      
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
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Amd 3, Version 2022-0722 
INCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
radiation therapy (whichever is most recent)] 
• 
No clinically significant ECG findings 
• 
No clinically significant pleural effusion 
• 
Baseline O2 saturation > 92% on room air 
* A subject will not be excluded because of pancytopenia ≥ Grade 3 if it 
is felt by the investigator to be due to underlying leukemia/lymphoma. 
 
LVEF 
 
 
ECG 
Pleural 
SaO2 
      
 
 
      
      
      
3. CNS Status  
Subjects with CNS involvement are eligible as long as there 
are no overt signs or symptoms that in the evaluation of the 
investigator would mask or interfere with the neurological 
assessment of toxicity.   
 
 
      
4. Females of childbearing potential must have a negative serum 
or urine pregnancy test within 7 days of lymphodepleting 
chemotherapy (females who have undergone surgical 
sterilization or who have been postmenopausal for at least 2 
years are not considered to be of childbearing potential) 
 
 
      
5. Contraception 
Subjects of child-bearing or child-fathering potential must be 
willing to practice birth control from the time of enrollment 
on this study and for four (4) months after receiving the 
preparative lymphodepletion regimen. 
 
 
 
 
      
 
6. Ability to give informed consent.   
Must be able to give informed consent.  Legal authorized 
representative (LAR) is permitted if subject is cognitively 
able to provide verbal assent. 
 
 
      
Subjects meeting any of the following criteria are not eligible for participation in Step 2 
(Lymphodepleting Chemotherapy and CD22-CAR T cell infusion) on the study: 
EXCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
1. Recurrent or refractory ALL limited to isolated testicular 
disease. 
 
 
      
2. Hyperleukocytosis (≥ 50,000 blasts/μL) or rapidly 
progressive disease that in the estimation of the investigator 
and sponsor would compromise ability to complete study 
therapy. 
 
 
      

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
CCT5029 / IRB-50836 
135 of 150 
Amd 3, Version 2022-0722 
EXCLUSION CRITERIA 
Yes 
No 
Supporting 
Documentation† 
3. Presence of active fungal, bacterial, viral, or other infection 
that is uncontrolled requiring intravenous antimicrobials.  
Simple UTI and uncomplicated bacterial pharyngitis are 
permitted if responding to active treatment.   
 
 
 
 
      
 
4. Women who are pregnant or breastfeeding.   
 
 
      
5. In the investigator’s judgment, the subject is unlikely to 
complete all protocol-required study visits or procedures, 
including follow-up visits, or comply with the study 
requirements for participation.  
 
 
      
6. Acute neurological toxicity > Grade 1 (with the exception of 
peripheral sensory neuropathy) 
 
 
      
†All subject files must include supporting documentation to confirm subject eligibility.  The method of confirmation 
can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record 
review.   
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in Step 2 Lymphodepleting Chemotherapy and CD22-CAR T cell infusion in the 
study.  This study is approved by the Stanford Cancer Institute Scientific Review Committee, the 
Stanford IRB, and has finalized financial and contractual agreements as required by Stanford School 
of Medicine’s Research Management Group.   
Treating Physician Signature: 
Date: 
Printed Name: 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
Study Coordinator Signature: 
Date: 
Printed Name: 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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13.8.2 Informed Consent Process 
All participants must be provided a consent form prior to Stage 1 Leukapheresis (if leukapheresis is 
to be performed on this study) and prior to Stage 2 Lymphodepleting Chemotherapy and Cell Infusion 
describing the study parts with sufficient information for subjects to make an informed decision 
regarding their participation.  The investigational nature and research objectives of this trial, the 
procedures and treatments involved and their attendant risks and discomforts and potential benefits, 
and alternative therapies will be carefully explained to the subject, and the subject/LAR asked to 
review the consent form and to ask questions prior to agreeing to participate in each stage of this 
protocol.  The subject is reassured that participation on trial is entirely voluntary and that he/she can 
withdraw or decide against treatment at any time without adverse consequences. 
The original signed copy of the consent documents must be retained in the research file and a copy 
placed in the medical record. 
 
