ADMINISTRATION OF MOST CLOSELY MATCHED THIRD PARTY RAPIDLY GENERATED LMP, BARF1 and EBNA1 SPECIFIC CYTOTOXIC T-LYMPHOCYTES TO PATIENTS WITH EBV-POSITIVE LYMPHOMA AND OTHER EBV-POSITIVE MALIGNANCIES
Phase: PHASE1
Conditions: Hodgkin Disease, Non-Hodgkin Lymphoma, Severe Chronic Active Epstein Barr Virus, T/NK-lymphoproliferative Disease, Nasopharyngeal Carcinoma, Smooth Muscle Tumor
Sponsor: Baylor College of Medicine

Coversheet 
Protocol and Statistical analysis plan 
Official Study 
Title: 
ADMINISTRATION OF MOST CLOSELY MATCHED THIRD PARTY RAPIDLY 
GENERATED LMP, BARF1 AND EBMA1 SPECIFIC CYTOTOXIC T-LYMPHOCYTES 
TO PATIENTS WITH EBV-POSITIVE LYMPHOMA AND OTHER EBV-POSITIVE 
MALIGNANCIES (MABEL) 
NCT number 
NCT02287311 
Document Date 
05/25/2021 
 

Version 1.0 (07-30-2014) 
Version 4.0 (10-8-2015) 
Version 7.0 (11-06-2017) 
Version 9.1 (09-22-2020) 
Version 1.1 (08-21-2014) 
Version 4.1 (01-22-2016) 
Version 8.0 (08-18-2018) 
Version 10.0 (05-25-2021) 
Version 2.0 (10-06-2014) 
Version 5.0 (02-22-2016) 
Version 8.1 (10-01-2018) 
Version 3.0 (05-06-2015) 
Version 6.0 (05-03-2017) 
Version 9.0 (04-23-2020) 
 
 
ADMINISTRATION OF MOST CLOSELY MATCHED THIRD PARTY RAPIDLY GENERATED 
LMP, BARF1 and EBNA1 SPECIFIC CYTOTOXIC T-LYMPHOCYTES TO PATIENTS WITH 
EBV-POSITIVE LYMPHOMA AND OTHER EBV- POSITIVE MALIGNANCIES (MABEL) 
 
 
 
 
PRINCIPAL INVESTIGATORS 
 
Rayne Rouce, MD 
Helen Heslop, MD  
Cliona Rooney, PhD 
 
CO-INVESTIGATORS 
 
Andrea Marcogliese, MD 
Ann Leen, PhD 
George Carrum, MD 
Rammurti Kamble, MD 
Carlos Ramos, MD 
Robert Krance, MD 
Adrian Gee, PhD 
Bambi Grilley, RPh 
Carl Allen, MD, PhD 
Premal Lulla, MD 
Ravi Pingali, MD 
 
STATISTICAL CO-INVESTIGATOR 
 
Tao Wang, PhD 
 
IND #15086 
 
 
Center for Cell and Gene Therapy 
Dan L. Duncan Comprehensive Cancer Center 
Baylor College of Medicine 
 
Texas Children’s Hospital 
6621 Fannin St. 
Houston, TX  77030 
and  
Houston Methodist Hospital 
6565 Fannin St. 
Houston, TX  77030 
 

