Phase I/II Study of Cellular Immunotherapy Using Central Memory-Enriched CD8+ T Cells Lentivirally Transduced to Express A CD19-Specific Chimeric Immunoreceptor Following Peripheral Blood Stem Cell Transplantation for Patients With High-Risk Intermediate Grade B-Lineage Non-Hodgkin Lymphoma
Phase: PHASE1
Conditions: Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Non-Hodgkin Lymphoma
Sponsor: City of Hope Medical Center

 
 
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CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY/ HEMATOPOEITIC CELL TRANSPLANTATION 
TITLE:  
PHASE I/II STUDY OF CELLULAR IMMUNOTHERAPY USING CENTRAL 
MEMORY-ENRICHED CD8+ T CELLS LENTIVIRALLY TRANSDUCED TO 
EXPRESS A CD19-SPECIFIC CHIMERIC IMMUNORECEPTOR FOLLOWING 
PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR PATIENTS WITH 
HIGH-RISK INTERMEDIATE GRADE B-LINEAGE NON-HODGKIN LYMPHOMA 
CITY OF HOPE PROTOCOL NUMBER: 
09174 
VERSION: 
11 
 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
 
 
Initial Approval 
Protocol Dated 08/01/11 
Version: 00 
COH Amendment 01 
Protocol Dated 10/31/11 
Version: 01 
COH Amendment 02 
Protocol Dated 12/12/11 
Version: 02 
COH Amendment 03 
Protocol Dated 02/17/12 
Version: 03 
COH Amendment 04 
Protocol Dated 04/30/12 
Version: 04 
COH Amendment 05 
Protocol Dated 06/04/12 
Version: 05 
COH Amendment 06 
     Protocol Dated 07/12/12 
Version: 06 
COH Amendment 07 
     Protocol Dated 11/20/12 
Version: 07 
COH Amendment 08 
     Protocol Dated 05/20/13 
Version: 08 
COH Amendment 09 
     Protocol Dated 10/28/13 
Version: 09 
COH Amendment 10 
     Protocol Dated 02/12/14 
Version: 10 
COH Amendment 11 
     Protocol Dated 06/10/14 
Version: 11 
 
SPONSOR/IND NUMBER: 
City of Hope/IND 14645 
 
DISEASE SITE: 
 
Lymph Nodes and/or Bone Marrow 
 
STAGE (if applicable): 
Not applicable 
 
MODALITY: 
Cellular Immunotherapy Using CD19-Specific Chimeric 
Immunoreceptor Expressing TCM-Enriched CD8+ T Cells 
 
PHASE/TYPE: 
Phase I/II 
 
PRINCIPAL INVESTIGATOR: 
 
Leslie Popplewell, MD,  
Dept of Hem & HCT, COH 

 
 
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COLLABORATING INVESTIGATOR(S): 
 
City of Hope: 
Stephen Forman, MD, Dept of Hem/ HCT 
Christine Brown, PhD, Dept of CITI & Hem/ HCT 
University of Washington: 
Michael Jensen, M.D. 
Fred Hutchinson Cancer Research Center: 
Stanley Riddell, M.D. 
David Maloney, M.D. 
 
PARTICIPATING CLINICIANS:     Ahmed Aribi, M.D.; Ravi Bhatia, M.D.; Smita Bhatia, M.D.; 
Ji Lian Cai, M.D., Kaiser; Robert Chen, M.D.; Warren Chow, M.D.; Len Farol M.D., Kaiser;  
Myo Htut, M.D.; Chatchada Karanes, M.D.; Samir Khaled, M.D.;  Amrita Krishnan, MD; 
Auayporn P. Nademanee, M.D.; Ryotaro Nakamura, M.D.; Margaret R. O’Donnell, M.D.; Pablo 
Parker, M.D.; Anna Pawlowska, M.D.; Michael Rosenzweig, M.D.; Firoozeh Sahebi, M.D., 
Kaiser;  Tanya Siddiqi, M.D.; Eileen Smith, M.D.; David Snyder, M.D.; George Somlo, M.D.; 
Ricardo Spielberger, M.D., Kaiser; Anthony Stein, M.D. 
 
STUDY STATISTICIAN: 
Suzette Blanchard, PhD, Dept of Info. Sciences 
 

 
 
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Experimental Design Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Leukapheresis for T cell manufacturing may be drawn prior to or after cycles of Salvage 
Chemotherapy  
2Phase I portion includes HPC back-up product, reference Section 7.5.2 
3 Research participants will enter the protocol in cohorts of 3 and receive T cell infusion on 
approximately day +2 or +3 post HSCT.  The starting dose will be 50M CAR+ cells (where M = 
106).  Dose escalation will take whole steps (in black) until a DLT is seen.  Once a DLT is seen 
the study will move in half steps (in grey) as described in Section 12, Table 5. 
Myeloablative 
Conditioning Regimen 
Infusion of HPC(A)  
Reinfusion (Day 0) 
T Cell Infusion (Day +2 or +3) 3 
Protocol-Specified Clinical and 
Laboratory Correlative Follow-Up 
Studies 
Consent/Enrollment 
Baseline Evaluations 
Leukapheresis1 
(T Cell Collection) 
Derivation and 
Cryopreservation of 
Autologous TCM-
Enriched CD19R-
CAR+/CD8+ Cell 
Product 
Salvage/Priming 
Chemotherapy & 
Rituxan 
Mobilization of HPC(A)’s 
HPC, Apheresis and 
Cryopreservation2 
Salvage Therapy, 
Hematopoietic 
Progenitor Cell, 
Apheresis (HPC(A)) 
Mobilization and 
Collection, 
Myeloablative 
Preparative Regimen, 
HPC Rescue, and 
Supportive Care per 
COH Hem/BMT 
Program Standard 
Practice SOP’s 

 
 
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Table of Contents 
1.0 
Goals and Objectives (Scientific Aims) ...............................................................10 
1.1 
Phase I ...................................................................................................10 
1.1.1 
Primary Objectives ..................................................................... 10 
1.2 
Phase II ..................................................................................................10 
1.2.1 
Primary Objectives ..................................................................... 10 
1.2.2 
Secondary Objectives ................................................................ 10 
2.0 
Background and Rationale .................................................................................10 
2.1 
High-Dose Chemotherapy with Autologous Peripheral Blood Stem Cell 
Support for NHL .....................................................................................11 
2.1.1 
Introduction ................................................................................ 11 
2.1.2 
Standard Preparative Regimens for Autologous Stem Cell 
Transplantation Utilized in Patients with NHL ........................................ 12 
2.2 
Cellular Immunotherapy for Human Disease ..........................................12 
2.2.1 
Adoptive therapy for human viral and malignant disease ........... 12 
2.2.2 
Development of AT for B-lineage malignancies using chimeric 
antigen receptor re-directed CD20 and CD19 specific T cells ................ 13 
2.2.3 
Strategies to improve the persistence of adoptively transferred T-
cells 
 .................................................................................................. 14 
2.2.3.1 Lymphodepletion ......................................................................14 
2.2.3.2 Intrinsic programming of central memory T cells for 
persistence ................................................................................14 
2.3 
Potential Toxicities Associated with the Infusion of CD19-Specific TCM-
Enriched CD8+ T Cell Lines ....................................................................15 
3.0 
Therapeutic Agents ............................................................................................18 
3.1 
Salvage/HPC Priming Chemotherapy .....................................................18 
3.2 
Rituximab (Rituxan, IDEC-C2B8) ...........................................................19 
3.3 
Granulocyte-Colony Stimulating Factor (Figrastim, Amgen) ...................20 
3.4 
Plerixafor (Mozobil™, Genzyme Corp.) ..................................................20 
3.5 
Hematopoietic Progenitor Cell, Apheresis, Collection, Cryopresevation, 
and Re-Infusion ......................................................................................20 
3.6 
Cryopreserved Autologous TCM-Enriched CD19R-CAR+ CD8+ T cell 
Product ...................................................................................................20 
3.6.1 
Lentiviral Vector CD19Rop-epHIV7 ............................................ 21 
4.0 
Staging Criteria ..................................................................................................21 

 
 
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4.1 
Pre-Enrollment .......................................................................................21 
4.1.1 
Verification of Lymphoma........................................................... 21 
4.1.2 
Imaging and/or Histophatological Confirmation .......................... 21 
4.1.3 
Relapsed Disease ...................................................................... 21 
5.0 
Research Participant Eligibility ...........................................................................22 
5.1 
Inclusion Criteria at Time of Enrollment ..................................................22 
5.1.1 
Confirmation of Diagnosis .......................................................... 22 
5.1.2 
History of Relapse ..................................................................... 22 
5.1.3 
Life expectancy .......................................................................... 22 
5.1.4 
Age ............................................................................................ 22 
5.1.5 
KPS ........................................................................................... 22 
5.1.6 
Pregnancy ................................................................................. 22 
5.1.7 
Selection Criteria ....................................................................... 22 
5.2 
Exclusion Criteria at Time of Enrollment .................................................22 
5.2.1 
Study Specific Exclusion Criteria................................................ 22 
5.3 
Pre Transplant Tests ..............................................................................23 
5.4 
Eligibility to Undergo Autologous Myeloablative Transplantation with 
HPC(A) Rescue ......................................................................................23 
5.4.1 
Candidate for Autologous Transplant ......................................... 23 
5.4.2 
Scheduled for Chemotherapy .................................................... 23 
5.4.3 
Cryopreserved HPCA Product ................................................... 23 
5.4.4 
Evidence of Stable or Improved Disease ................................... 23 
5.5 
Eligibility Criteria at Time of Infusion of Genetically Modified Autologous T 
Cells .......................................................................................................23 
5.5.1 
Released T Cell Product ............................................................ 23 
5.5.2 
Cryopreserved Back-up ............................................................. 23 
5.5.3 
Autologous HPC(A) Procedure .................................................. 23 
5.5.4 
Pulmonary ................................................................................. 24 
5.5.5 
Cardiovascular ........................................................................... 24 
5.5.6 
Renal Function ........................................................................... 24 
5.5.7 
Liver Function ............................................................................ 24 
5.5.8 
Neurological ............................................................................... 24 
5.5.9 
Infectious diseases .................................................................... 24 
5.6 
Criteria for Delaying or Cancelling T Cell Dose .......................................24 
5.6.1 
Delaying T Cell Dose ................................................................. 24 

 
 
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5.6.2 
Canceling the T Cell Dose ......................................................... 24 
6.0 
Study Design .....................................................................................................24 
7.0 
Treatment Plan ..................................................................................................25 
7.1 
PBMC Collection ....................................................................................25 
7.2 
Salvage/Priming Chemotherapy .............................................................25 
7.3 
Pre-transplant Rituximab Therapy for B-Cell Depletion ...........................25 
7.4 
Mobilization with G-CSF and/or Plerixafor ..............................................25 
7.5 
Hematopoietic Progenitor Cell, Apheresis and Product Manipulation .....26 
7.5.1 
HPC, Apheresis Procedure ........................................................ 26 
7.5.2 
Cryopreservation of Back-Up HPC Product – Phase I Arm ........ 26 
7.6 
Myeloablative Conditioning Regimen ......................................................26 
7.7 
HPC(A) Cell Infusion ..............................................................................26 
7.8 
Adoptive Transfer of Cryopreserved TCM-Enriched CD19R+CD8+ T Cell 
Products .................................................................................................26 
7.9 
Summary of Correlative Studies .............................................................27 
7.9.1 
WPRE Q-PCR Determination of Frequency of Gene Modified 
Cells in the Circulation/Bone Marrow ..................................................... 27 
7.9.2 
Ex vivo Immunophenotyping/Functional Analysis ....................... 27 
7.9.3 
Cytokine Analysis ...................................................................... 27 
7.10 
Supportive Care .....................................................................................27 
7.10.1 Supportive Care for Regimen Related Toxicities ........................ 27 
7.10.2 Infectious Disease Prophylaxis and Monitoring .......................... 28 
7.10.3 Contra-Indicated Medications .................................................... 28 
8.0 
Study Parameters and Calendar ........................................................................28 
8.1 
Enrollment ..............................................................................................28 
8.1.1 
Evaluation of Eligibility ............................................................... 28 
8.2 
HPC(A) Transplant .................................................................................29 
8.2.1 
Prior to HPC(A) .......................................................................... 29 
8.2.2 
Day 0 - HPC(A) Transplant ........................................................ 29 
8.2.3 
Day +2 or Day + 3 Post HPC(A) Transplant ............................... 29 
8.2.4 
Day +5 (+/-3) Post Stem Cell Transplant .................................... 30 
8.2.5 
Day +60 (+/- 3) Post Stem Cell Transplant ................................. 30 
8.2.6 
Day +100 (+/- 3) Post Stem Cell Transplant ............................... 30 
8.2.7 
6 month Evaluations: +6, +12, +18 and +24 months Post Stem 
Cell Transplant ...................................................................................... 30 

 
 
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8.3 
T Cell Infusion ........................................................................................30 
8.3.1 
Within 24 hours Post T Cell Infusion .......................................... 30 
8.3.2 
Day 7 (+/- 3) Post T Cell Infusion ............................................... 30 
8.3.3 
Day 14 (+/- 3) Post T Cell Infusion ............................................. 30 
8.3.4 
Day 21 (+/- 3) Post T Cell Infusion ............................................. 31 
8.3.5 
Day 28 (+/- 3) Post T Cell Infusion ............................................. 31 
8.3.6 
Monthly Post T Cell Infusion for 1 year (starting at Month 2) ...... 31 
8.3.7 
3 month Evaluation: Post T Cell Infusion (may be combined with 
Day +100 visit) ...................................................................................... 31 
8.3.8 
6 Month Evaluation Post T Cell Infusion ..................................... 31 
8.3.9 
Yearly Evaluations: 12, 24 and 36 Months Post T Cell Infusion . 32 
8.4 
Short-term Follow-up Plan ......................................................................32 
8.5 
Long-term Follow-up Plan ......................................................................32 
9.0 
Monitoring Toxicities ..........................................................................................33 
9.1 
Management of Constitutional Symptoms Associated with T cell Infusion
 ...............................................................................................................33 
9.1.1 
Fever ......................................................................................... 33 
9.1.2 
Hypotension ............................................................................... 33 
9.1.3 
Hypoxemia ................................................................................. 34 
9.2 
Management of Acute Adverse Event(s) Attributable to This Study ........34 
9.2.1 
Management of Acute Adverse Event(s) Attributable to Infused T 
Cells  .................................................................................................. 34 
9.2.2 
Management of aHSCT Engraftment Failure ............................. 34 
9.2.3 
Management of Infectious Complications from Prolonged 
Lymphopenia ......................................................................................... 34 
9.3 
Schedule of Systemic Corticosteroids to Ablate Side Effects of 
Genetically Modified T cells ....................................................................34 
9.4 
Expected Adverse Events Associated with this Protocol .........................35 
9.5 
Adverse Events to Be Monitored ............................................................36 
9.6 
Criteria for Research Participant Accrual ................................................37 
9.6.1 
Phase I Accrual Interval ............................................................. 37 
9.6.1.1 Accrual within a Cohort ............................................................37 
9.6.1.2 Accrual for Cohort Advancement ............................................37 
9.6.2 
Accrual for Advancement into the Phase II Arm ......................... 37 
9.7 
Research Participant Premature Discontinuation ....................................37 
9.8 
Study Closure .........................................................................................38 