13.8.3 Subject Screening Using Two Stages for Consent and Enrollment 
13.8.3.1 Screening for Step 1 
(a) CD22 expression  
For R/R ALL subjects: Expression will be evaluated by immunohistochemistry or by flow 
cytometry in a CLIA approved laboratory and documentation at screening will be required (testing 
is permitted to be conducted at any time since diagnosis, unless subject has received anti-CD22 
targeted therapy, such as Moxetumomab pasudotox or inotuzumab ozogamicin, in which case the 
specimen must be collected after such therapy). 
For R/R aggressive B-cell NHL:  CD22 expression at any level, including undectable, will be 
acceptable.  Subjects must have archival tissue available for analysis of CD22 expression or must 
be willing to undergo a biopsy of easily accessible disease. 
(b) Medical history and concomitant medication 
The subject’s complete history through review of medical records and by interview will be 
collected and recorded.  Concurrent medical signs and symptoms must be documented to establish 
baseline severities.  A disease history, including the date of initial diagnosis and list of all prior 
treatment including BMSCT and CAR therapies, responses, and duration of response to the prior 
treatment also will be recorded. Most current disease status will be determined to include presence 
and location of current disease. Prior therapy washout periods will be calculated. History of known 
infection with HIV, hepatitis B and hepatitis C will be elicited, but viral testing is not necessary, 
as this will be performed standard of care prior to the leukapheresis procedure.  
(c) Physical examination  
A complete physical examination will be performed.  The exam will include general appearance 
of the subject, height and weight, examination of the skin, eyes and ears, nose, throat, lungs, heart, 
abdomen, extremities, musculoskeletal system, and nervous system.   
(d) Vital signs, including blood pressure, heart rate, oxygen saturation and temperature  
(e) Performance status (ECOG or Karnofsky) see Appendix A, Section 13.1 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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(f) β-HCG pregnancy test on all women of child-bearing potential 
(g) General Laboratory Tests: The following will be obtained during the screening process for 
Step 1: 
o Chemistries: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, calcium, AST, ALT, alkaline phosphatase, bilirubin, albumin, total 
protein 
o CBC with differential  
13.8.3.2 Screening for Step 2 
(a) Physical examination will be performed and changes from Step 1 noted.   
(b) Vital signs, including blood pressure, heart rate, oxygen saturation and temperature  
(c) Performance status (ECOG or Karnofsky) see Appendix A, Section 13.1 
(d) Electrocardiogram (ECG)  
(e) ECHO, MUGA or Cardiac MRI for LVEF and pericardial effusion assessment [performed within 
180 days or after most recent anthracycline based treatment or mediastinal radiation 
therapy (whichever is most recent)] 
(f) Creatinine clearance: A measured 24 hour urine creatinine clearance test may be performed if the 
serum creatinine is elevated, and the measured value will be recorded in the CRF and may be used 
to qualify the subject for study participation. 
(g) β-HCG pregnancy test on all women of child-bearing potential (within 7 days prior to starting 
chemotherapy) 
(h) Coagulation tests including prothrombin time (PT)/ partial thromboplastin time (PTT) 
(i) General Laboratory Tests: The following will be obtained during the screening process for Stage 
2 (unless previously performed within 28 days with no subsequent treatment initiated): 
o Chemistries: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, calcium, AST, ALT, alkaline phosphatase, bilirubin, albumin, total 
protein 
o Phosphorus and magnesium 
o CBC with differential  
o C-reactive protein (CRP), ferritin and Triglyceride level 
o Urinalysis 
(j) Additional Tests:  
The investigator may order additional tests in some subjects if needed to fully assess clinical status 
and obtain baseline results.  Examples of such tests include: haptoglobin, soluble IL2R, 
immunoglobulin levels, and viral serology or PCR for cytomegalovirus (CMV), herpes simplex 
virus (HSV), varicella zoster virus (VZV), and Epstein-Barr virus (EBV). 
(k) Disease Evaluation (methods will be determined by investigator based on subjects’ location of 
disease, not all are required on all subjects), including determination of measurable disease. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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o Imaging Studies appropriate to sites relevant to subject’s disease: subjects with 
aggressive B-cell NHL will undergo PET/CT; other imaging studies (e.g. MRI of the 
brain) will be performed as determined by investigator 
o Bone marrow aspirate/biopsy: subjects with ALL will undergo bone marrow biopsy, 
subjects with bone marrow involvement prior to therapy or if new abnormalities in the 
peripheral blood counts or blood smear cause suspicion of bone marrow involvement 
will undergo bone marrow aspirate and biopsy 
o Lumbar puncture, if determined as clinically necessary by the investigator 
(a) Concomitant Medication 
A list of concomitant medications will be captured at the end of screening at the time of confirmation 
of eligibility.  Medications that are stopped during the screening period prior to eligibility sign off do 
not need to be recorded.  The concomitant medication list will be updated at each clinic visit. 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
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13.8.4 Study Calendar Using Two Stages for Enrollment 
 