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TABLE OF CONTENTS 
 
1. 
MABEL CHECKLIST FOR PATIENT ELIGIBILITY AND NECESSARY INFORMATION: . 4 
2. 
OBJECTIVES ..................................................................................................................... 6 
3. 
BACKGROUND AND RATIONALE ................................................................................... 6 
3.1 
IMMUNE CONTROL OF EBV INFECTIONS ............................................................................ 6 
3.2 
HODGKIN’S LYMPHOMA (HL): BACKGROUND AND ASSOCIATION WITH EBV ................... 7 
3.3 
NON-HODGKIN LYMPHOMA (NHL): BACKGROUND AND ASSOCIATION WITH  EBV .......... 7 
3.4 
TUMOR SPECIFIC CTL AS TREATMENT FOR LYMPHOMA ..................................................... 8 
3.5 
RATIONALE FOR CURRENT PROTOCOL ............................................................................. 13 
3.6 
RISKS OF ADMINISTRATING LMP-SPECIFIC CTL .............................................................. 14 
3.7 
RISKS OF 3RD PARTY CTL.................................................................................................. 14 
3.8 
RISK OF CYTOKINE RELEASE SYNDROME ......................................................................... 15 
3.9 
RISKS OF LYMPHODEPLETING CHEMOTHERAPY ............................................................... 15 
4. 
PATIENT  ELIGIBILITY .....................................................................................................16 
4.1 
ELIGIBILITY FOR SCREENING ............................................................................................ 16 
4.2 
ELIGIBILITY CRITERIA AT TIME OF TREATMENT ............................................................... 16 
5. 
STUDY DESIGN ................................................................................................................19 
5.1 
INFORMED CONSENT ........................................................................................................ 19 
5.2 
DONOR ELIGIBILITY ......................................................................................................... 19 
5.3 
BLOOD PROCUREMENT FOR CTL AND ANTIGEN-PRESENTING CELL (APC) GENERATION . 20 
5.4 
ADMINISTRATION AND MONITORING ................................................................................ 21 
6. 
TREATMENT PLAN ..........................................................................................................22 
6.1 
DOSE LEVELS ................................................................................................................... 22 
6.2 
DOSING SCHEDULES ......................................................................................................... 22 
6.3 
ADMINISTRATION GUIDELINES ......................................................................................... 23 
7. 
PATIENT EVALUATION ...................................................................................................24 
7.1 
ROUTINE LABORATORY INVESTIGATIONS......................................................................... 24 
7.2 
DIAGNOSTIC IMAGING ...................................................................................................... 24 
7.3 
IMMUNE FUNCTION AND PERSISTENCE STUDIES ............................................................... 24 
7.4 
OTHER TISSUES ................................................................................................................ 25 
7.5 
STUDY CALENDAR ............................................................................................................ 26 
8. 
EVALUATION DURING STUDY .......................................................................................30 
8.1 
FOLLOW UP INTERVAL ...................................................................................................... 30 
8.2 
EARLY TERMINATION OF STUDY AND MODIFICATIONS OF DRUG DOSAGES ..................... 30 
8.3 
MEASUREMENT OF EFFECT ............................................................................................... 30 
9. 
STATISTICAL CONSIDERATIONS ..................................................................................32 
9.1 
STUDY DESIGN SYNOPSIS ................................................................................................. 32 
9.2 
SAMPLE SIZE AND DESIGN CHARACTERISTICS ................................................................. 33 
9.3 
DOSE LIMITING TOXICITY ................................................................................................ 34 
9.4 
DATA ANALYSIS ............................................................................................................... 35 

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10. MODIFIED FOLLOW - UP AND OFF-STUDY CRITERIA .................................................36 
10.1 
MODIFIED FOLLOW-UP CRITERIA: ................................................................................ 36 
10.2 
OFF STUDY CRITERIA:  .................................................................................................. 37 
11. RECORDS TO BE KEPT ..................................................................................................37 
12. REPORTING REQUIREMENTS ........................................................................................37 
12.1 
REGISTRATION .............................................................................................................. 37 
12.2 
DRUG TOXICITY AND/OR ADVERSE REACTIONS ............................................................ 37 
13. INFORMED CONSENT .....................................................................................................38 
14. CLINICAL TRIAL OVERSIGHT AND MONITORING ........................................................38 
15. REFERENCES ..................................................................................................................39 
 
 
 

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1. MABEL CHECKLIST FOR PATIENT ELIGIBILITY AND NECESSARY 
INFORMATION:  
 
 
PATIENT ID   
 
 
 PATIENT NAME _______________________ 
 
YES 
NO 
VALUE/DATE 
 
Any “NO” answers will make a patient ineligible for study participation. 
 
 
 
 
 
 
Any patient regardless of age or sex, with diagnosis of either 
1) EBV positive Hodgkin’s lymphoma 
2) EBV positive non-Hodgkin’s Lymphoma (regardless of 
histologic subtype)  
3) EBV (associated)-T/NK-lymphoproliferative disease  
4) Severe Chronic Active EBV (CAEBV)*  
5) Other EBV positive malignancies (e.g. nasopharyngeal 
carcinoma, smooth muscle tumors, etc.) 
 