 
 
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9.8.1 
Lack of Improvement ................................................................. 38 
9.8.2 
Persistence of TCM Cells ............................................................. 38 
9.8.3 
Study Termination ...................................................................... 38 
10.0 
Criteria for Evaluation and Endpoint Definitions .................................................38 
10.1 
Criteria for Evaluation .............................................................................38 
10.2 
Disease Status .......................................................................................38 
10.3 
Dose Limiting Toxicity (see also Section 12.0)........................................38 
11.0 
Data and Safety Monitoring ................................................................................39 
11.1 
Definition of Risk Level ...........................................................................39 
11.2 
Monitoring and Personnel Responsible for Monitoring ............................39 
11.3 
Definitions ..............................................................................................40 
11.4 
Reporting of Unanticipated Problems and Adverse Events .....................41 
ADDITIONAL REPORTING REQUIRMENTS ....................................................44 
12.0 
Statistical Considerations ...................................................................................45 
12.1 
Phase I Study Arm .................................................................................45 
12.1.1 Design and Sample Size for Phase I Arm of Study .................... 45 
12.1.1.1 Amendments to Dose Plan .....................................................48 
12.1.2 Endpoints for Phase I Arm of Study ........................................... 49 
12.2 
Phase II Study Arm ................................................................................50 
12.2.1 Design and Sample Size for Phase II Arm of Study ................... 50 
12.2.2 Endpoint for Phase II Arm of Study ............................................ 50 
12.3 
Stopping Rules .......................................................................................50 
12.3.1 Failure of hematologic engraftment at 21 days ........................... 50 
12.3.2 Futility ........................................................................................ 51 
12.3.3 Feasibility ................................................................................... 51 
12.4 
Statistical Analysis ..................................................................................52 
12.5 
Accrual ...................................................................................................52 
13.0 
Registration Guidelines ......................................................................................52 
13.1 
Procedures for On-Study and Treatment Deviations ..............................52 
14.0 
Records to be Kept and Data Submission Schedule ..........................................52 
14.1 
Data Collection Forms ............................................................................52 
14.2 
Research Participant Consent Forms .....................................................52 
14.3 
Documentation of Registration Eligibility .................................................53 
14.3.1 Results Reporting ...................................................................... 53 

 
 
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15.0 
Minorities and Gender Statement .......................................................................53 
16.0 
Ethical and Regulatory Considerations ..............................................................53 
16.1 
Institutional Review Board ......................................................................53 
16.1.1 Informed Consent ...................................................................... 53 
16.2 
Termination of Study ..............................................................................54 
17.0 
Pathological Review ...........................................................................................54 
18.0 
Research Participant-Specific Biological Materials .............................................54 
19.0 
References ........................................................................................................55 
APPENDIX B ..........................................................................................64 
APPENDIX C .........................................................................................67 
APPENDIX D .........................................................................................68 

 
 
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1.0 Goals and Objectives (Scientific Aims) 
1.1 Phase I 
1.1.1 Primary Objectives 
 
To assess the safety of cellular immunotherapy utilizing ex vivo expanded 
autologous TCM-enriched CD8+ T cells genetically-modified to express a 
CD19-specific chimeric antigen receptor (CAR) in conjunction with a standard 
myeloablative autologous HSCT (aHSCT) for research participants with high-
risk intermediate grade B-lineage non-Hodgkin lymphomas (NHL) who have 
relapsed after primary therapy, or who did not achieve complete remission 
with primary therapy. 
 
To determine the maximum tolerated dose (MTD) on dose limiting toxicities 
(DLTs) and to describe the full toxicity profile 
1.2 Phase II 
1.2.1 Primary Objectives 
To determine the rate of research participants receiving TCM-enriched CD8+ T 
cells genetically-modified to express a CD19-specific CAR for which the 
transferred cells are detected in the circulation 28 days (+/- 3 days)  by WPRE Q-
PCR 
1.2.2 Secondary Objectives 
 
To determine the tempo, magnitude, and duration of engraftment of the 
transferred T cell product as it relates to the number of cells infused. 
 
To study the impact of this therapeutic intervention on the development of 
CD19+ B-cell precursors in the bone marrow as a surrogate for the in vivo 
effector function of transferred CD19-specific T cells 
 
To describe the progression-free and overall survival of treated research 
participants on this protocol 
2.0 Background and Rationale 
This Phase I/II, open-label, nonrandomized study proposes to enroll adult research 
participants with high-risk intermediate grade B-cell lymphomas who are candidates for 
an autologous myeloablative stem cell transplant to examine the safety and feasibility of 
administering autologous ex vivo expanded central memory (TCM)-enriched CD8+ T cell  
that are genetically modified using a SIN lentiviral vector to express a CD19-specific 
CAR to research participants in this population.   
The trial consists of dose escalation by cohort (pilot portion), followed by expanded 
enrollment at the tolerable dose (phase II portion) for a potential total enrollment of fifty-
seven research participants.  Infusion of genetically modified TCM cells will take place 
following a “standard of care” HSCT during the period of lymphopenia.  CD8+ TCM will be 
isolated from research participant peripheral blood mononuclear cells (PBMC) using the 
CliniMACS® device to select for CD8+/CD45RO+/CD62L+ TCM precursors.  These T cells 

 
 
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will then undergo a Dynal CD3/CD28 activation culture in combination with genetic 
modification using a SIN lentiviral vector that directs the expression of a CD19-specific 
scFvFc:ζ CAR.  The activated/genetically modified CD8+ TCM will be expanded in vitro 
with IL-2/IL-15 and then cryopreserved.  In the meantime, research participants will 
undergo standard practice salvage chemotherapy (if indicated), mobilization, 
hematopoietic progenitor cells (HPC) collection, then receive a standard myeloablative 
preparative regimen and HPC rescue conducted per standard operating procedures.  
The T cell product will be administered on approximately Day +2 or +3 following HSCT.  
Dose will be dependent on CAR positive (CAR+) T cells (i.e., if a product is 80% CAR+ 
at the first dose of 50M, then 50M CAR+ T cells will be infused which equals 
approximately 62.5M total cells).   
The primary safety endpoints of the phase I arm of the study will address the safety of T 
cell product infusion, the identification of any alteration in the side effects associated with 
HSCT and the kinetics of engraftment and determine the (MTD) based on DLTs and to 
describe the full toxicity profile.  The primary safety endpoints of the phase II arm of the 
study will determine the rate in research participants receiving TCM-enriched CD8+ T cells 
genetically-modified to express a CD19-specific CAR for.  Secondary objectives of this 
protocol are: 1) to determine the tempo, magnitude, and duration of engraftment of the 
transferred T cell product as it relates to the number of cells infused; 2) to study the 
impact of this therapeutic intervention on the development of CD19+ B-cell precursors in 
the bone marrow as a surrogate for the in vivo effector function of transferred CD19-
specific T cell; and 3) to describe the progression-free and overall survival of treated 
research participants on this protocol. 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP) and the applicable regulatory requirements. 
2.1 High-Dose Chemotherapy with Autologous Peripheral Blood Stem 
Cell Support for NHL 
2.1.1 Introduction 
Over 55,000 new cases of NHL are diagnosed each year in the United States 
and recent epidemiological data demonstrates that the incidence of this disease 
is increasing.  Intermediate grade B-cell lymphomas (diffuse large cell, mantle 
cell, marginal zone) are the most common sub-types of NHL and account for 
approximately 30% of cases. Nearly 50% of these patients have widespread 
disease at the time of diagnosis and are treated with combination chemotherapy 
and/or radiation therapy.  Unfortunately, over two-thirds of these patients will 
relapse with their disease and only 10% of these patients can be salvaged with 
conventional modalities.  Efforts to improve the survival of these patients with 
recurrent disease have focused primarily on the use of consolidative 
myeloablative stem cell transplantation.  This strategy may be curative in 
approximately 46% of selected patients.  This selected group of salvageable 
patients (age <60 years, complete remission after primary treatment, and no 
known marrow or central nervous system disease), however, constitutes less 
than one-third of patients with relapsed intermediate grade lymphomas.  Patients 
with chemotherapy-resistant recurrent disease have a <15%, 5-year event-free 
survival following stem cell transplantation and those with refractory disease at 
the time of transplant are rarely cured.  Thus, the major limitation of autologous 
transplantation for NHL is the high incidence of relapse even at maximally 

 
 
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tolerated preparative regimen intensities.  Autologous HCT is not curative in 
patients with advanced mantle cell lymphoma (MCL), even when transplanted in 
first remission; with a pattern of late relapse in the majority of patients so treated.  
Five-year overall survival rates with this approach range from 50 to 75 percent.  
These findings have prompted the evaluation of additional strategies to eradicate 
minimal residual disease (MRD) following the autologous transplantation 
procedure. 
2.1.2 Standard Preparative Regimens for Autologous Stem Cell 
Transplantation Utilized in Patients with NHL 
Preparative regimens including BEAM 1, and BCNU, CY, and VP-16 (CBV) 2-3 are 
considered standard myeloablative procedures at City of Hope (COH) for 
patients undergoing autologous transplant for recurrent NHL who are not on 
specific study protocols.  With improved supportive care measures the early 
mortality associated with autografting has been reduced to 5% or less, and for 
most patients, the majority of acute regimen-related toxicities resolve within the 
first four weeks following stem cell rescue.  Hematopoietic graft failure is defined 
as failure of granulocyte counts to reach 0.5 × 109/L by day 28.   
Historical data indicates that engraftment failure following autologous stem cell 
transplantation is influenced by log-dose CFU-GM and the number of prior 
chemotherapy regimens.  Patients who received less than 2.5 x 106 CD34+ cells 
have delayed hematopoietic recovery of all three cell lines, and a 5% likelihood of 
failing to meet definition of neutrophil recovery by day +28 after transplantation.  
Minimum cell dose specified in the COH Hematology SOP is greater than or 
equal to 2 x 106 CD34+ cell/kg of recipient weight.  Overall survival at 100 days in 
patients treated at COH with the preparative regimens BEAM and CBV is 92 -
100%, per submitted institutional Research Identifiable File (RIF) data submitted 
to the American Society for Blood and Marrow Transplantation (ASBMT) 4.  
Standard preparative regimens as described in the Heme/HCT SOP will be 
utilized for research participants enrolled in this protocol at the treating 
hematologist's discretion because of City of Hope's extensive transplant 
experience with these agents. 
2.2 Cellular Immunotherapy for Human Disease 
2.2.1 Adoptive therapy for human viral and malignant disease 
The feasibility of isolating and expanding antigen-specific T cells for adoptive 
therapy (AT) of human disease has been validated in clinical trials 5-13.  Dr. 
Riddell initially studied adoptive T cell therapy with donor-derived CD8+ cytotoxic 
T-lymphocyte (CTL) clones specific for cytomegalovirus (CMV) as a means of 
reconstituting deficient viral immunity in allogeneic HCT recipients; and defined 
the principles and methodologies for T cell isolation, cloning, expansion, and re-
infusion 14-16.  A similar approach pioneered by Heslop et al using polyclonal 
Epstein Barr Virus (EBV)-specific T cells has been effective for preventing or 
treating post-transplant EBV-associated lymphoproliferative disease after 
allogeneic HCT 17-18.  These studies and others have demonstrated that virus-
specific T cells, derived from donors with established viral immunity, and 
expanded in vitro can be transferred with minimal toxicity, mediate virus specific 
effector functions, and control viral replication as well as eradicate virally (EBV) 
transformed B-cell immunoblastic lymphoma 18-36. 

 
 
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While the adoptive transfer of tumor-specific T cells can result in tumor 
eradication in a variety of animal models 37-48, adoptive T cell therapy for human 
malignancy has been significantly more challenging and less effective than for 
viral diseases.  Perhaps the most clinically robust AT data comes from efforts of 
the Surgery Branch at the National Cancer Institute to treat melanoma 49-59.  Their 
studies demonstrated that administration of lymphodepleting chemotherapy 
followed by the adoptive transfer of polyclonal tumor infiltrating lymphocytes 
(TILs) specific for melanocyte-lineage antigens/tumor-testis antigens and high-
dose rhuIL-2, results in demonstrable tumor regressions in nearly one half of 
treated patients.  Of note, the response rate in patients that exhibited high-level 
persistent engraftment of transferred T cells was nearly 90%, while no 
responders are seen in the approximately 50% of patients without T cell 
engraftment.  Interestingly, persisting TILs represented only a small subset of the 
infused product repertoire, suggesting that the capacity for engraftment and 
persistence may be linked to the intrinsic programming of a rare population of 
T cells derived from TIL 59-60.  The generalization of the NCI group’s AT results for 
melanoma to other tumor types, including NHL, is the subject of intense ongoing 
investigation. 
2.2.2 Development of AT for B-lineage malignancies using chimeric 
antigen receptor re-directed CD20 and CD19 specific T cells 
Tumor antigens presented by HLA molecules and recognized by T cells have 
been identified and can originate from processing of normal or over-expressed 
tissue-specific proteins, aberrantly expressed onco-fetal antigens and mutated 
proteins, or minor histocompatibility (H) antigens in the setting of allogeneic HCT 
61.  However, isolating and expanding high-affinity major histocompatability 
complex (MHC)-restricted tumor-reactive T cells from tumor-bearing patients is 
technically difficult and even when successful, these T cells often fail to eliminate 
tumors after adoptive transfer 62-65.  Our evolving understanding of the counter-
regulatory mechanisms that impede successful tumor therapy have been derived 
largely from murine models 66.  Because many tumor antigens are self-proteins 
that are expressed in some normal tissues, tolerance mechanisms shape the 
frequency, avidity, and function of tumor-reactive T cells.  Additionally, tumors 
evade immune recognition through a variety of mechanisms including local 
recruitment of regulatory T cells (TREG) and other suppressor cells, loss of antigen 
expression, down-regulation of MHC and co stimulatory molecules, and 
expression or secretion of inhibitory molecules or cytokines 67-79.  Finally, cultured 
tumor-reactive T cells often exhibit limited persistence in vivo after adoptive 
transfer, even if high doses of rhuIL-2 are administered to support their survival 
80-83. 
In order to overcome some of these obstacles, we have focused on T cell genetic 
engineering strategies that serve to equip T cells with tumor specificity through 
the expression of CARs 84-85.  We have developed CARs consisting of tumor 
targeting single-chain variable fragments (ScFvs) specific for CD20 and CD19 
41,86-88.  These chimeric cell-surface molecules have the ability to bind antigen 
and transduce activation signals via immunoreceptor tyrosine activation motifs 
(ITAMs) present in the CD3-ζ cytoplasmic tail 10, or both activation and co-
stimulatory signals when CD28 and/or 4-1BB/OX40 domains are incorporated in 
series with CD3-ζ 89.  Adoptively transferred CAR-modified T cells can eradicate 

 
 