Stage 1: Leukapheresis 
Stage 2: Lymphodepleting Chemotherapy and CD22-CAR T Cell Infusion 
 
ScreeningA 
(≤ 28 days of 
enrollment, 
unless 
specified) 
ApheresisD 
(up to 24h 
prior unless 
noted) 
ScreeningA 
(≤ 28 days of 
enrollment, 
unless 
specified) 
Preparative Regimen 
and Cell Infusion 
Post Treatment Assessment 
Long Term Follow-UpL 
Long 
Term 
Gene 
Therapy 
Follow Up 
(until year 
15) 
 
Procedure 
Day -5, 
Day -4, 
Day -3 
Prior to 
cell 
infusion 
(< 24 h) 
Day 0 
5x per 
weekI, 
Day 1 to 
Day 14  
(± 2 d) 
Twice 
weekly, 
Day 15 to 
Day 27 
(± 4 d) 
Day 28 
(± 4 d) 
Monthly, 
Month 2-3 
(±2  weeks) 
Month 6 (±1 mo) 
 9, (±1  mo)  
12 (±2 mo) 
q6-12 months to 
5 years 
Annually
,Year 6 
to 15 
(±3 mo) 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
X 
X 
XI 
XI 
X 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
XF 
XF 
XF 
X 
X 
X 
 
 
Neurologic exam 
 
 
X 
 
X 
XH 
XH 
XH 
XH 
XH 
XH 
 
 
Performance Status 
X 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
Height 
X 
 
 
XS 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
XS 
 
 
 
 
X  
X 
X 
 
 
Labsc 
• CBC with diff 
X 
XD 
X 
X 
X 
X 
XI 
XI 
X 
X 
X 
 
 
• PT/PTT  
 
 
X 
 
 
 
 
 
 
 
 
 
 
• ChemistriesB 
X 
XD 
X 
X 
X 
X 
XI 
XI 
X 
X 
 
 
 
• Phosphorus 
 
XD 
X 
XS 
 
X 
XI 
XI 
 
 
 
 
 
• Magnesium 
 
XD 
X 
XS 
X 
X 
XI 
XI 
 
 
 
 
 
• CRP 
 
XD 
X 
XS 
X 
X 
XI 
XI 
X 
 
 
 
 
• Ferritin 
 
 
X 
XS 
 
 
XI 
XI 
X 
 
 
 
 
• Uric acid and LDH 
 
 
 
XS 
 
X 
XI 
XI 
 
 
 
 
 
• CD22 staining by IHC 
or flow cytometry  
XP 
 
 
 
 
 
 
 
 
 
 
 
 
• Quantitative IgG 
immunoglobulins 
 
 
 
 
 
 
 
 
XM 
XM 
 
 
 
• Urine analysis 
 
 
X 
 
 
 
 
 
 
 
 
 
 
• β-HCG pregnancy test 
on all females of 
child-bearing potential 
X 
XC 
X 
XC 
 
 
 
 
 
 
 
 
 
• RCL blood sample 
 
 
 
 
XN 
 
 
 
 
XN 
XN 
 
 
ECG  
 
 
X 
 
 
 
 
 
 
 
 
 
 
ECHO, MUGA or cardiac 
MRI 
 
 
XQ 
 
 
 
 
 
 
 
 
 
 
Correlative Research 
Studies  
Correlative samples outlined in Section 13.7, Appendix G 
• 
Leukapheresis  
 
X 
 
 
 
 
 
 
XJ 
XJ 
XJ 
 
 
Disease Evaluation  

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
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Stage 1: Leukapheresis 
Stage 2: Lymphodepleting Chemotherapy and CD22-CAR T Cell Infusion 
 