AND  
a) in first or subsequent relapse (Group A)  or 
b) with persistent active disease despite therapy (Group B) or 
c) with active disease if immunosuppressive chemotherapy is 
contraindicated e.g. patients who develop Hodgkin disease 
after solid organ transplantation or if the lymphoma is a 
second malignancy e.g. a Richter's transformation of CLL. 
(Group C) 
 
 
* CAEBV is defined as patients with high EBV viral load in plasma 
or PBMC  (>4000 genomes per μg PBMC DNA) and/or biopsy 
tissue positive for EBV 
 
 
 
 
EBV positive tumor (can be pending at this time) 
 
 
 
Weighs at least 12 kg 
 
 
 
Informed consent obtained from patient/guardian.  
 
 
Signature of MD ______________________ 
Date ____________________ 
 
To check eligibility of a patient, telephone Dr. Rayne Rouce at 832-824-4716. To register a patient, telephone the 
Center for Cell and Gene Therapy research coordinator at 832-824-4391.  

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MABEL CHECKLIST FOR PATIENT ELIGIBILITY FOR TREATMENT 
 
PATIENT ID   
 
 
 PATIENT NAME _______________________ 
YES 
NO 
VALUE/DATE 
 
Any “NO” answers will make a patient ineligible for study participation. 
 
 
Please indicate dx 
1, 2, 3, 4 or 5    
 
Any patient regardless of age or sex, with diagnosis of either 
1) EBV positive Hodgkin’s lymphoma 
2) EBV positive non-Hodgkin’s Lymphoma (regardless of histologic 
subtype)  
3) EBV (associated)-T/NK-lymphoproliferative disease  
4) Severe Chronic Active EBV (CAEBV)* 
5) Other EBV positive malignancies (e.g. nasopharyngeal carcinoma, 
gastric cancers, smooth muscle tumors, etc.) 
AND  
a) in first or subsequent relapse (Group A) or 
b) with active disease persisting despite therapy (Group B) or 
c) with active disease if immunosuppressive chemotherapy is contraindicated 
e.g. patients who develop Hodgkin disease after solid organ transplantation 
or if the lymphoma is a second malignancy e.g. a Richter's transformation of 
CLL. (Group C) 
 
* CAEBV is defined as patients with high EBV viral load in plasma or PBMC 
(>4000 genomes per μg PBMC DNA) and/or biopsy tissue positive for EBV 
Please indicate 
Group a, b, or c. 
 
 
 
EBV positive tumor 
 
 
 
Patients with life expectancy ≥ 6 weeks 
 
 
 
Bilirubin ≤ 3x upper limit of normal 
 
 
 
AST ≤ 5x upper limit of normal 
 
 
 
Hgb ≥ 7.0 (may be a transfused value) 
 
 
 
Creatinine ≤ 2x upper limit of normal for age 
 
 
 
Pulse oximetry of > 90% on room air 
 
 
 
Off investigational therapy for at least 30 days at time of infusion.  
 
 
 
Karnofsky or Lansky score of ≥> 50% 
 
 
 
Sexually active patients must be willing to utilize one of the more effective birth 
control methods during the study and for 6 months after the study is concluded.  
The male partner should use a condom. 
 
 
 
Informed consent obtained from patient/guardian. 
 
YES 
NO 
 
Any “YES” answers will make a patient ineligible for study participation. 
 
 
Pregnant or lactating 
 
 
Severe intercurrent infection. 
 
 
Current use of systemic corticosteroids >0.5mg/kg/day 
 
 
Use of ATG, Campath, or other immunosuppressive T cell monoclonal antibodies within 
30 days of infusion. 
 
 
Signature of MD ______________________ Date ____________________ 
 
To check eligibility of a patient, telephone Dr. Rayne Rouce at 832-824-4716. To register a patient, telephone the 
Center for Cell and Gene Therapy research coordinator at 832-824-4391.  
 
 
 

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2. OBJECTIVES  
 
2.1 Primary: To determine the feasibility and safety of administering banked allogeneic, 
partially HLA-matched rapid EBV Specific T cells (ESTs) in patients with EBV-
associated Hodgkin’s Disease or non-Hodgkin’s lymphoma or T/NK-
lymphoproliferative disease and CAEBV.  
 
2.2 Secondary: To assess the anti-viral and anti-tumor effects of ESTs. 
  
2.3 Exploratory:  
2.3.1 To determine the survival and the immune function of EST lines.  
2.3.2 To obtain preliminary information on the safety and response to an extended 
dosage regimen.  
 