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established tumors in a variety of animal models 90-92. Moreover, T cells 
expressing CARs consisting of co-stimulatory signaling domains appear to be 
more resistant to activation induced cell death, exhaustion, and TREG mediated 
functional anergy 45,93-94.  While T cell genetic modification can address some of 
the issues relevant to tumor AT, our animal studies as well as data from our initial 
clinical trial demonstrate that the capacity of gene-modified CAR+ effector T cells 
to persist following adoptive transfer is a major obstacle to achieving therapeutic 
responses. 
2.2.3 Strategies to improve the persistence of adoptively transferred 
T-cells 
2.2.3.1 Lymphodepletion 
The induction of lymphopenia results in the proliferation of residual naïve and 
memory T cells to restore the size of the T cell pool 59,95-97.  A variety of 
mechanisms may make the lymphopenic environment favorable for T cell 
transfer including less competition for cytokines, such as IL-15 and IL-7, which 
promote lymphocyte homeostatic proliferation and survival 98-101; the availability 
of “space” in the lymphoid compartment 96; and the elimination of 
CD4+CD25+FOXP3+ regulatory T cells 102-103. Direct evidence that the induction 
of lymphopenia improves the persistence of transferred T cells was provided by 
studies from Rosenberg et al. in which melanoma patients were rendered 
lymphopenic by treatment with fludarabine and cytoxan prior to the adoptive 
transfer of 1010-1011 TIL-derived polyclonal melanoma-specific T cells.  As 
described above, a subset of these patients achieve prolonged high-level 
engraftment that correlates directly with tumor regression 55,57,104-105.  We 
hypothesize that infusing T cells shortly after a myeloablative HSCT will 
facilitate engraftment based on a window of lymphopenia when serum 
homeostatic cytokines (especially IL-15) are elevated. 
2.2.3.2 Intrinsic programming of central memory T cells for persistence 
The persistence of cultured T cells is improved by depletion of host 
lymphocytes before cell transfer and by the administration of IL-2 after cell 
transfer, but in half of treated melanoma patients these interventions still did 
not result in long-term persistence of transferred T cells or sustained tumor 
regression 104-105.  We hypothesized that intrinsic properties of T cells may be a 
critical determinant of their fate in vivo following adoptive transfer.  The pool of 
peripheral blood lymphocytes from which T cell products are derived ex vivo 
consist of naïve T cells (TN), and antigen experienced memory T cells (TM), 
which can be divided into central memory T cells (TCM) and effector memory T 
cells (TEM) subsets that differ in their homing, phenotype, and function 106-108.  
CD8+ TCM express CD62L and CCR7 which promote migration into lymph 
nodes, produce IL-2, and proliferate rapidly in response to antigen stimulation.  
CD8+TEM lack CD62L/CCR7, accumulate in tissue bed niches, and exhibit 
immediate effector function.  In response to antigen in vivo, both CD8+ TCM and 
TEM differentiate into cytolytic effector T (TE) cells that express high levels of 
granzymes and perforin, but are otherwise short-lived 109-110.  Thus, 
differentiation to a terminal TE phenotype during culture has been suggested to 
explain the poor survival of transferred T cells in clinical trials 111-112. 

 
 
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In the normal host, T cell memory persists for life, suggesting that some TM 
cells have the ability to self-renew or to revert to the memory pool after 
differentiating to TE in response to antigen re-exposure 107.  TCM and TEM have 
distinct phenotypic and functional properties, but it is unknown if TE cells 
enriched from each of these TM subsets retain any intrinsic properties of the 
parental cell from which they came. Using an immunodeficient mouse model, 
as well as a non-human primate model (Macaca nemestrina) relevant for 
human translation, we examined whether TE cells derived from purified TCM 
versus TEM differed in their ability to persist in vivo and establish T cell memory 
after adoptive transfer 113-114.  The studies identified a surprising dichotomy:  TE 
cells derived from CD62L- circulating TEM that were purified by cell sorting and 
expanded ex vivo, survived in the blood for only a short duration after AT; failed 
to persist in lymph nodes (LN), bone marrow (BM), or peripheral tissues; and 
did not reacquire phenotypic markers of TM during their brief life-span in vivo, 
while TE cells derived from sort-purified CD62L+ TCM persisted in the blood 
long-term after adoptive transfer, migrated to memory T cell niches in the LN 
and BM, reacquired phenotypic properties of TM, and responded to antigen 
challenge in vivo 113-114.  We hypothesize that human TCM-derived effectors will 
retain their programming for persistence after their genetic modification and ex 
vivo propagation and, upon adoptive transfer to lymphoma patients shortly 
following a myeloablative preparative regimen, will engraft and establish a 
reservoir of persistent memory T cells capable of targeting CD19+ lymphoma 
cells. 
2.3 Potential Toxicities Associated with the Infusion of CD19-Specific 
TCM-Enriched CD8+ T Cell Lines 
Various short-term toxicities have been associated with CD19-specific ACIT.  As 
mentioned above, we have observed both lymphopenia and eosinophilia with 
possible correlation to CD19-redirected CTL administration.115   
The NCI has also reported on a single adult patient with NHL, who received 
autologous CD19-specific, CD28-costimulatory CAR expressing T cells, and 
exhibited a fever for two days which self-resolved.116  In a more recent publication 
summarizing all 8 patients with advanced B-cell malignancies that were treated on 
this same trial, the most prominent toxicities that were observed included fever, 
hypotension, fatigue, renal failure, and obtundation.117 While these toxicities 
generally peaked within the first eight days after T cell administration, and resolved 
over time, the severity of the toxicities that were experienced by the patients 
appeared to correlate with serum IFN-
-
.117 
In a trial conducted at Memorial Sloan Kettering (MSKCC) using autologous CD19-
specific, CD28-costimulatory CAR expressing T cells for the treatment of chronic 
lymphocytic leukemia (CLL), eight of nine patients received T cells without serious 
adverse events (SAE), but exhibited common side effects of rigors, chills and 
transient fevers, all occurring within 24 hours of receiving the modified T cell 
infusions.118  The one CLL patient who had an SAE with subsequent death is 
discussed below.119 Autologous CD19-specific, CD28-costimulatory CAR expressing 
T cells were also used in an MSKCC trial for adults with relapsed acute B 
lymphoblastic leukemia (B-ALL).120 After T cell infusion, transient fevers and relative 
hypotension, as well as transient mental status changes were observed and found to 
be associated with serum cytokine surges..120 

 
 
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A recent University of Pennsylvania (UPENN) trial for CLL patients who received 
CD19-specific, 41BB-costimulatory CAR modified autologous T cells also revealed 
fever as a common infusional toxicity.121-122   Furthermore, between one and three 
weeks later, during which the modified T cells exhibited impressive in vivo 
expansion, the patients were re-admitted to the hospital with symptoms of tumor lysis 
syndrome, as well as variety of symptoms including rigors and diarrhea, which 
resolved over a 3-4 day period, and fevers that lasted up to two weeks.  One of the 
three reported patients did require corticosteroids at day 18 after the first T cell 
infusion for heart dysfunction in the setting of fevers, rigor and dyspnea, all of which 
were then resolved. In a newer UPENN trial using the CD19-specific costimulatory-
CAR modified autologous T cells to treat children with relapsed/refractory B-
malignancies, the first two patients have also been reported to have developed fever 
and “cytokine release syndrome”. 123 In one case the associated hypotension, acute 
vascular leak syndrome and acute respiratory distress syndrome was life 
threatening, but was reversed by cytokine blockade with etanercept and 
tocilizumab.123 
It is important to note that elevated proinflammatory serum cytokines represent a 
common, and in certain instances severe, short-term toxicity associated with T cells 
expressing second generation, or costimulatory, CD19-specific CAR. The observed 
cytokine elevations, as reported by the NCI, MSKCC and UPENN, have been 
observed for a subset a patients and appears to correlate with disease burden at the 
time of T cell infusion.117,120,123  For some patients, cytokine-mediated toxicities were 
transient. For other patients, toxicities were controlled by administration of 
corticosteroids120-121 or cytokine-blockade with etanercept and tocilizumab.123 [ 
Two grade 5 SAEs have been reported in the literature in relation to therapy with 
CAR-expressing T cells. The first was a patient receiving a CAR targeting ErbB2 who 
had pulmonary toxicity and cytokine release syndrome immediately following the 
infusion of T cells.124  The patient had received 1010 T cells, and on autopsy, was 
found to have large numbers of transferred T cells in the lung tissue – hypothetically 
due to low level ErbB2 expression on lung epithelial cells. The relevance of this SAE 
is then considerably diminished by the fact that the current protocol is targeting CD19 
and not ErbB2.  The second event, as mentioned above, occurred in a CLL patient 
who developed a sepsis like reaction following infusion of 1.2-3x107 T cells 
expressing a CD19-specific, CD28-costimulatory CAR.119  An overt cause of death 
was not revealed by autopsy, but the investigators have hypothesized that the 
patient had low-grade sepsis prior to the infusion of T cells that was magnified in the 
context of the lymphodepleting preparative regimen inherent in the adoptive transfer 
protocol. Indeed, serum cytokine analysis revealed elevated levels of pro-
inflammatory cytokines following cyclophosphamide chemotherapy and preceding 
the T-cell infusion, and it is this scenario which was consistent with sepsis due to 
infection, that was thought to lead to hypotension, acute renal failure and ultimately 
death. It must also be taken into consideration that infection is a leading cause of 
mortality in patients with advanced CLL. 
The most likely acute toxicity associated with adoptive transfer is a cytokine storm 
syndrome when infused cells are synchronously activated by a large burden of 
antigen expressing target cells.  Two deaths within 24-hours of infusion of CAR 
redirected T cell products have been reported to date.  In each of these deaths 
patients received a large number of cells and had extensive tumor burdens (CD19+ 
CLL and HER2+ breast cancer).  In order to address this risk, our protocol will treat 

 
 
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patients in MRD for lymphoma burden and based on the myeloablative preparative 
regimen and rituximab therapy, circulating CD19+ B-cells will be minimal.  
Additionally, in light of these fatalities we have elected to stratify patients into 
increasing cell dose cohorts, the first cohort being 50 x 106 (5 x 107) total cells, a 
modest dose at which in our prior trials we have not observed infusional toxicities.  
There are also at least two potential long-term toxicities to be considered in the 
context of CD19-speific ACIT.  The first is particular to targeting CD19.  The second 
is a general concern of genetically manipulating T cells.  Since non-malignant CD19+ 
B-cells will be subject to recognition by re-directed CTL, the long-term persistence of 
the adoptively transferred CD19-specific CTL has the potential to cause B-cell 
immunodeficiency or exacerbate the B-cell lymphopenia resulting from prior 
rituximab therapy.  In research participants who are predicted to succumb to 
recurrent/progressive lymphoma, the clinical sequelae of B-cell lymphopenia may be 
an acceptable side effect of CD19-directed immunotherapy, especially since 
prolonged ablation of normal CD20+ B cells in patients receiving rituximab therapy 
does not appear to result in clinically significant complications attributable to depleted 
numbers of normal B cells 125.  If the hypogammaglobulinemia becomes clinically 
significant, then the research participant may be given intravenous immunoglobulin 
(IVIG) as replacement therapy until B-cell function returns.   
The second potential long-term toxicity is the potential of neoplastic transformation of 
the genetically modified T cell product as a consequence of insertional mutagenesis 
and/or lentiviral vector integration that perturbs the expression cell regulatory genes 
126-128.  Dr. Alain Fischer’s gene therapy trials at the Necker children's hospital in 
Paris 129-130 have involved a cohort of 10 patients with a SCID-X condition treated 
with autologous bone marrow-derived CD34+ cells with a -retrovirus encoding the 
common cytokine-receptor -chain gene that forms a T cell growth-factor receptor.  
Following re-infusion of the transduced stem cells, there is a selective advantage for 
the survival of T cells that bear intact cytokine receptors that is manifested by the 
emergence of peripheral transduced T cells within 6 to 12 weeks of treatment 131-132.  
However, as of October 2002 at least two of the children treated on this protocol 
developed a clonal “lymphoproliferation” of (
) T cells apparently manifested by an 
increased white blood cells (WBC), hepatosplenomegally and anemia.  Preliminary 
analysis revealed that the retrovirus used for transduction was inserted into a child’s 
abnormal T cells.  This adverse event has raised concern that retroviral transduction 
may have caused the lymphoproliferation as the consequence of an insertional 
mutagenesis event 133. 
However, it is unclear what the significance of this adverse event is for the use of 
CD19-specific T cell therapy.  Our study differs from Dr. Fischer’s protocol in several 
important aspects: (a) we are genetically modifying cells with a lentiviral vector that 
to date has not resulted in transformation of T cells, and not -retrovirus; (b) the 
targets of the genetic modification are terminally differentiated T cells and not stem 
cells; (c) we are enrolling research participants with a life-threatening lymphoma and 
not young patients with an immunodeficiency syndrome; and (d) the genetically 
modified CD19-specific T cells do not have an inherent selective survival advantage 
compared with the transduced T cells in Dr. Fischer’s study which are modified to 
express a functional growth factor receptor. 
The ScFv portion of the CD19Rop CAR does encode a murine Ig protein with human 
CD19 specificity and associated idiotype.  The immunogenicity of this sequence is 

 
 
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currently not known; however, the construct has been used in previous clinical trials 
(COH IRB Protocol No. 01160) in plasmid form and has not been associated with 
immunogenicity and/or serious adverse events 115.  Furthermore, the cytoreductive 
chemotherapy and rituximab therapy would also minimize the possibility of a patient 
being able to mount significant immune responses against the T cell product. 
In summary, we believe that the potential toxicities associated with the use of CD19-
specific T cell therapy are outweighed by the need to develop novel treatment for 
patients with life-threatening lymphoma. 
3.0 Therapeutic Agents 
3.1 Salvage/HPC Priming Chemotherapy 
The hematopoietic cell transplantation (HCT) physician may choose to use a 
disease-specific chemotherapy regimen for mobilization in research participants with 
active disease who, in the opinion of the treating physician, require additional tumor 
debulking.  At least two cycles of salvage chemotherapy are considered a standard 
of therapy for debulking and demonstration of chemotherapy-sensitivity. Salvage 
regimens which can be used for mobilization of HPC-A includes, but is not limited to, 
the regimens shown in Table 1: Salvage/HPC Priming Chemotherapy.   
Alternatively, the treating physician may choose to use a cytokine-only mobilization 
regimen using G-CSF, or Plerixafor, or a priming chemotherapy regimen used 
specifically for the purpose of HPC-A mobilization including varying doses of high-
dose cyclophosphamide (with or without etoposide or taxol). 
The chemotherapy regimens listed in Table 1, are outlined in the current COH HCT 
Standard Operating Policies, Procedures and Protocols.  In addition, pre-printed 
orders are available, and will be used to order the disease-specific chemotherapy 
regimen when chosen for cytoreduction and mobilization. 
Time interval between salvage therapy and conditioning regimen will be according to 
institutional standard of practice.  Salvage therapy will not delay the start of the 
conditioning regimen beyond standard practice. 
 