ScreeningA 
(≤ 28 days of 
enrollment, 
unless 
specified) 
ApheresisD 
(up to 24h 
prior unless 
noted) 
ScreeningA 
(≤ 28 days of 
enrollment, 
unless 
specified) 
Preparative Regimen 
and Cell Infusion 
Post Treatment Assessment 
Long Term Follow-UpL 
Long 
Term 
Gene 
Therapy 
Follow Up 
(until year 
15) 
 
Procedure 
Day -5, 
Day -4, 
Day -3 
Prior to 
cell 
infusion 
(< 24 h) 
Day 0 
5x per 
weekI, 
Day 1 to 
Day 14  
(± 2 d) 
Twice 
weekly, 
Day 15 to 
Day 27 
(± 4 d) 
Day 28 
(± 4 d) 
Monthly, 
Month 2-3 
(±2  weeks) 
Month 6 (±1 mo) 
 9, (±1  mo)  
12 (±2 mo) 
q6-12 months to 
5 years 
Annually
,Year 6 
to 15 
(±3 mo) 
• PET/CT 
chest/abdomen/pelvis, 
brain MRI (or other 
appropriate imaging) 
 
 
XK 
 
 
 
 
 
XK 
XK 
XK 
 
 
• Lumbar puncture 
 
 
XK 
 
 
 
 
 
XK 
XK 
XK 
 
 
• Bone marrow aspirate 
 
 
XK 
 
 
 
 
 
XK 
XK 
XK 
 
 
• MRD blood sample 
(Subjects with ALL only 
with identifiable clones) 
 
 
XK 
 
 
 
 
 
XK 
XK 
XK 
 
 
• Lymph node biopsy 
 
 
XR 
 
 
 
XR 
 
XR 
 
XR 
 
 
Treatment Regimen 
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
• Lymphodepleting 
chemotherapy 
 
 
 
XE 
 
 
 
 
 
 
 
 
 
• CD22-CAR T cells 
infusion 
 
 
 
 
 
XG 
 
 
 
 
 
 
 
Response EvaluationK,L 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Adverse EventsU 
 
X 
 
X 
 
 
 
 
X 
XO 
XO 
 
XO 
Concomitant Medications 
X 
X 
X 
 
 
 
 
 
X 
XO 
XO 
 
XO 
Long term follow up 
questionnaires 
 
 
 
 
 
 
 
 
 
 
 
XT 
XT 
A: Within 28 days prior to enrollment on this step, unless otherwise specified. 
B: Laboratory evaluation to include; Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Urea nitrogen (BUN), Creatinine, Glucose, Calcium (Ca) total, ALT/GPT, 
AST/GOT, Alkaline Phosphatase, Bilirubin, Albumin, Total Protein); creatinine clearance may be performed if the serum creatinine is elevated.  The PI may order additional tests in some 
subjects if needed to fully assess clinical status and obtain baseline results.  Examples of such tests include: haptoglobin, soluble IL2R, immunoglobulin levels, and viral serology or PCR for 
cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), and Epstein-Barr virus (EBV). 
C: Within 7 days prior to leukapheresis procedure and Day -5 (not repeated if screening labs performed within 7 days). 
D: For cell acquisition for product development.  Visit may be skipped if subject has cryopreserved cells that meet IND criteria. Labs required within 7 days prior to leukapheresis. 
E: 
Subjects will receive hydration and prophylactic medications according to institutional standard practice prior to, during and after lymphodepletion chemotherapy.   
F: 
Vital signs (blood pressure, heart rate, respiratory rate, pulse oximetry, temperature) collected on Day 0: prior to infusion, at the conclusion of the infusion (±10 min), 60 min. (±10 min) and as 
clinically indicated, then Day 1-28: every shift (± 2 hrs) during hospitalization, and with each visit after discharge.   
G: Premedications will be provided as described in protocol Section 6.6.  Subject may be offered additional CAR T cell treatments if enough cells were manufactured from the initial preparation, 
the subject experienced at least partial response to the first infusion, and the subject meets all eligibility criteria.  Subsequent infusions will follow the same procedures as the first. 
H: Neurologic exam daily and ICE score every shift (± 2 hrs) during hospitalization, then neurologic exam with each visit after discharge. After Day 28, continue until end of neurotoxicity or at 
investigator discretion. 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; following lymphodepleting chemotherapy 
 