3.  
BACKGROUND AND RATIONALE  
 
3.1 Immune Control of EBV Infections 
 
Epstein-Barr virus (EBV) is a gammaherpesvirus that infects more than 95% of the 
world's population. Primary infection usually produces a mild self-limiting disease, 
which is followed by latent infection in B cells and productive replication in B cells 
and mucosal epithelium. There are at least four types of viral latency: type 1, 
expressing only the virus nuclear antigen 1 (EBNA1); type 2, expressing in addition 
to EBNA1, the latent membrane proteins, LMP1 and LMP2; and type 3, expressing 
all seven latency-associated proteins including the immunodominant EBNA3 viral 
antigens.1,2 In these types of latency, the viral small RNAs and EBERs are 
abundantly expressed as well as transcripts from the BamHI A region of the viral 
genome, BARTs. In individuals with a normal immune response, malignant 
outgrowth of infected cells is prevented by the mounting of a complex immune 
response comprised of HLA-restricted EBV-specific cytotoxic T-cells and MHC-
unrestricted effectors.2 
 
In individuals with a compromised immune system, EBV is potentially oncogenic. 
EBV-positive lymphoproliferative disease after solid organ or stem cell transplant 
expresses all of the EBV latent antigens (type 3 latency) and can be fatal.3 
Evidence for control of EBV-positive lymphoproliferative disease post allogeneic 
bone marrow transplant (BMT) by cytotoxic T lymphocytes (CTL) comes from our 
study using EBV-specific gene-modified CTL and extension studies at other sites.4-
7 We have recently collated data from the 114 patients entered on these studies in 
a long-term follow up study.7 101 patients received CTLs as prophylaxis (90 after 
a selectively T cell depleted transplant and 11 with high risk diagnoses). Thirteen 
patients received CTLs as therapy for EBV lymphoma. None of the patients had 
any acute Grade 3-5 infusion-related toxicity from CTL infusion. No patients 
developed de novo GVHD, although 8 of 51 patients with previous GVHD 
developed a recurrence of disease (grade 1 in 6 patients and grade 2 in 2 patients) 
all of whom responded to GVHD therapy.  The main adverse event was 
inflammatory response seen in patients with active disease during a therapeutic 
response in 4 patients, all of whom recovered. None of the 101 patients who 
received CTL prophylaxis developed EBV- lymphoproliferative disorder (LPD), and 
11 of 13 patients treated with CTLs for biopsy-proven or probable LPD achieved 
sustained complete remissions. The gene-marking component of this study 
showed the persistence of functional CTLs for up to 9 years. Other studies have 
confirmed the activity of EBV specific CTLs post-transplant.8,9  

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In the immunocompetent host, other EBV associated tumors have been 
recognized. However, these express a much more limited range of EBV associated 
antigens (type I and type II latency). For example, nasopharyngeal carcinomas 
express EBNA-1, BARF1, LMP1, and LMP2A (latency type II), whereas Burkitt's 
lymphomas express only EBNA-1 (Latency type I).10 In EBV-positive Hodgkin’s 
lymphoma and non-Burkitt’s non-Hodgkin lymphoma (NHL) the EBV-antigens 
expressed on the tumor cells are restricted to the expression of the subdominant 
latent proteins LMP1and LMP2A, BARF1 and EBNA1 (Type II latency). 11   
 
3.2 Hodgkin’s Lymphoma (HL): Background and Association with EBV 
 
HL, a malignant neoplasm of lymphoreticular cell origin, has an incidence of 
about 2.4 per 100,000 per year12. Modern radiotherapy and/or chemotherapy 
regimens have dramatically improved the cure rate of patients with HL. However, 
despite the identification of clinical prognostic factors and the optimal use of 
primary and secondary treatments, HL remains fatal for more than 15% of 
patients.13 Even in patients who are cured, the morbidity and excess mortality of 
therapy are substantial and long lasting.14-16 New therapeutic agents are 
therefore required both to further reduce mortality and to alleviate morbidity.  
 