Table 1:  Salvage HPC Priming Chemotherapy 
REGIMEN 
DRUG 
TREATMENT 
ICE regimen 2 
Q2w x 3 cycles 
Ifosfamide 
5000 mg/m2 mixed with Mesna 5000 mg/m2 iv over 24 hrs d2 
Carboplatin 
 AUC 5 (max 800mg) iv d2 
Etoposide 
100 mg/m2/d iv d1-3 
  
G-CSF 5 ug/kg sc qd d5-12 
RICE 
Q2w x 3 cycles 
Rituximab 
375 mg/m2 iv d1 q2w x 3 cycles 
Ifosfamide 
5000 mg/m2 mixed with Mesna 5000 mg/m2 iv over 24 hrs d2 
Carboplatin 
 AUC 5 (max 800mg) iv d2 
Etoposide 
100 mg/m2/d iv d1-3 
  
G-CSF 5 ug/kg sc qd d5-12 
ESHAP 
Etoposide 
40 mg/m2/d iv over 1 hr d1-4 

 
 
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REGIMEN 
DRUG 
TREATMENT 
Q3-4w x 6-8 cycles 
Methylprednisolone 
500 mg/d iv over 15 min d1-5 
Cisplatin 
25 mg/m2/d civi d1-4 
Cytarabine 
2000 mg/m2 iv over 2 hr d5 
DHAP 
Q3-4w 
Dexamethasone 
40 mg po qd d1-4 
Cisplatin 
100 mg/m2 iv over 24 hrs d1 
Cytarabine 
2000 mg/m2 iv q12 hrs for 2 doses d2 
EPOCH 
Q3w x 6-8 cycles 
Etoposide 
50 mg/m2/d civi d1-4 
Prednisone 
60 mg/m2/d po d1-5 
Vincristine 
0.4 mg/m2/d civi d1-4 
Adriamycin 
10 mg/m2/d civi d1-4 
Cyclophosphamide 
750 mg/m2 iv over 14 mins d5 
Bactrim DS 
1 tablet po bid tiw 
Neupogen 
5 mcg/kg sc qd beginning on d6 until ANC> 10,000/uL 
Hyper-CVAD/MTX-Ara-C 
Cycle 1,3,5,7 (3-4 wks/cycle) 
Cyclophosphamide 
300 mg/m2 iv over 2 hrs q12 hrs x 6 doses d1-3 
Mesna 
600 mg/m2/d civi d1-3 to start 1 h before cyclophosphamide 
f
f
Vincristine 
2 mg iv d4, 11 
Adriamycin 
50 mg/m2 iv over 24 hrs (over 448 hrs if LVEF <50%) d4 
Dexamethasone 
40 mg po or iv qd d1-4 and d11-14 
Cycle 2,4,6,8 (3-4 wks/cycle) 
Methotrexate (MTX) 
200 mg/m2 iv over 2 hrs followed by 800 mg/m2 civi over 22 
hrs d1 
Cytarabine (Ara-C) 
3 g/m2 (1 g/m2 for patients over 60 yo) iv oer 2 hrs q12 hrs x 4 
doses d2-3 
Leucovorin 
50 mg iv q6 hrs starting 12 hrs after completion of MTX untill 
MTX level < 0.05 uM 
Intrathecal Chemotherapy 
Prophylaxis 
MTX 12 mg d2 of each cycle for a total of 3-4 treatments 
Ara-C 100 mg d8 of each cycle for a total of 3-4 treatments  
Therapeutic 
Intrathecal chemotherapy twice a week (MTX 12 mg and Ara-C 100 mg respectively) 
until no more cancer cells in CSF, then decrease intrathecal chemotherapy to once a 
week x 4, followed by MTX 12 mg d2, Ara-C 100 mg d8 for the remaining 
chemotherapy cycles 
 
3.2 Rituximab (Rituxan, IDEC-C2B8) 
Rituximab may be used as part of the cytoreduction and mobilization regimen if 
desired by the treating physician, and if so, will be ordered in the pre-printed order 
sheets as noted above.  Rituximab infusion will be per COH standard practice 

 
 
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including possible premedication with diphenhydramine, acetominophen and 
possibly hydrocortisone. 
3.3 Granulocyte-Colony Stimulating Factor (Figrastim, Amgen) 
Granulocyte-Colony Stimulating Factor (G-CSF) will initially be administered to the 
research participant according to COH standard of care.  In autologous donors, there 
is a dose-response relationship for G-CSF with higher doses of G-CSF (16 – 24 
µg/kg/day given in two divided doses 10 to 12 hours apart) resulting in better CD34+ 
cell yields than conventional mobilization doses.  Thus the HCT physician or the 
Blood Bank staff physician may choose to order a higher dose of G-CSF or alter the 
G-CSF dose if deemed necessary.  G-CSF will begin 24 hours after the last dose of 
chemotherapy and will continue until the end of stem cell collection.  It will be 
administered at approximately the same time each day as defined in the institutional 
standard operating procedures.  The dose should be given at least one hour prior to 
HPC(A) apheresis on the days of apheresis.  Daily dosing of G-CSF will continue 
until the last day of stem cell collection has been reached. 
3.4 Plerixafor (Mozobil™, Genzyme Corp.) 
Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with G-
CSF to mobilize hematopoietic stem cells and may be used in combination with or as 
an alternative to GCSF for stem cell mobilization at the discretion of the primary COH 
hematologist as outlined in the Hematology standard operating procedure (SOP). 
3.5 Hematopoietic Progenitor Cell, Apheresis, Collection, 
Cryopresevation, and Re-Infusion 
Current institutional operating procedures shall be used in collection, processing and 
cryopreservation of the autologous peripheral blood stem cell product.  Current 
institutional operating procedures shall also be used during infusion of the HPC(A)  
product.  
3.6 Cryopreserved Autologous TCM-Enriched CD19R-CAR+ CD8+ T cell 
Product 
Peripheral blood mononuclear cell (PBMC) preparations from research participants’ 
leukapheresis products will be isolated by Ficoll separation followed by a cell 
wash/concentration procedure.  PBMC’s will then undergo a two-step CliniMACS® 
immunomagnetic selection procedure to derive CD8+ TCM enriched T cell 
preparations.  The first step is to deplete PBMC’s of cells expressing CD4 (CD4 T 
cells), CD14 (monocytes), and CD45RA (naïve T cells).  The second step is an 
enrichment step for cells expressing CD62L, a marker on CD45RO+ T cells for the 
central memory subset.  The resulting cell preparation, highly enriched for 
CD8+CD45RO+CD62L+ TCM, will then be activated with anti-CD3/CD28 beads.  After 
activation the TCM cells will undergo a lentiviral transduction to express the CD19-
specific CAR. 
Following transduction cells will be expanded in vitro with IL-2/IL-15 to achieve cell 
numbers sufficient for the research participant’s planned clinical cell dose and all 
related product release testing.  At the end of the culture, cells will be harvested, 
washed and formulated in cryopreservation media, and transferred to a 
cryopreservation bag.  Samples will be taken from each product prior to 
cryopreservation, and cryopreserved bag(s) will be frozen using a controlled rate 

 
 
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freezer.  Cryopreserved cells will be stored in the vapor phase in a controlled access 
LN2 freezer until released for clinical use. 
3.6.1 Lentiviral Vector CD19Rop-epHIV7 
The cloned DNA that will be used for the genetic modification of autologous T 
cells consists of a CD19-specific chimeric immunoreceptor (designated CD19R), 
which was generated by fusion of the human GM-CSF receptor alpha signal, 
CD19-specific ScFv, IgG4 Fc hinge, CD4 transmembrane and CD3zeta 
cytoplasmic signaling domain sequences, and was synthesized de novo by 
Geneart after codon optimization (thus, the name CD19Rop).  This CD19Rop 
sequence was inserted into the multiple cloning site of the epHIV7 lentiviral 
vector, so that its transcription is driven by the EF1 promoter.  The CD19Rop-
epHIV7 construct does not contain an intact 3’ long terminal repeat (LTR) 
promoter, so the resulting expressed and reverse transcribed DNA proviral 
genome in targeted cells will have inactive LTRs. 
As a result of this design, no HIV-I derived sequences will be transcribed from 
the provirus and only the therapeutic CD19Rop sequence will be expressed.  The 
removal of the LTR promoter activity in this self-inactivating vector is also 
expected to significantly reduce the possibility of unintentional activation of host 
genes 134.  Furthermore, this study will employ replication-incompetent lentivirus 
produced by the 4-plasmid co-transfection of producer cells (i.e., 293T renal 
carcinoma cells) 135. 
Briefly, the crippled CD19Rop-epHIV7 containing lentivirus was harvested from 
cultures of 293T cells that had been transiently transfected with the following four 
plasmids encoding the required components: 1) pCgp containing the HIV-1 gag 
and pol genes required for viral vector assembly; 2) pCMV-G containing the VSV-
G gene required for viral vector infectivity; 3) pCMV-rev containing the rev gene 
which assists in the transportation of the viral genome for efficient packaging; and 
4) the above described CD19Rop-epHIV7 transfer vector.   
4.0 Staging Criteria 
4.1 Pre-Enrollment  
4.1.1 Verification of Lymphoma 
Verification of history of intermediate grade B-cell lineage lymphoma (e.g., diffuse 
B-cell lymphoma, Mantle Cell lymphoma, transformed Follicular lymphoma), 
including histological verification.   
4.1.2 Imaging and/or Histophatological Confirmation 
Imaging and/or histopathological confirmation of relapsed disease after achieving 
first remission with primary therapy, or failure to achieve remission with primary 
therapy. 
4.1.3 Relapsed Disease 
Standard staging studies for extent of relapsed disease. 

 
 
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5.0 Research Participant Eligibility 
5.1 Inclusion Criteria at Time of Enrollment  
5.1.1 Confirmation of Diagnosis 
COH pathology review confirms that research participant’s diagnostic material is 
consistent with history of intermediate grade B-cell NHL (e.g., diffuse B-cell 
lymphoma, Mantle Cell lymphoma, transformed Follicular lymphoma). 
5.1.2 History of Relapse 
History of relapse after achieving first remission with primary therapy, or failure to 
achieve remission with primary therapy. 
5.1.3 Life expectancy 
Life expectancy >16 weeks 
5.1.4 Age 
Age at time of enrollment is ≥18 years.  
5.1.5 KPS 
KPS ≥70% 
5.1.6 Pregnancy 
Negative serum pregnancy test for women of childbearing potential. 
5.1.7 Selection Criteria 
Research participant has an indication to be considered for autologous stem cell 
transplantation. 
5.2 Exclusion Criteria at Time of Enrollment 
5.2.1 Study Specific Exclusion Criteria 
 
Fails to understand the basic elements of the protocol and/or the 
risks/benefits of participating in this phase I/II study.  Evidence of 
understanding includes passing the Protocol Comprehensive Screening given 
by the Research Subject Advocate (RSA).  A legal guardian may substitute 
for the research participant. 
 
Any standard contraindications to myeloablative HSCT per standard of care 
practices at COH. 
 
Dependence on corticosteroids. 
 
Currently enrolled in another investigational therapy protocol. 
 
HIV seropositive based on testing performed within 4 weeks of enrollment. 
 
History of allogeneic HSCT or prior autologous HSCT. 
 
Active autoimmune disease requiring systemic immunosuppressive therapy. 
 
Research participants who are to receive radioimmunotherapy (Zevalin-
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Research participants with known active hepatitis B or C infection. 
5.3 Pre Transplant Tests 
The following pre-study tests should be obtained prior to stem cell transplantation in 
accordance with good medical practice.  Results of these tests do not determine 
eligibility.  Minor deviations would be acceptable if they do not impact on research 
participant safety in the clinical judgment of the treating physician.   
 
CMV Titer 
 
Hepatitis Panel (which includes Hep A antibody, Hep B surface antigen, Hep 
B core antibody, and Hep C antibody) 
 
Hepatitis B Surface Antibody 
 
EBV, HSV and VZV Titer 
 
LDH measurement 
 
HIV 1/2 Antibody 
5.4 Eligibility to Undergo Autologous Myeloablative Transplantation 
with HPC(A) Rescue 
5.4.1 Candidate for Autologous Transplant 
Research participant meets all standard clinical parameters for candidates of 
autologous transplant as described in the current COH Hematopoietic Cell 
Transplant Standard Operating Policies, Procedures and Protocols – Patient 
Evaluation & Selection or Deferral for HCT. 
5.4.2 Scheduled for Chemotherapy 
Research participant is scheduled to receive a standard chemotherapy-based 
conditioning regimen, such as CBV or BEAM.  
5.4.3 Cryopreserved HPCA Product 
Research participant has a cryopreserved unselected HPCA product of at least 2 
x 106/kg CD34+ cells.  
5.4.4 Evidence of Stable or Improved Disease 
Research participant has evidence of improvement or stable disease after 
salvage therapy.  
5.5 Eligibility Criteria at Time of Infusion of Genetically Modified 
Autologous T Cells 
5.5.1 Released T Cell Product 
Research participant has a released cryopreserved T cell product. 
5.5.2 Cryopreserved Back-up 
Research participant has a cryopreserved back-up unselected HPC(A) product of 
at least 2 x 106/kg CD34+ cells. 
5.5.3 Autologous HPC(A) Procedure 
Research participant has undergone an autologous HPC(A) procedure. 

 
 
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5.5.4 Pulmonary 
Not requiring supplemental oxygen or mechanical ventilation, oxygen saturation 
90% or higher on room air. 
5.5.5 Cardiovascular 
Not requiring pressor support, not having symptomatic cardiac arrhythmias. 
5.5.6 Renal Function 
Adequate renal function defined as: Lack of acute renal failure/requirement for 
dialysis, as evidenced by creatinine <1.6. 
5.5.7 Liver Function 
Adequate liver function defined as: Total bilirubin 5.0. 
5.5.8 Neurological 
Research participant without clinically significant encephalopathy/new focal 
deficits. 
5.5.9 Infectious diseases 
No evidence of uncontrolled active infectious process. 
5.6 Criteria for Delaying or Cancelling T Cell Dose 
5.6.1 Delaying T Cell Dose 
Research participants who do not meet eligibility for T cell infusion on day +2 or 
day +3 may receive T cell infusion at a later date, after the medical issues are 
appropriately addressed, and once eligibility criteria for this event is achieved. 
5.6.2 Canceling the T Cell Dose 
Following are the criteria for canceling the T Cell Dose 
 
Failure to meet eligibility criteria on Section 5.5: (Eligibility Criteria at Time of 
Infusion of Genetically Modified Autologous T Cells) by day +45 post HPC(A) 
rescue 
 
Significant and rapid progression of lymphoma requiring alternative medical 
intervention that, in the opinion of the principal investigator or his/her 
designee, is not compatible with T cell therapy. 
6.0 Study Design 
This will be a Phase I/II, open-label, nonrandomized study in which adult research 
participants with high-risk intermediate grade B-cell lymphomas who are candidates for 
an autologous myeloablative stem cell transplant procedure will receive post-transplant 
immunotherapy with adoptively transferred autologous TCM-Enriched CD19R+ CD8+ T 
cells.  The trial consists of dose escalation by cohort (phase I portion), followed by 
expanded enrollment at the tolerable dose (phase II portion) for a potential total 
enrollment of fifty-seven research participants.  Cryopreserved T cell products will be 
infused at approximately day +2 or day +3 following HPC(A) reinfusion.  Research 
participants whose modified cellular product cannot be generated in sufficient numbers 
to achieve the assigned cell dose level will not be removed from the study and may 

 
 