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I: 
Five (5) times per week from Day 1 to  Day 14 (± 2 days) (unless otherwise indicated) with visits no more than 48 hours apart, and then twice weekly until Day 28  (± 4 days).  LDH testing only 
required if elevated at baseline (prior to lymphodepletion chemotherapy). Uric acid only at baseline (Day -5 or -6). Phosphorus, magnesium, CRP, Ferritin, and LDH daily while hospitalized 
during initial hospitalization, then Day 14 (± 3 days) and Day 21 (± 3 days).  
J: 
Subjects may undergo a small volume apheresis (approx. one to two blood volumes) in lieu of standard blood draw to obtain peripheral blood lymphocytes for correlative studies including Day 
28 (±7 days), and 3 (± 2 weeks) , 6 (± 1 month) , 9 (± 1 month) , and 12 (± 2 months) months. 
K: Subjects with leukemia will undergo bone marrow biopsy and patients with aggressive B-cell NHL will undergo PET/CT (or PET at the investigator’s discretion) at screening, Day 28 (±4 days) 
and Month 3  (± 1 month), 6  (± 1 month), then per standard of care frequency.  Disease evaluations may be repeated if >28 days passes between enrollment and start of lymphodepletion 
chemotherapy or if bridging anti-neoplastic therapy is used post-enrollment (per Section 5.3.1).  Other methodologies including lumbar puncture, x-rays, MRI, MRD evaluation, lymphocyte 
subsets, etc determined by investigator based on sites and type of disease may be used; consistency throughout protocol evaluations is necessary.  Day 28  will be considered the response 
evaluation for subjects with ALL.  Month 3 will be considered the response evaluation for subjects with aggressive B-cell NHL.   
L: 
Subjects will be monitored by physical exams, disease evaluations, vitals, CBC with diff, Chemistries, and IgG levels until relapse or subject proceeds to other therapies at investigator’s 
discretion; at which time Long-Term Gene Therapy follow-up will proceed as per Section 5.5.5. Subjects with progressive disease or who start alternative therapies will undergo evaluations for 
long term gene therapy follow up ONLY; additional testing (i.e. correlative samples, quantitative immunoglobulins, etc) may be performed at the investigator’s discretion.  Evaluations may be 
performed by an outside physician or oncologist as long as required measures are included and maintained in the subject’s research record. 
M: Immunoglobulin levels every 3-12 weeks post infusion until Month 3 (±2 weeks).  
N: RCL samples collected and sent to IU GTTL: prior to cell infusion; and at 3 (± 1 month), 6 (± 1 month), and 12 months (± 2 months) post cell infusion, unless FDA approved for archived 
specimens.  Subsequent RCL blood samples will be stored annually for 4 additional years if all RCL in first year negative. 
O: Targeted adverse/serious adverse event reporting and concomitant medication collection until Month 24, disease progression, or start of alternate therapy (whichever occurs first).   
P: 
For R/R ALL: CD22 expression can be any time since diagnosis but must be re-demonstrated if patient has received targeted anti-CD22 therapy. For R/R aggressive B-cell NHL:  CD22 
expression is not required.  Subjects must have archival tissue available or must be willing to undergo a biopsy of easily accessible disease. 
Q: Testing performed within 180 days or after most recent anthracycline based treatment or mediastinal radiation therapy may be used for confirmation of eligibility 
R: If feasible and easily accessible, lymph node biopsy will be obtained from subjects with lymphoma at baseline, and once between Day 7 and Day 28.  A PBMC sample (for CAR T cells, etc) and 
lymph node biopsy may be collected at the time of progression, prior to starting any subsequent anticancer therapy, if clinically feasible.   
S: 
 Height within 30 days prior to Day -5. Others collected once, Day -5 or Day -6 only. 
T: 
After 5 years, health status data will be obtained from surviving subjects via telephone contact or mailed questionnaires.  The long term follow up period for lentiviral vectors is 15 years.   
U: All adverse events will be recorded and reported from the start of lymphodepletion chemotherapy and conclude 30 days after the last study treatment.  Prior to the start of lymphodepletion 
chemotherapy, only unexpected serious adverse events related to study procedures will be collected (see Section 7.3.1). 
 
 
 

Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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Protocol: CD22 CAR T-cell in Adults 
  
Agent: Autologous T cells transduced with lentiviral vector (CD22.BB.Z) chimeric antigen receptor (CD22-CAR) gene; 
following lymphodepleting chemotherapy 
 
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following lymphodepleting chemotherapy 
 
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