Hodgkin’s lymphoma is unusual in that the bulk of the tumor is composed of 
normal cells within which the malignant Hodgkin-Reed-Sternberg cells, derived 
from germinal center B cells, are found.17  In about 40% of HL, tumor cells 
express viral latency proteins of EBV.18,19 While more immunogenic proteins 
(EBNAs and Lytic proteins) are not usually expressed by Hodgkin Reed 
Sternberg (HRS) cells, EBNA 1, LMP1 and 2 are usually detectable. There are 
divergent reports in the literature as to whether EBV positivity confers a worse 
prognosis19 or has no influence on outcome.20 
  
3.3 Non-Hodgkin Lymphoma (NHL): Background and Association with EBV 
 
Non-Hodgkin lymphomas broadly can be divided into B, T, and NK cell categories. 
Latent EBV infection is associated with a heterogeneous group of NHL, including 
Burkitt’s lymphoma, NK-T lymphomas and B cell diffuse large B cell lymphoma.21 
Most EBV-associated NHLs are aggressive tumors characterized by rapid growth 
and necrosis, and the NK and T lymphomas in particular are also associated with 
hemophagocytosis. 
 
3.3.1 B cell NHL 
EBV-positive B cell lymphomas that occur in the immunocompetent host include 
diffuse large B cell lymphoma (DLBCL) and CD30+ anaplastic large cell lymphoma 
of B cell type. The rate of positivity varies between 5 and 30% in different series 
depending on criteria for EBV positivity and geographic location.22 T cell-rich-B cell 
NHL can be difficult to distinguish from Hodgkin disease, but when strict 
morphological and immunophenotypic criteria are applied, approximately 20% of 
these tumors are found to be LMP1 positive.23    
 
The 2008 WHO classification also recognizes some DLBCL entities in which the 
EBV-infected cells may express type 3 latency antigens. These include  
lymphomatoid granulomatosis, EBV-positive DLBCL of the elderly, and DLBCL 
associated with chronic inflammation.24 Large B-cell lymphomas with a phenotype 
of terminal B-cell differentiation are also often infected by EBV.25 

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3.3.2 T Cell Lymphomas 
 
3.3.2.1 T-NK cell NHL 
Extranodal natural killer/T-cell lymphoma, nasal-type, or nasal NK/T-cell lymphoma, 
was formerly called angio-centric lymphoma. It is an extranodal lymphoma, usually 
with an immature NK-cell phenotype and positive for Epstein-Barr virus (EBV), with 
a broad morphologic spectrum, frequent necrosis, and angioinvasion.26 It is 
designated NK/T because of uncertainty regarding its cellular lineage. Although 
originally thought to be T cells, the malignant cells express CD2 and CD56 but lack 
surface CD3 and T cell receptor gene rearrangements. Thus, these tumors are 
probably of NK cell origin. 
 
3.3.2.2 Angioimmunoblastic lymphoma 
Angioimmunoblastic lymphoma is characterized by oligoclonal proliferation of T 
and B cells, and EBV is detected in many cases in either T or B cells. The clinical 
presentation usually includes systemic disease with B symptoms, while pathology 
reveals a polymorphous infiltrate involving lymph nodes, with a prominent 
proliferation of endothelial and dendritic cells. Some patients develop a secondary 
EBV-positive large B-cell lymphoma.  
 
3.3.2.3 Aggressive NK LGL leukemia/lymphoma 
This syndrome presents with lymphadenopathy, hepatosplenomegaly, and the 
presence of atypical lymphocytes in blood and marrow. The phenotype is similar 
to that of the NK-T lymphomas described above, and the disease is aggressive 
with a poor prognosis.  Infection with EBV has been implicated in more than 50% 
of the cases of NK LGL leukemia reported in Japan.  
 
3.3.2.4 CAEBV 
Another syndrome associated with defective immune control of EBV is severe 
chronic active EBV (CAEBV) infection syndrome, a rare Epstein-Barr virus 
associated disorder that may involve T cells, NK cells, or B cells.27,28 Patients 
present 
with 
fever, 
hepatosplenomegaly 
and 
lymphadenopathy 
and 
characteristically have elevated antibody titers to the virus capsid antigen (VCA) 
and low or absent antibody to EBNA and free virus in serum or other body fluids. 
This disorder may be complicated by life-threatening complications, such as multi 
organ 
failure, 
chronic 
interstitial 
pneumonia 
and 
lymphoproliferative 
disease/lymphoma. The mechanisms responsible for the inability of these patients 
to produce an effective T cell response to control EBV infection are still unknown 
and no effective treatment is currently available.  
 