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receive the modified cell dose generated.  Cell dose cohort advancement will be rule-
based as described in Section 12 (Statistical Considerations).  The research 
participant’s primary COH hematologist will manage the non-study specific aspects of 
their patient's medical management throughout the duration of this protocol and 
indefinitely thereafter. 
7.0 Treatment Plan 
7.1 PBMC Collection 
The leukapheresis product will be collected at COH Donor Apheresis Center (DAC) 
according to DAC operating procedures. The research participant must be evaluated 
by a physician prior to leukapheresis and not have a standard contraindication for 
this procedure per COH standard practices, this process may take approximately 1 
hour.  The procedure will be a single apheresis run of approximately 2-4 hours.  
Apheresis duration may be modified by the DAC physician as required by DAC 
policies without prior notification to the PI and will not result in a deviation.  Should a 
technical issue arise during the procedure or in the immediate processing of the 
product, such that it cannot be used for T cell production, a second procedure may 
be needed. 
7.2 Salvage/Priming Chemotherapy 
Research participants will commence with standard salvage chemotherapy per 
standard practice as prescribed by their treating hematologist who will use agents 
best suited for individual research participants based on their response to prior 
therapy and organ toxicity considerations.  Mobilization for autologous stem cell 
collection with cytoreductive chemotherapy and G-CSF and/or Plerixafor will be 
conducted per current COH HCT Clinical Program Standard Operating Policies, 
Procedures and Protocols.  Research participants with evidence of progressive 
disease after salvage chemotherapy will not be considered for this study (see 
Section 5.4.4). 
7.3 Pre-transplant Rituximab Therapy for B-Cell Depletion 
Since CD19-specific T cells will also target normal CD20+ (CD19+) B cells, the B cell 
numbers will be lowered using rituximab to reduce infusional toxicities attributable to 
TCM cell activation upon receiving the genetically modified CTL and also increase 
availability of infused T cells to immediately target lymphoma cells.  Furthermore, 
rituximab may blunt a humoral immune response against the genetically modified T 
cells.  If rituximab is not given as part of the Salvage/Priming chemotherapy regimen, 
research participants will receive a single intravenous infusion of rituximab (chimeric 
anti-CD20 antibody) at the discretion of the PI at 375 mg/m2 within 4-weeks of the 
planned auto-HSCT procedure.  Rituximab infusion will be per COH standard 
practice including premedication with diphenhydramine and acetaminophen and 
hydrocortisone  
7.4 Mobilization with G-CSF and/or Plerixafor 
Mobilization with G-CSF and/or with Plerixafor will be started after completion of 
salvage/priming chemotherapy and rituximab, if salvage chemotherapy is required.  
G-CSF and/or Plerixafor will be used per institutional standard of practice (HCT SOP 

 
 
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“Mobilization of Peripheral Blood HPCs for Apheresis”) for mobilization of peripheral 
blood stem cells and will be started after stem cell transplant at Day +5. 
7.5 Hematopoietic Progenitor Cell, Apheresis and Product Manipulation 
7.5.1 HPC, Apheresis Procedure 
Apheresis will be performed on a continuous flow cell separator according to 
Donor Apheresis Center guidelines and standard of care.   
7.5.2 Cryopreservation of Back-Up HPC Product – Phase I Arm 
During the time of initial stem cell collection, an additional number of CD34+ cells 
will be collected to re-establish normal hematopoiesis after high dose 
chemotherapy (minimum of 2.0 x 106 cells/kg) for research participant’s within the 
Phase I Arm of the study.  
7.6 Myeloablative Conditioning Regimen 
Conditioning regimen for the autologous stem cell transplant will be administered per 
institutional standards, as outlined in the current COH HCT Clinical Program 
Standard Operating Policies, Procedures, and Protocols.  
7.7 HPC(A) Cell Infusion 
The cryopreserved HCT product will be thawed and infused according to institutional 
standard of practice on Day 0 of transplantation.  Premedication with 
diphenhydramine, mannitol, hydrocortisone and acetaminophen will be as per 
institutional policy. 
7.8 Adoptive Transfer of Cryopreserved TCM-Enriched CD19R+CD8+ T 
Cell Products 
The autologous cryopreserved T cell product will be manufactured and released for 
use in accordance with SOPs provided in an FDA IND for this project.  A description 
of the manufacturing and release for use requirements are provided within the IND 
which is managed by COH Office of IND Development and Regulatory Affairs 
(OIDRA).  On Day +2 or Day +3 after HSCT, when research participants meet 
protocol specified eligibility criteria for T cell infusion (Section 5.5: Eligibility Criteria 
at Time of Infusion of Genetically Modified Autologous T Cells), the cryopreserved 
unit will be thawed, washed, reformulated based on % CAR positivity and then 
transported to research participant’s bedside.  Research participants will be pre-
medicated at least 30 minutes prior to T cell infusion with 15 mg/kg of 
acetaminophen P.O. (max. 650 mg.) and diphenhydramine 0.5-1 mg/kg I.V. (max 
dose 50 mg).   Clinically acceptable alternatives may be used if research participant 
is intolerant. 
The morning of T cell infusion preparation a sample of the T cell product will be sent 
for sterility analysis.  Results will be obtained after the product has been infused.  In 
the event that there is a positive microbiology culture the PI or designee must be 
notified immediately.  Standard practice of care will be followed to treat participants 
having a bacterial, fungal or viral infection in addition to standard prophylaxis, with 
the agent chosen to cover the specific organism identified while taking into account 
any patient specific antibiotic allergies.  Treatment will be at the PI or designee’s 
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7.9 Summary of Correlative Studies 
Peripheral blood, bone marrow and lymph node samples will be collected from 
research participants at the designated time points defined in Section 8.0: Study 
Parameters and Calendar, and Appendix B: Study Parameters and Calendar.  
Samples will be delivered, processed, stored, and evaluated in accordance with 
established laboratory practices at COH.  Correlative studies performed, but not 
limited to, are as follows:  
7.9.1 WPRE Q-PCR Determination of Frequency of Gene Modified 
Cells in the Circulation/Bone Marrow 
The magnitude and duration of persistence of adoptively transferred TCM cells 
and accumulation of infused T cells in bone marrow and lymph node will be 
measured by Q-PCR with primers specific for the lentiviral WPRE (woodchuck 
hepatitis virus post-transcriptional regulatory element) sequence normalized to 
cell numbers to read out frequency of gene marked cells in mononuclear cell 
preps. 
7.9.2 Ex vivo Immunophenotyping/Functional Analysis   
Direct ex vivo analyses of persisting infused cells will be performed directly on 
peripheral blood, bone marrow samples or lymph node samples using 
multiparameter flow cytometric analyses. In vivo activation/memory/effector 
phenotype of persisting and expanded infused cells will be analyzed if at least 
1% of total lymphocytes in samples collected is shown to be immunoreceptor–
positive and appropriate antibody reagents are available to detect 
immunoreceptor-positive cells in whole blood samples.  A panel of specific 
antibodies will be used to evaluate the differentiation status (such as naïve, 
effector, memory, effector memory, central memory) of persisting gene-modified 
T cells.  Correlation of initial activation status of infused cells and in vivo T cell 
persistence and direct ex vivo characterization of anti-tumor effector functions of 
persisting infused cells will also be performed. 
7.9.3 Cytokine Analysis 
Research participants will have weekly peripheral blood draws for the first month 
post T cell infusion, and then monthly for the first year, which will be analyzed for 
the presence of cytokines such as IFN-g. We will also test the level of IFN-g and 
other cytokines released by the corresponding final cell product after in vitro 
antigen stimulation.   
7.10 Supportive Care 
7.10.1 Supportive Care for Regimen Related Toxicities 
All standard supportive care measures for patients undergoing HSCT will be 
used at the discretion of the research participant's COH oncologist.  Standard 
supportive care guidelines are outlined in Hematopoietic Cell Transplant Clinical 
Program Standard Operating Policies, Procedures, and Protocols. 
Decisions regarding antibiotics choices, when hyperalimentation is used and 
when to use blood products will be determined by the treating clinician.  
Menstruating females should receive an anovulatory agent during the 

 
 
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thrombocytopenic period.  The use of cytokines, such as G-CSF to facilitate 
engraftment, is permitted per institutional guidelines. 
7.10.2 Infectious Disease Prophylaxis and Monitoring 
Active infections occurring after study enrollment will be treated according to the 
standard of care as defined by the COH HCT Clinical Program Standard 
Operating Policies, Procedures, and Protocols. 
7.10.3 Contra-Indicated Medications 
Unless the Principal Investigator or her designee provides an exception, the 
following agents, other than specified in the protocol, are not allowed once T cell 
infusion commences through day 100: 
 
systemic corticosteroids   
 
chemotherapy 
 
immunosuppressive agents  
 
immunotherapy  
 
other investigational agents 
8.0 Study Parameters and Calendar 
COH Standard Policies and Procedures will be performed and followed in addition to the 
listed study procedures below.  Bone marrow examination and lymph node sampling 
may be cancelled by the PI or designate.  Note that the planned amount of blood drawn 
for this protocol in the first year (time of enrollment to month +12 post T cell infusion) is 
approximately 669 cc.  Additional diagnostic test may be performed as required for AE 
reporting under Sections 11.5 of the protocol to delineate AEs. 
8.1 Enrollment 
8.1.1 Evaluation of Eligibility 
Evaluation of research participant’s eligibility after signing the informed consent 
will include the following; however, procedures completed within 30 days of the 
informed consent signing will not be duplicated and will, therefore, be used to 
document eligibility: 
 
Documented protocol comprehension assessment by Research Subject 
Advocate  
 
Review by COH pathologists of available pathologic specimens to confirm 
history of intermediate grade B-cell NHL (e.g., diffuse B-cell lymphoma, 
Mantle Cell lymphoma, transformed Follicular lymphoma). 
 
Documentation of relapsed disease after achieving first remission with 
primary therapy or failure to achieve remission with primary therapy. 
 
Review of available CT and nuclear medicine scans. 
 
History and Physical Exam, Vital Signs, KPS. 
 
Females and males of reproductive potential must use a physician-approved 
contraceptive method for at least two weeks prior to, during, and two months 
after T cell infusion. 

 
 
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Serum pregnancy test for post-menarchal women without a history of tubal 
ligation or hysterectomy 
 
Initiation of the following tests: 
o 
EBV, CMV and HIV serologies 
 
BSA (will be re-calculated throughout treatment as needed) 
 
CBC, Differential, Platelet Count 
 
Comprehensive Metabolic Panel 
 
Bone marrow examination per COH standard policies and procedures for 
HCT (may be cancelled at the PI or designees discretion) 
o 
Ex vivo Immunophenotyping / Functional Analysis Correlative Studies 
8.2 HPC(A) Transplant  
8.2.1 Prior to HPC(A) 
Prior to HPC(A) the following must be performed. 
 
CT and FDG-Pet or PET/CT combination to evaluate lymphoma disease 
status.  
 
Bone marrow examination that in addition to standard disease specific 
pathologic evaluation includes Correlative Studies (may be cancelled at the 
PI or designees discretion). 
 
55 cc peripheral blood collected for Correlative Studies and Cryopreservation 
of PBMC and Plasma 
8.2.2 Day 0 - HPC(A) Transplant 
On Day 0 of HPC(A) Transplant, COH standard policies and procedures for HCT 
must be followed. 
8.2.3 Day +2 or Day + 3 Post HPC(A) Transplant 
T Cell Infusion on Day +2 or Day +3 post HPC(A) Transplant, the following must 
be performed.  If, in the opinion of the PI, or her designee this must be delayed, 
the procedure may be delayed up to Day+45 following HSCT. 
 
Progress notes including vital signs (pulse rate, temperature, respiratory rate, 
blood pressure) 
 
KPS  
 
Complete blood count, differential, platelet count 
 
Chemistry panel - per COH standard policies and procedures for HCT 
 
35 cc peripheral blood will be collected for Correlative Studies (drawn prior to 
TCM cell infusion) including, but not limited to, the following: 
o 
WPRE Q-PCR 
o 
Ex vivo Immunophenotyping/Functional Analysis 
 
CTCAE evaluation using version 4 

 
 
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8.2.4 Day +5 (+/-3) Post Stem Cell Transplant 
At Day +5, begin G-CSF (5 µg/kg/day) following institutional standard of practice. 
8.2.5 Day +60 (+/- 3) Post Stem Cell Transplant 
 
CT and FDG-Pet or PET/CT combination  
 
Bone marrow examination that in addition to standard disease specific 
pathologic evaluation (may be cancelled at the PI or designees discretion), 
includes Correlative Studies.  Correlative tests to include, but not limited to, 
the following: 
o WPRE Q-PCR 
o Ex vivo Immunophenotyping/Functional Analysis 
8.2.6 Day +100 (+/- 3) Post Stem Cell Transplant 
 
Bone marrow examination that in addition to standard disease specific 
pathologic evaluation (may be cancelled at the PI or designees discretion), 
includes: 
o WPRE QPCR 
o Ex vivo Immunophenotyping/Functional Analysis 
 
Lymph node biopsy/removal of a pathologic lymph node that is accessible 
(such as in the axilla or groin) if lymph node is detectable within 100 days 
post transplant. 
8.2.7 6 month Evaluations: +6, +12, +18 and +24 months Post Stem 
Cell Transplant 
 
CT and FDG-Pet or PET/CT combination  
Scans may be cancelled if they were/are performed as part of standard of 
care within +/- 1 month. 
8.3 T Cell Infusion 
8.3.1 Within 24 hours Post T Cell Infusion  
35 cc peripheral blood will be drawn for Correlative Studies including, but not 
limited to, the following: 
 
WPRE QPCR 
 
Ex vivo Immunophenotyping/Functional Analysis 
8.3.2 Day 7 (+/- 3) Post T Cell Infusion 
At Day 7 (+/- 3) Post T Cell Infusion 35 cc peripheral blood will be drawn for 
Correlative Studies including, but not limited to, the following: 
 
WPRE QPCR 
 
Ex vivo Immunophenotyping/Functional Analysis 
8.3.3 Day 14 (+/- 3) Post T Cell Infusion 
At Day 14 (+/- 3) 35 cc peripheral blood will be drawn for Correlative Studies 
including, but not limited to, the following: 
 
WPRE QPCR 
 
Ex vivo Immunophenotyping/Functional Analysis 

 
 
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8.3.4 Day 21 (+/- 3) Post T Cell Infusion 
At Day 21 (+/- 3) Post T Cell Infusion, 35 cc peripheral blood will be drawn for 
Correlative Studies including, but not limited to, the following: 
 
WPRE QPCR 
 
Ex vivo Immunophenotyping/Functional Analysis 
8.3.5 Day 28 (+/- 3) Post T Cell Infusion 
Day 28 (+/- 3) Post T Cell Infusion: 
35 cc peripheral blood will be drawn for Correlative Studies including, but not 
limited to, the following: 
 
WPRE QPCR 
 
Ex vivo Immunophenotyping/Functional Analysis 
Unilateral Bone Marrow Aspirate (may be cancelled at the PI or designees 
discretion) 
 
Standard pathological evaluation 
 
WPRE Q-PCR 
 
Ex vivo Immunophenotyping/Functional Analysis 
8.3.6 Monthly Post T Cell Infusion for 1 year (starting at Month 2) 
35 cc peripheral blood will be drawn for Correlative Studies including, but not 
limited to, the following: 
 
WPRE QPCR 
 
Ex vivo Immunophenotyping/Functional Analysis 
o B cell  and IgG analysis 
 
CBC, Differential, Platelet Counts, Comprehensive Metabolic Panel and LDH 
measurements 
8.3.7 3 month Evaluation: Post T Cell Infusion (may be combined with 
Day +100 visit) 
 
Additional 25 cc peripheral blood will be drawn for Correlative Studies for a 
total of 60 cc at this time point.  Correlative tests to include, but not limited to, 
the following: 
o WPRE QPCR 
o Ex vivo Immunophenotyping/Functional Analysis 
 
HIV-1/2 antibody testing for short-term follow-up plan (reference Section 8.4) 
8.3.8 6 Month Evaluation Post T Cell Infusion 
 
HIV-1/2 antibody testing for short-term follow-up plan (reference Section 8.4) 

 
 
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Up to 60 cc peripheral blood will be drawn for Correlative Studies including, 
but not limited to, the following: 
o WPRE QPCR 
o Ex vivo Immunophenotyping/Functional Analysis (B cell  and IgG 
analysis) 
o CBC, Differential, Platelet Counts, Comprehensive Metabolic Panel and 
LDH measurements 
 
Bone marrow examination that in addition to standard disease specific 
pathologic evaluation (may be cancelled at the PI or designees discretion), 
includes: 
o WPRE QPCR 
o Ex vivo Immunophenotyping/Functional Analysis 
8.3.9 Yearly Evaluations: 12, 24 and 36 Months Post T Cell Infusion 
 
CT and FDG-Pet or PET/CT combination  
 
Up to 60 cc peripheral blood will be drawn for Correlative Studies including, 
but not limited to, the following: 
o WPRE QPCR 
o Ex vivo Immunophenotyping/Functional Analysis (B cell  and IgG 
analysis) 
o CBC, Differential, Platelet Counts, Comprehensive Metabolic Panel and 
LDH measurements 
 
Bone marrow examination that in addition to standard disease specific 
pathologic evaluation (may be cancelled at the PI or designees discretion), 
includes: 
o WPRE QPCR 
o Ex vivo Immunophenotyping/Functional Analysis 
 
HIV-1/2 antibody testing for short-term follow-up plan (reference Section 8.4) 
8.4 Short-term Follow-up Plan 
COH patients who are recipients of gene transfer products involving the use of 
lentiviral vectors are required by the FDA to undergo follow-up testing for replication 
competent lentivirus (RCL) for no less than 15 years.  The short-term follow-up 
testing for RCL will be performed under COH IRB 09174 until the research 
participant completes the protocol specified follow-up period of 36 months and will 
consist of analysis of whole blood samples for Human Immunodeficiency Virus (HIV-
1/2) antibody at the pre-treatment (baseline), 3 month, 6 month, 12 month, 24 month, 
and 36 month time points. 
8.5 Long-term Follow-up Plan 
Research participants treated on this study will be asked to participate in two of 
COH’s long-term follow-up protocols: (1) COH IRB 02025: Long-Term Follow-up of 
Recipients of Gene Transfer Research at City of Hope, as specified in the guidance 
“Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events” 
and (2) COH IRB 00029: Long-Term Following Hematopoietic Cell Transplantation 
per institutional policy.  

 
 
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COH patients who are recipients of hematopoietic cell transplantation enroll onto 
COH IRB 00029 after receiving transplantation.  COH IRB 00029 consists of the use 
of an annual status short form, a periodic Long-Term Follow-up Complications form, 
and a secondary malignancies form.  In the event of the death of a research 
participant in the time period between the follow-up time-points, information will be 
obtained from the responsible physician or a specified family member (usually a 
parent or a spouse). 
COH patients who are recipients of gene transfer products enroll onto COH IRB 
02025 upon completion of the protocol required follow-up period.  COH IRB 02025 
consists of the continued testing for RCL (initial testing at the pre, 3, 6, 12, 24 and 36 
month time points previously required under COH IRB 9174 follow-up, reference 
Appendix B).  Follow-up under COH IRB 02025 will include the following: 
 
Physical examination which will include assessment for reproductive risk and 
risk to the fetus; autoimmune toxicities (such as new evidence or 
exacerbation of a prior rheumatologic or other autoimmune disorder); 
 
Continued testing for RCL (initial testing at the pre, 3, 6, 12, 24 and 36 month 
time points previously required under COH IRB 09174 follow-up) which will 
be 
performed 
by 
analysis 
of 
whole 
blood 
samples 
for 
Human 
Immunodeficiency Virus (HIV-1/2) antibody on an annual basis; 
 
Evaluation of T cell persistence which will include testing for long-term vector 
persistence and insertional mutagenesis until at such time T cells become 
undetectable. 
All long-term toxicities will be reported to the Agency in accordance with CFR 
312.32. 
9.0  Monitoring Toxicities 
9.1 Management of Constitutional Symptoms Associated with T cell 
Infusion 
Mild transient symptoms have been observed with LAK, TIL, and T cell clone 
infusions and may occur in research participants being treated with TCM-enriched 
CD19R+CD8+ T cell infusions.  The management of these symptoms is outlined 
below. 
9.1.1 Fever 
Fever, chills and temperature elevations >101°F will be managed with additional 
Tylenol as clinically indicated.   Demerol I.V. (max dose 50 mg) may be given for 
chills.  Additional methods such as cooling blankets may be employed for fevers 
resistant to these measures.  Research participants that develop fever or chills 
will have a blood culture drawn.  Appropriate selection of empiric antibiotics for 
treatment of neutropenic fever will be administered to research participants who, 
in the opinion of the physician in attendance, appear septic; alternate antibiotic 
choices will be used as clinically indicated. 
9.1.2 Hypotension 
Transient hypotension will initially be managed by intravenous fluid 
administration; however, research participants with persistent hypotension will be 
admitted for definitive medical treatment. 

 
 
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9.1.3 Hypoxemia 
Hypoxemia will be managed with supplemental oxygen.  An etiology for 
hypoxemia will be worked up per standard clinical practice. 
9.2 Management of Acute Adverse Event(s) Attributable to This Study 
9.2.1 Management of Acute Adverse Event(s) Attributable to Infused 
T Cells 
Following T cell infusions, the following rules will be applied for adverse events 
that are greater than grade 2 and are probably or definitely attributed to T cell 
infusion: 
 
Research participants experiencing a new grade 3 or higher toxicity with 
an attribution of ≥4 (probable or definite) to the infused T cells rather than 
expected toxicities attributable to the myeloablative preparative regimen, 
that in the opinion of the Principal Investigator puts the research 
participant in significant risk of an untoward outcome if measures are not 
taken to ameliorate the toxicity and commence with corticosteroid 
treatment (reference section 9.3).   
 
Additional measures may also be taken to resolve the toxicity should the 
protocol specified corticosteroid treatment plan failure to ablate side 
effects associated with T cell infusion such as, but not limited to, 
immunosuppressive medications such as ATG/Campath and calcineurin 
inhibitors, or chemotherapy agents with immunosuppressive properties 
the administration of other immunosuppressive agents. 
 
If applicable, all research participants will be hospitalized for at least the 
first 72 hours of receiving corticosteroids. 
9.2.2 Management of aHSCT Engraftment Failure 
Back-up cryopreserved HPC(A) product (reference section 7.5.2) will be 
available to those research participants experiencing engraftment failure 
(reference section 12.3.1). 
9.2.3 Management of Infectious Complications from Prolonged 
Lymphopenia 
Standard of practice will be used for the treatment of infectious complications 
from prolonged lymphopenia including, but not limited to, trimethoprim-
sulfamethoxazole (or an equivalent) for the prevention of pneumocystis jiroveci, 
acyclovir for herpes simplex and herpes zoster infection, and an azole drug for 
prevention of invasive fungal disease. Routine screening and treatment of CMV 
reactivation will also be performed in these research participants. 
9.3 Schedule of Systemic Corticosteroids to Ablate Side Effects of 
Genetically Modified T cells 
The following table (Table 2: Steroid Dose Schedule for Ablation of T cell Side 
Effects) shows the dose schedule for steroids dose used to ablate any side effects 
observed upon T cell infusion: 
 

 
 
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Table 2: Steroid Dose Schedule for Ablation of T cell Side Effects 
Day of Dose 
Steroid Dose  
1 
Intravenous Solu-Medrol at 2 mg/kg divided q 8hr  
2 
Intravenous Solu-Medrol at 1 mg/kg divided q 8hr  
3-4 
Prednisone at 1 mg/kg P.O. BID or Intravenous Solu-Medrol at 0.8 mg/kg BID 
(begin wean if symptom improvement)  
5-6 
Prednisone at 0.5 mg/kg P.O. BID or Intravenous Solu-Medrol at 0.4 mg/kg BID 
7-8 
Prednisone at 0.25 mg/kg P.O. BID or Intravenous Solu-Medrol at 0.2 mg/kg BID  
9-10 
Prednisone at 0.1 mg/kg P.O. BID or Intravenous Solu-Medrol at 0.08 mg/kg 
BID  
11+ 
Prednisone at 0.1 mg/kg P.O. q day or IV Solu-Medrol at 0.08 mg/kg q day   
*Corticosteroid dosing may be extended at the discretion of the PI or designee should significant symptoms fail to resolve. 
Such steroid treatment strategies have been clinically shown to reverse the side 
effects of adoptively transferred cytolytic immune cells such as T cells 136-138. 
9.4 Expected Adverse Events Associated with this Protocol 
CTCAE v4.0 parameters will be used for toxicity grading.  The table below (Table 3: 
Expected Adverse Events Attributable to Stem Cell Transplant or T Cell Infusion) 
lists regimen related toxicities attributable to the following treatment procedures listed 
below. 
 
Table 3: Expected Adverse Events Attributable to Stem Cell Transplant or 
T Cell Infusion  
Expected Adverse Events Attributable to Stem Cell Transplant 
Treatment/Procedure 
Symptoms Associated with Treatment/Procedure 
Placement of Hickman 
catheter 
Pain, Bruising, Bleeding, Pneumothorax, Insertion site infection, 
Bacteremias 
High dose chemotherapy 
Nausea, Vomiting, Mucositis, Fatigue, Alopecia, Anorexia, Diarrhea, 
Neutropenic Fevers, Amemorrhea, Infertility, Pancytopenia, Bacteremia, 
Myelodysplastic syndrome, Elevations of liver enzymes, Veno-occlusive 
disease of the liver (VOD), Pneumonitis, Neuropathy, Myalgias, Palmar-
plantar erythema 
Rituximab 
Fever, Chills, Rigors, Nausea, Urticaria, Angioedema, Bronchospasm, 
Hypotension 
Expected Adverse Events Attributable to T Cell Infusion 
Treatment 
Adverse Events Associated with Treatment 

 
 
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T Cell Infusion 
 ≤ Grade 4 Fever for less than 48 hours after T cell infusion  
 ≤ Grade 2 Chills lasting for less than 24 hours after T cell infusion  
 ≤ Grade 3 Cough lasting for less than 24 hours after T cell infusion  
 ≤ Grade 3 Transaminases for lasting for less than 7 days after T cell 
infusion  
 ≤ Grade 2 Tachycardia lasting for less than 48 hours after T cell 
infusion 
 ≤ Grade 3 Hypotension lasting for less than 48 hours after T cell 
infusion 
 ≤ Grade 3 Cytokine release syndrome lasting for less than 48 hours 
after T cell infusion 
 
Adverse events from the above list occurring within the specified time will: 
 
Not result in an expedited adverse event reporting to the FDA 
 
Not result in ablation of T cells with corticosteroids 
9.5 Adverse Events to Be Monitored 
Toxicity criteria for this protocol will be per the NCI Common Toxicity Criteria For 
Adverse Events (CTCAE) v4.0.1  A copy of the complete CTCAE may be 
downloaded from the CTEP home page (http://ctep.info.nih.gov/).  Any toxicity 
reported by research participants while receiving treatment or in follow-up for which 
there is no specific CTCAE designation will be graded on the following scale: 
 
Grade 0 - no toxicity, 
 
Grade 1 -mild toxicity, usually transient, requiring no special treatment and 
generally not interfering with usual daily activities,  
 
Grade 2 - moderate toxicity that may be ameliorated by simple therapeutic 
maneuvers, and impairs usual activities,  
 
Grade 3 -severe toxicity that requires therapeutic intervention and interrupts 
usual activities.  Hospitalization may be required or may not be required.  
 
Grade 4 - life-threatening toxicity that requires hospitalization 
 
Grade 5 - death related to adverse event 
To ensure that treatment-related conditions are distinguished from disease-related 
conditions, attribution of causality will be established in grading adverse events. All 
symptoms, signs, or diseases (including abnormal laboratory findings), that might be 
associated with investigational agents or therapies will be captured and graded.  For 
each event, the Principal Investigator or his/her designee in conjunction with the 
physician or research nurse who examined and evaluated the research participant, 
will assign the attribution.  Data managers who are removed from the clinical 
assessment of the research participant will not perform this.  Attribution of adverse 
events attributed to the infused genetically modified T cells should be determined 
using the following criteria: 
 
Definite – (5) The adverse event is clearly related to the infused T cells 
                                                     
1 ncictephelp@ctep.nci.nih.gov 
 

 
 
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Probable – (4) The adverse event is likely related to the infused T cells 
 
Possible – (3) The adverse event may be related to the infused T cells 
 
Unlikely – (2) The adverse event is doubtfully related to the infused T cells 
 
Unrelated – (1) The adverse event is clearly not related to the infused T cells 
Deaths occurring 30 days or later from T cell infusion and death from tumor 
progression will be scored as a grade 5 toxicity; however, those with an attribution of 
unlikely or not related, as determined by the Principal Investigator and his/her 
designee, will not result in termination of the study. 
All Serious Adverse Events (SAEs) regardless of attribution shall be reported in an 
expedited manner according to Section 11.5: Adverse Event Reporting. 
Common Toxicity and Adverse Events shall be documented on an approved Case 
Report Form (see Appendix C). 
9.6 Criteria for Research Participant Accrual 
9.6.1 Phase I Accrual Interval 
9.6.1.1 Accrual within a Cohort 
 
Cohort Advancement Rule for Dose Level 0 (50x106 CAR+ TCM): The 
minimum time interval between infusion of TCM cells in one research 
participant and infusion of TCM cells in the next research participant receiving 
Dose Level 0 (50x106 CAR+ TCM) is four weeks. 
 
Cohort Advancement Rule for Dose Level 1 and Above:  Research 
participants will receive their assigned T cell dose in cohorts of 3 (reference 
Section 12 [Statistical Considerations]). 
9.6.1.2 Accrual for Cohort Advancement 
The minimum time interval between first infusion of TCM cells at a set dose 
and the first infusion of TCM cells at the next dose escalation is 3 months and 
is dependent on the dose escalation guidelines provided in Section 12.1.1, 
Table 5: Dose Escalation Guidelines. 
9.6.2 Accrual for Advancement into the Phase II Arm 
The minimum time interval between infusion of TCM cells in the last research 
participant on the Phase I arm of the study and infusion of TCM cells in the first 
research participant on the Phase II arm of the study is 3 months.  
9.7 Research Participant Premature Discontinuation 
Research participants who do not receive the T cell infusion will be considered to 
have prematurely discontinued the study.  The reasons for premature discontinuation 
(for example, voluntary withdrawal, toxicity, and death) must be recorded on the case 
report form.  Research participants who do not receive T cell therapy may continue 
to be monitored as stipulated in the protocol.  Potential reasons for premature 
discontinuation include: 
 
In the judgment of the PI, or his/her designee, the research participant is too 
ill to continue. 
 
Research participant/family is noncompliant with study therapy and/or clinic 
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Pregnancy. 
 
Voluntary withdrawal; a research participant or his/her parents/legal 
guardians may remove himself/herself from the study at any time without 
prejudice. 
 
Significant progression of lymphoma requiring alternative medical 
interventions that in the opinion of the PI or his/her, designee, are not 
compatible with T cell therapy. 
9.8 Study Closure 
The study will be halted: 
9.8.1 Lack of Improvement 
If any research participant receiving systemic corticosteroids for ablation of T 
cell-mediated side effects does not show an improvement to a toxicity grade of 
<3 within 14 days of initiating ablation procedures or;  
9.8.2 Persistence of TCM Cells 
If there is no identifiable persistence of infused TCM cells in 0 of the first 6 
research participants after reaching the MTD or highest manufactureable dose 
(reference Section 12.3.2).  
9.8.3 Study Termination 
The study is terminated by the PI or her designate, the COH IRB, or the Food 
and Drug Administration.   
10.0 Criteria for Evaluation and Endpoint Definitions 
10.1 Criteria for Evaluation 
Toxicity and adverse event will be assessed using CTCAE v4.0 from data obtained 
at each clinical assessment as outlined in Appendix B.  Symptoms and toxicities will 
be evaluated as follows:  
 
Physical exam and Blood Chemistry/Hematology results 
 
Adverse event reporting 
10.2 Disease Status 
The grading of the tumor responses will be performed according to the Revised IWG 
response criteria (Cheson et al., J Clin Oncol 25:579, 2007), reference Appendix A. 
10.3 Dose Limiting Toxicity (see also Section 12.0) 
Definition of Dose Limiting Toxicity (DLT): 
 
any grade 3 or higher toxicity, with the exception of those listed in Section 
9.4; and designated as definitely or probably related (level of attribution) to 
the infusion of the TCM cells; and occurring within 28 days of T-cell infusion; 
 
any toxicity requiring the use of steroids to ablate side effects attributable to 
the infusion of the TCM cells, and occurring within 28 days of T-cell infusion; 
 
any toxicity which is a lower grade, but that increases in grade to a grade 3 or 
higher as a direct result of the TCM, and occurring within 28 days of T-cell 
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any grade 2 or greater autoimmune toxicity, and occurring within 28 days of 
T-cell infusion. 
Toxicities of any grade normally expected with an autologous stem cell transplant, as 
defined in Section 9.4, will not be considered a DLT with respect to protocol 
continuation, or dose escalation/de-escalation of TCM cell dose.  
11.0 Data and Safety Monitoring 
11.1 Definition of Risk Level 
This is a Risk Level 4 study, as defined in the “City of Hope Data and Safety 
Monitoring Plan”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx 
involving COH as the IND holder and a first-in-human gene therapy for ex vivo 
expanded autologous TCM-Enriched CD19R-CAR+ CD8+ T cells in conjunction with 
myeloablative chemotherapy and autologous HSCT rescue for patients with 
recurrent/refractory B-lineage non-Hodgkin lymphomas. 
11.2 Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, CRA/protocol nurse, and statistician is responsible for monitoring the 
data and safety of this study, including implementation of the stopping rules for 
safety and efficacy (as listed in Section 12.3).   
This study will utilize the Phase I tracking log to monitor data and safety for dose 
escalation, recording doses administered, and resultant adverse events. The tracking 
log will contain dose levels administered, DLT-defining adverse events, and 
documentation that the data from a dose level is complete before dose escalation.  
Those data and safety elements will be reported to the COH DSMC as applicable 
within the PMT report, which will be submitted quarterly from the anniversary date of 
activation, as noted in Table I below.. Protocol specific data collection will include the 
following items:  
 
Phase I arm:  
Assessment of Feasibility (i.e., ability to manufacture the required T cell dose 
from research participant’s leukapheresis product) data.   
 
 
Phase II arm (in addition to review listed in Phase I arm above): 
(1) Assessment of Hematologic engraftment,  
(2) Assessment of TCM persistence/Futility (the inability to achieve TCM 
persistence). 
 
In addition to the above, a Safety Committee will be convened, which is responsible 
for review of all adverse events associated with this protocol.    
General responsibilities of the committee include review of adverse events 
associated with the protocol, including grading of severity, and assignation of level of 
attribution to the stem cell transplant and the T cell infusion.   
Members   
The Committee shall consist of the following three members: 

 
 
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Protocol PI 
 
Physician from the Department of Hematology/Hematopoietic Cell 
Transplantation with expertise in transplantation, (one required, two allowed) 
 
Protocol Statistician, Suzette Blanchard (Dr. Longmate and Dr. Palmer can 
serve as alternate in Dr. Blanchard’s absence)  
 
Table I:  City of Hope PMT Reporting Timelines for the DSMC 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
 
11.3 Definitions 
Adverse event (AE) - An adverse event is any untoward medical experience 
or change of an existing condition that occurs during or after treatment, 
whether or not it is considered to be related to the protocol intervention.  
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is 
unexpected if it is not listed in the investigator’s brochure and/or package 
insert; is not listed at the specificity or severity that has been observed; is not 
consistent with the risk information described in the protocol and/or consent; 
is not an expected natural progression of any underlying disease, disorder, 
condition, or predisposed risk factor of the research participant experiencing 
the adverse event. 
Expected Adverse Event - Any event that does not meet the criteria for an 
unexpected event OR is an expected natural progression of any underlying 
disease, disorder, condition, or predisposed risk factor of the research 
participant experiencing the adverse event. 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or 
unexpected adverse event that results in any of the following outcomes: 
 
Death 

 
 
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Is life-threatening event (places the subject at immediate risk of death 
from the event as it occurred); 
 
Requires in-patient hospitalization (not required as part of the treatment) 
or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect 
 
Secondary Malignancy, or 
 
Any other adverse event that, based upon appropriate medical 
judgment, may jeopardize the subject’s health and may require medical 
or surgical intervention to prevent one of the outcomes listed above 
(examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood 
dyscrasisas of convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse). 
Unanticipated problem (UP) – Any incident, experience or outcome that 
meets all three of the following criteria: 
 
Unexpected (in term nature, severity, or frequency) given the following: 
a) the research procedures described in the protocol-related documents 
such as the IRB approved research protocol, informed consent 
document or Investigator Brochure (IB); and b) the characteristics of the 
subject population being studied; AND 
 
Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcomes may have been caused by the drugs, devices 
or procedures involved in the research); AND 
 
Suggests that the research places subjects or others at greater risk of 
harm (including physical, psychological, economic, or social harm) than 
previously known or recognized. 
11.4 Reporting of Unanticipated Problems and Adverse Events 
Unanticipated Problems: Most unanticipated problems must be reported to 
the COH DSMC and IRB within 5 calendar days according to definitions 
and guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any 
unanticipated problem that occurs during the study conduct will be reported to 
the DSMC and IRB by submitting electronically in iRIS (http://iris.coh.org). 
Serious Adverse Events - All SAEs occurring during this study, whether 
observed by the physician, nurse, or reported by the patient, will be reported 
according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and Table II below.  Those 
SAEs that require expedited reporting will be submitted electronically in iRIS 
(http://iris.coh.org/). 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse 
events that do not meet the criteria of serious OR are not unanticipated 
problems will be reported only in the continuation reports and PMT reports 
(see Table II below). 
 
 

 
 
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Table II:  City of Hope Adverse Event and Unanticipated Problem Reporting 
Timelines for the DSMC and IRB 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies 
Required Reporting Timeframe to DSMC  
Attribution 
UNEXPECTED 
EXPECTED 
 
Death while on active treatment or within 30 days of last day 
of treatment 
Possibly, Probably, Definitely 
5 calendar days 
Unlikely, Unrelated 
 
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar  days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
 
Grade 1 and 2 AND resulting in “hospitalization”  
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
 
 
 
 
 
 
 
 

 
 
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Externally Sponsored Studies 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days of last day 
of treatment 
Possibly, Probably, Definitely 
No DSMC reporting required - IRB reporting may be necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
No DSMC reporting required - IRB reporting may be necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, Definitely 
No DSMC reporting required - IRB reporting may be necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, Definitely 
No DSMC reporting required - IRB reporting may be necessary 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations Director. The 
DSMC will review the case and make a determination as to whether the study will be suspended, 
terminated, amended, or allowed to continue without amendment. 

 
 
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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a UP   
Possibly, Probably, Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
 
ADDITIONAL REPORTING REQUIRMENTS  
SAEs meeting the requirements for expedited reporting to the FDA, as defined in 21 
CFR 312.32, will be reported as an IND safety report using the MedWatch Form FDA 
3500A for Mandatory Reporting which can found at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
The PI or designee will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the 
FDA.  OIDRA will assist the PI with the preparation of the report and submit the report to 
the FDA in accordance with the following: 
 
any unexpected fatal or life threatening adverse experience associated 
with use of the drug must be reported to the FDA no later than 7 
calendar days after initial receipt of the information [21 CFR 
312.32(c)(2)]; 
 
any adverse experience associated with use of the drug that is both 
serious and unexpected must be submitted no later than 15 calendar 
days after initial receipt of the information [21 CFR 312.32(c)(1)] 
 
any follow-up information to a study report shall be reported as soon as 
the relevant information becomes available. [21 CFR 312.32(d)(3)] 
 
Special instructions 
Under COH-sponsored IND 14645, OIDRA, along with study staff, will prepare and 
submit the SAEs that meet the requirements of 21 CFR 312.32 to the FDA, followed by 
any required reporting to the NIH. 
 

 
 
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National Institutes of Health-Office of Biotechnology Activities (NIH-OBA) and FDA 
Reporting 
Since this study involves gene therapy, and City of Hope holds the IND, adverse events 
must also be reported to the NIH-OBA  
The PI/designee will submit the adverse event report through the City of Hope electronic 
reporting system, and then OIDRA will take responsibility for reporting of the adverse 
event to NIH-OBA.  
Follow up of study participants  
As required by the FDA, study patients will be followed long term (up to 15 years) and 
the PI will continue to report data and safety concerns to the FDA, DSMC, and IRB as 
they arise during this follow-up period. 
 
12.0 Statistical Considerations 
12.1 Phase I Study Arm  
12.1.1 Design and Sample Size for Phase I Arm of Study 
The objectives of the Phase I arm of the study are to assess the safety of cellular 
immunotherapy utilizing ex vivo expanded autologous TCM-Enriched CD8+ T cells 
genetically-modified to express a CD19-specific CAR in conjunction with a 
standard myeloablative autologous HSCT for patients with high-risk intermediate 
grade B-lineage non-Hodgkin lymphomas, and determine the MTD based on 
DLTs and describe the full toxicity profile. 
This study will use a two stage design based on the target toxicity equivalence 
range design 139 patterned after Ji, Li, Bekele (2007) 124, and Ji, Liu, Li, Bekele 
(2009).140-141 to define the escalation and de-escalation rules to evaluate select 
doses of TCM to determine the MTD.  The decision to escalate to a higher dose, 
stay at the same dose, or de-escalate to a lower dose is determined by the 
portion of the toxicity probability scale (0-1) in which our toxicity rate lands. The 
toxicity probability scale is portioned into three pieces based on the target toxicity 
probability (pT) and the identified range of equivalence (pT-ε1 to pT+ ε2).  If the 
study DLT rate is in the 0 to pT- ε1 range the guideline indicates escalate, if it is 
in the pT-ε1 to pT+ ε2 range the guideline indicates stay, and if the rate is in the 
pT+ ε2 to 1 range the guideline mandates de-escalate. Further we also 
implement the additional rules: 1) terminate the trial if dose level 1 is too toxic, 
and 2) if the current dose is safe but based on the data the next dose is deemed 
too toxic, stay at the current dose. 
Research participants will enter the protocol in cohorts of 3.  The dose schedule 
is provided in Table 4.  The dose guidelines will be assessed after 3 evaluable 
participants receiving the T cell dose being studied have completed the 28 day 
post T cell infusion follow-up.  In the first stage dose escalation will take whole 
steps (even numbered doses labeled in black starting at Dose 0) until a DLT is 
seen.  If a DLT is not seen, dose escalation will continue in whole steps using 
only the even numbered doses.  Once a DLT is seen, the dose will decrease to a 
dose (odd numbered doses labeled in grey) that is half way between the current 
dose and the next lower whole step dose.  All further escalation will be done in 

 
 
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half-steps.  For example if a DLT is seen at the 100M dose, the next dose 
studied would be 75M. 
The starting dose is 50M CAR+ T cells.  
Table 4: CAR+ Cell Dose Schedule 
Dose -1 
Starting Dose 
Dose 0 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Dose 6 
10M 
50M 
75M 
100M 
300M 
500M 
750M 
1000M 
* M = 106 CAR+ T cells 
 
 
Table 5 below provides the dose escalation/de-escalation guidelines for a target 
toxicity of 20% and ε1= ε2= 5% giving an equivalence range of 15%-25%. The 
numbers of research participants treated at the current dose is provided in the 
columns and the number of research participants experiencing a DLT in the rows.  
Note that this design is slightly more conservative than a 3+3 design as it de-
escalates at 1 DLT in 3 research participants, stays at 1 DLT in 6 research 
participants and escalates at 1 DLT in 9 research participants.  The Phase I portion 
of the study will end when 12 research participants are studied at a single dose level.  
Toxicity levels of 0.34 or higher are considered too toxic and doses that achieve that 
level will not be revisited.  The MTD will be the dose closest to target of 0.20 below 
0.34 based on isotonic regression. 
Note in the case that the cell sample manufactured is smaller than the defined dose, 
but is in the dose schedule range, we will allow the research participant to enter the 
study at the lower TCM dose level.  This data will be included in the calculation of the 
MTD using isotonic regression at the end of the study. 
 
Table 5: Dose escalation guidelines                                                                
(E= escalate, D=de-escalate, S=stay, DU=de-escalate and do not return to this 
dose). 
 
No. of Research participants Treated on 
the Current Dose Level 
No. of Research participants 
Experiencing a DLT 
 
3 
6 
9 
12 
0 
E 
E 
E 
E 
1 
D 
S 
E 
E 
2 
DU 
D 
S 
S 
3 
DU 
DU 
D 
S 
4 
 
DU 
DU 
D 

 
 
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Table 5: Dose escalation guidelines                                                                
(E= escalate, D=de-escalate, S=stay, DU=de-escalate and do not return to this 
dose). 
 
No. of Research participants Treated on 
the Current Dose Level 
No. of Research participants 
Experiencing a DLT
 
3 
6 
9 
12 
5 
 
DU 
DU 
DU 
 
Based on the results of 1,000 simulated trials considering 4 toxicity probability 
schedules (Table 6) for the 8 doses in combination with the trial specifications listed 
above, the median sample size was 24 with 95% confidence limits of 15 and 39 and 
the sample size at the MTD was  ≥ 12 in at least 93% of trials. Note Table 6 provides 
the rates at which each dose level for each schedule was chosen as the MTD (MTD 
rate) and the average number of research participants seen at each dose (Ave # 
Pts.). 
 

 
 
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Based on the above trial simulation data, the maximum sample size we expect for 
the Phase I portion of the trial will be 39 research participants +3 for replacement of 
unevaluable research participants, for a total of 42 research participants.  
Participants who do not receive T cells will be replaced. 
 
12.1.1.1 Amendments to Dose Plan 
 
Protocol Amendment V07 dated 11/20/2012:  
This study was initiated and has treated a total of two (2) patients where the T cell 
infusion dose was defined as total T cells (i.e., a dose of 50M equaled 50M total T cells 
infused). However, the protocol has been revised to define the infusion dose as total 
CAR+ T cells (i.e., a dose of 50M CAR+ T cells where the product is 80% CAR+ equals 
~62.5M total T cells infused).   
 
The definition of T cell infusion dose was revised to more accurately review toxicities 
associated with a cell dose of the active product (i.e., it is only the CD19-specific CAR + 
T cells that are expected to exhibit anti-tumor activity).  Toxicities attributable to CAR+ T 
Table 6:  Four Dose toxicity probability schedules for the above dose schedule 
and associated rates each dose level is identified as the MTD.   
Toxicity 
ProbabilitySchedules 
Dose levels 
 
1 
2 
3 
4 
5 
6 
7 
8 
Schedule 1 
0.025 
0.05 
0.10 
0.15 
0.20 
0.25 
0.35 
0.45 
MTD rate 
0.01 
0.1 
0.14 
0.25 
0.20 
0.22 
0.06 
0.02 
Ave # Pts. 
0.62 
4.6 
3.1 
5.9 
3.6 
4.4 
1.6 
0.9 
 
 
 
 
 
 
 
 
 
Schedule 2 
0.025 
0.10 
0.20 
0.37 
0.53 
0.69 
0.79 
0.84 
MTD rate 
0.04 
0.37 
0.41 
0.17 
0.01 
0 
0 
0 
Ave # Pts 
1.5 
7.3 
6.6 
4.9 
0.8 
0.56 
0 
0 
 
 
 
 
 
 
 
 
 
Schedule 3 
0.01 
0.02 
0.05 
0.1 
0.15 
0.2 
0.35 
0.50 
MTD rate 
0.00 
0.03 
0.07 
0.19 
0.19 
0.39 
0.11 
0.02 
Ave # Pts 
0.2 
3.6 
1.9 
5.7 
4.0 
6.5 
2.8 
1.2 
 
 
 
 
 
 
 
 
 
Schedule 4 
0.025 
0.025 
0.025 
0.20 
0.20 
0.20 
0.40 
0.40 
MTD rate 
0 
0.02 
0.21 
0.29 
0.14 
0.27 
0.04 
0.03 
Ave #Pts 
0.2 
3.5 
4.0 
6.7 
2.8 
4.5 
1.6 
1.0 

 
 
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cells are believed to be due to the interaction between CAR+ T cells and cells presenting 
the target antigen and as such our colleagues have also moved toward the approach of 
infusing doses based on CAR positivity.118,121  However, based on the manufacturing 
capacity of the GMP platform, the maximal dose that could be administered to a 
research participant (i.e., at Dose 6, 1000M CAR+ T cells) is limited to 3.0x109 total T 
cells (3000M). 
 
The first 4 research participant’s manufactured products have revealed a range of 46 to 
92% CAR+ T cell products.  With this range in CAR+ T cells, and our minimal range 
between doses, it will be difficult to evaluate dose level toxicities (reference figure 1 
below).   
 
Based on this change in definition of dose, the following decision has been made:  
Patient Numbers 01, 03 and 04 will be included in the cohort evaluation of dose level 0 
(50M).  Patient Number 02 (since their T cell product was only 46% CAR+) will be 
evaluated at dose level -0.5 (25M).  Moving forward, all doses will be based on the new 
definition of “T cell infusion dose = total CAR+ T cells”. 
 
Figure 1: Review of First 4 Research Participant’s Product and Dose Level 
Patient 
# 
Product % 
CAR + 
Infusion Details 
Dose Level for Evaluation 
Infused 
Dose 
Corrected 
Based on % 
CAR+ 
Dose Level  
Anticipated # 
CAR+ T Cells 
01 
86% 
50M total 
43M 
0 
50M 
02 
46% 
50M total 
23M 
-0.5 
25M 
03 
92% 
50M total 
46M 
0 
50M 
04 
91% 
50M CAR+ 
50M 
0 
50M 
 
 
Protocol Amendment V08 dated 03/01/2013: 
Since we have not seen T cell related toxicity on this protocol, we are requesting a 
revision to the accrual guidelines to allow study participants to accrue in cohorts of 3. 
This change will make it easier to accrue patients to this study in a more timely fashion.  
The changes are in Sections 9.6.1.1 (Accrual within a Cohort) and 12.1.1 (Design and 
Sample Size for Phase I Arm of Study).   
 
12.1.2 Endpoints for Phase I Arm of Study 
The objectives for the Phase I Arm of the Study are the determination of the MTD 
based on DLTs as previously defined in Section 10.3, and defining the full toxicity 
profile.  Determination of the full toxicity profile will include analysis of adverse 
events attributable to TCM adoptive transfer as reporting using CTCAE version 
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12.2 Phase II Study Arm 
12.2.1 Design and Sample Size for Phase II Arm of Study 
The objectives of the Phase II arm of the study are 1) to determine the tempo, 
magnitude, and duration of engraftment of the transferred T cell product as it 
relates to the number of cells infused, 2) to study the impact of this therapeutic 
intervention on the development of CD19+ B-cell precursors in the bone marrow 
as a surrogate for the in vivo effector function of transferred CD19-specific T-cells 
and 3) to describe the progression-free and overall survival of treated research 
participants on this protocol. 
The Phase II study is a prospective treatment study to estimate the rate of 
research participants receiving TCM-derived CD8+ T cells genetically-modified to 
express a CD19-specific CAR for which the transferred cells are detected in the 
circulation for 28 days (+/- 3 days) by WPRE Q-PCR.  The Phase II dose will be 
the MTD dose from the Phase I portion of the trial and the Phase I research 
participants seen at this dose will be included in the analysis for Phase II.  Based 
on 1000 simulated trials, 93% of the simulated trials had at least 12 research 
participants at the MTD.  The Phase II portion of the trial will begin when after we 
follow the last patient on the Phase I portion for 3 months and determine the 
MTD.  We will then add 12-15 more research participants at the MTD dose to 
achieve an overall the Phase II sample size of 24. Given a sample size of 24 
research participants the widest half-width of the confidence limit for the rate of 
TCM persistence will be less than or equal to 0.21. If, for example, a TCM 
persistence rate of 0.50 (12 research participants showing persistence/24 
evaluable research participants) was observed, the 95% lower and upper 
confidence limits would be 0.29 and 0.71, respectively. 
12.2.2 Endpoint for Phase II Arm of Study 
WPRE detection above background 28 days (+/- 3 days) after T cells are infused. 
12.3 Stopping Rules 
12.3.1 Failure of hematologic engraftment at 21 days 
Although a higher than usual engraftment failure rate is not expected, additional 
guidelines and criteria have been established which will be used to flag an 
unexpected number of research participants who fail to engraft within 21 days of 
the autologous hematopoietic stem cell infusion (reference Section 9.2.2: 
Management of HSCT Engraftment Failure for management of engraftment 
failure).  
The risk set to be used in the safety monitoring decision (to trigger a review of 
the protocol) will include all research participants that have received the T cell 
product as part of the TCM protocol.  
Every time a research participant fails to engraft within 21 days of transplant, we 
will look at the column for the total number of research participants that failed to 
engraft (X), and compare the number of research participants, N, who are in the 
risk set to NX.  If the number of research participants, N, is greater than NX, the 
number given in the bottom row of Table 7, then accrual will continue.   If N is 
less than or equal to NX, then the monitoring boundary has been crossed and a 
careful review of the trial data will be mandated. 

 
 
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Table 7:  Criteria for Suspending Accrual to Evaluate Safety 
X: # research participants who fail to engraft within 21 days 
1 
2 
3 
4 
Nx: safety boundary crossed if # research participants in 
risk set  (N) is less than or equal to Nx  (if N  Nx) 
≤ 1 
≤ 26 
≤ 51 
≤ 60 
 
These rules were selected to ensure a low probability that the safety boundary 
would be crossed, indicating excessive failure to engraft, if the true chance of 
failure to engraft were less than 1% and a high probability that the boundary 
would be crossed if the true chance of failure to engraft reached 10%.  Criteria 
for flagging an excessive number of research participants that fail to engraft 
within 21 days are based on the sequential probability ratio test with =0.10, 
=0.05, po=0.01 and pa=0.10.  Table 8 below summarizes these probabilities.  
The values in the table below are based on 10,000 simulations.  
 
Table  8: Probability of Crossing the Safety Boundary 
(i.e., too many research participants have TOX) 
True Chance of failure to engraft in 21 
days 
1% 
2.5% 
5% 
7.5% 
10% 
Probability 
of 
Crossing 
the 
Safety 
Boundary 
0.04 
0.21 
0.56 
0.81 
0.93 
 
12.3.2 Futility   
The study will stop if 0 out of 6 research participants experience TCM persistence 
28 days (+/- 3 days)  post T cell infusion after reaching the MTD (or highest 
dose), as the probability of 50% of the research participants achieving TCM 
persistence for 28 days (+/- 3 days)  is <0.02.  Note that if there is no toxicity, this 
result will be achievable after 15 evaluable research participants have been 
followed through 28 days (+/- 3 days) on this protocol (3 research participants on 
each dose (50,100, 500M) and 6 on a dose of 1000M). The concept is similar to 
stopping after the first stage of a Gehan test 142. 
12.3.3 Feasibility  
Feasibility will be examined separately in research participants that have 1) 
received any salvage chemotherapy prior to leukapheresis and 2) those that 
have not.  If we reach a rate of greater than 50% inability to manufacture the 
needed number of cells for the research participant’s assigned dose level after at 
least 6 research participants in the research participant group that has received 
salvage chemotherapy prior to leukapheresis, we will rewrite the protocol to 
make those patients ineligible for entry. If we reach a rate of greater than 50% 
inability to achieve the needed number of cells for the research participant’s 

 
 
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assigned dose  level after at least 6 research participants in the patient group 
that have not received salvage chemotherpay prior to leukapheresis we will stop 
the study. 
12.4 Statistical Analysis 
Tables will be created to summarize all toxicities and side effects by dose, course, 
organ and severity.  Rates and associated 95% confidence limits will be estimated 
for failure to engraft from the HSCT within 21 days, and rates of engraftment and 
persistence for TCM for 28 days (+/- 3 days). Time to engraftment and Progression 
free survival, and overall survival will be estimated using Kaplan-Meier methods. 
Descriptive statistics will be provided for the research participant demographics. 
12.5 Accrual 
Accrual is expected to be 10 evaluable research participants per year, where an 
evaluable research participant is defined as having received the protocol prescribed 
T cell infusion. The median sample size based on simulations of 1000 similar trials is 
24 research participants assuming a minimum of 9 and a maximum of 39 plus 3 for 
replacement of evaluable research participants.  With the addition of up to 15 
research participants to fill out the MTD dose to 24 for the Phase II portion of the 
study, the total sample size should not exceed 57.  Thus, we expect to complete the 
study in 5 years. 
13.0 Registration Guidelines 
To register a research participant, the PI or his/her designee will contact the responsible 
protocol nurse to begin research participant education to assist with the informed 
consent process.  After signing of the informed consent, administration of protocol 
comprehension will be performed and documented by Research Subject Advocate, and 
eligibility criteria will be verified.  Once all the eligibility testing data is finalized the 
Protocol Management Team will review the data for determination of eligibility and 
proceed with protocol enrollment.  Enrolled research participants will then be scheduled 
for leukapheresis. 
13.1 Procedures for On-Study and Treatment Deviations  
The treating physician must contact the Principal Investigator or her designate to 
approve all waivers (i.e., deviations in eligibility) prior to research participant 
registration, and all treatment deviations prior to treatment.   
14.0 Records to be Kept and Data Submission Schedule 
Essential documents, as listed below, will be retained by the investigator for as long as 
needed to comply with national and international.  Essential documents include: 
14.1 Data Collection Forms 
The original data collection forms will be secured per institutional policies for patient 
medical records. 
14.2 Research Participant Consent Forms 
At the time of registration, signed and dated copies of the research participant 
Informed Consent form with the Experimental Bill of Rights must be available for the 

 
 
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research participant and the research participant's study binder.  The original shall 
be forwarded to the research participant’s medical record file. 
14.3 Documentation of Registration Eligibility 
At the time of registration, the information requested on the On-Study/Eligibility Form 
will be obtained by CRA and appropriate data collection forms shall be completed in 
a timely manner.   Only current approved data collection forms and checklists may 
be used.  
14.3.1 Results Reporting 
Following completion of the study the PI or his/her designee will assemble a 
summary report for the FDA and COH regulatory committees.  This data will be 
subject to submission as a manuscript to an appropriate peer-reviewed journal. 
15.0 Minorities and Gender Statement 
All eligible research participants will be included in this study without regard to gender or 
ethnicity, so that the distribution of the research participants should be representative of 
the gender/ethnicity makeup of the adult/pediatric population in the Southern California 
Area and the broader United States. 
16.0 Ethical and Regulatory Considerations 
16.1 Institutional Review Board 
In accordance with federal regulations (21 CFR 312.66), an Institutional Review 
Board (IRB) that complies with regulations in 21 CFR 56 must review and approve 
this protocol and the informed consent form prior to initiation of the study.  All 
institutional, Federal, and State of California regulations concerning the Informed 
Consent will be fulfilled. 
16.1.1 Informed Consent 
The PI or his/her designee must explain verbally and in writing the nature, 
duration, and purpose of the study and possible consequences of treatment to 
adult research participants, and if the research participant is a minor or is 
incapacitated, to both the child and his/her legal guardians.  Research 
participants/legal guardians must also be informed that they may withdraw from 
the study at any time and for any reason without jeopardizing their future 
treatment. After signing the informed consent, research participants will undergo 
eligibility testing. 
Following eligibility testing, but prior to enrollment, to the assigned Research 
Subject Advocate will assess the potential research participant or their legal 
guardian’s comprehension of the study.  Should sufficient doubt be raised 
regarding the adequacy of comprehension, further education will be administered 
and the evaluation repeated until a satisfactory result is obtained.  Potential 
research participants or legal guardians who cannot adequately comprehend the 
fundamental aspects of the protocol with a reasonable amount of education and 
proctoring will be ineligible for enrollment.  Following completion of the eligibility 
testing and study comprehension assessment the research team will determine if 

 
 
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the research participant may be enrolled.  After enrollment the research 
participant may proceed with leukapheresis. 
16.2 Termination of Study 
The PI reserves the right to terminate this study at any time.  Furthermore, the FDA, 
NIH-OBA or IRB may also terminate the study. 
17.0 Pathological Review 
All available pathology samples documenting intermediate grade B-cell lineage 
lymphoma (e.g., diffuse B-cell lymphoma, Mantle Cell lymphoma, transformed Follicular 
lymphoma) at diagnosis, response(s) and relapse(s) will be submitted to the COH 
pathology service for confirmation of diagnosis.  Should material be available that is in 
excess of that need for standard pathologic studies, then excess material may be used 
for correlative studies to assess susceptibility to re-directed T cell effector mechanisms. 
18.0 Research Participant-Specific Biological Materials 
At the completion of the T cell infusion for a particular research participant, the 
fibroblasts, T cells and leukapheresis product, serum samples, and cryopreserved 
PBMC will not be returned to the research participant or their family/families.  They will 
become property of COH and may be used in non-therapeutic experiments.  

 
 
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