3.4 Nasopharyngeal Carcinoma (NPC): Background and Association with EBV 
 
Nasopharyngeal carcinoma is a malignant disease with a variable range of 
incidence depending on age, geographical place, race and EBV exposure.29, 30 
The etiological link between NPC and EBV is based on serological evidence, 
EBV-DNA measurements in plasma31, 32, and confirmation of EBV-DNA within 
NPC tumor cells. The EBV-DNA in NPC biopsy samples is clonal, arising from a 
single EBV infected cell.33  EBV has been detected in virtually all cases of 
undifferentiated non-keratinizing NPC.29, 34, 35 
 
NPC is a radiosensitive tumor, and by modern radiation techniques, local control 
rates of greater than 80%are obtained.36 Despite the high rate of initial remissions with 

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radiation and concurrent chemotherapy (with 5-year survival rates of 55-70%), distant 
failures remain the major problem in patients with loco-regionally bulky disease, which is 
the most common form at presentation due to the lack of early symptoms. Unfortunately, 
40-50% of patients still relapse.37 Even in patients who achieve remission, treatment-
related morbidity and mortality are significant.38, 39 Late medical complications after 
treatment for NPC include growth hormone deficiency, hypothyroidism and pulmonary 
fibrosis.38 Fatal neoplastic complications include secondary leukemia related to 
alkylating agent chemotherapy and head and neck cancers (most likely radiation-
induced), and gastric cancer.40  It is therefore desirable to develop novel therapies that 
could improve disease free survival in relapsed/refractory patients and which might 
ultimately reduce the incidence of long-term treatment related complications in all 
patients. 
 
The almost uniform expression of the Type II latency EBV antigens in NPC makes it a 
prime target for immunotherapy with EBV-directed CTLs.36 We and other groups have 
previously demonstrated safety and efficacy targeting NPC with EBV-directed CTLs. 41-43  
 
3.5 Leiomyosarcoma and other Smooth Muscle Tumors: Background Association 
with EBV 
EBV–associated smooth muscle tumors (SMT) and leiomyosarcomas (LMS) are 
uncommon soft tissue neoplasms typically manifesting in patients with acquired or 
underlying immune deficiency, including those after solid organ transplant (SOT) and 
HIV-infected individuals. The association between SMT and immunosuppression was 
first described in 1970. It was only in 1995 that in 2 simultaneous publications the clear 
association with EBV was linked. These tumors typically exhibit a Type II latency 
phenotype.44 
Therapeutic strategies have historically targeted the tumor location as well as the 
etiology of immunosuppression. Different treatment modalities have been described for 
EBV-SMT, including chemotherapy, surgical resection, antiviral therapy, and reduced 
immunosuppression. However, EBV-associated LMSs are typically aggressive and 
respond poorly to conventional therapy. Given the rarity and uncertain behavior of these 
tumors, no fixed approach has been described to treat these tumors.45 
 
3.6 Tumor specific CTL as treatment for Lymphoma and other EBV+ Malignancies 
3.6.1 Tumor specific CTLs for Lymphoma 
 
LMP1 and 2 are consistently expressed on Reed-Sternberg cells and also detected 
in NHL tumor cells, which have a type II latency pattern of expression. This therefore 
represents a potential source of target epitopes.  Most donors have a low but 
measurable frequency of circulating LMP-specific CTL that can be activated and 
expanded in vitro.46 Hence LMP1 and 2 may be the proteins of choice to be targeted 
by CTL in patients with EBV-positive lymphoma, which arises in the 
immunocompetent host. EBNA1 is also expressed in Type II latency tumors and 
was initially thought to be a poor target for immunotherapy because it possesses 
gly-ala repeat sequences that inhibit HLA Class I antigen processing precluding 
presentation to CD8-positive T cells.47 More recent studies, however, suggest 
EBNA1 can still be exploited as a T-cell target.48, 49 BARF1 is also expressed in 
some EBV-positive lymphomas as a latent gene. 
 

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In our initial immunotherapy studies targeting EBV latency II lymphoma, we 
generated EBV-specific CTLs in patients with EBV-positive Hodgkin’s lymphoma,50 
using lymphoblastoid cell lines (LCL) as EBV-antigen presenting cells (APC). 
Although these CTLs homed to the tumor sites and produced transient clinical 
benefit51, only a small percentage of these CTLs were specific for the antigens 
expressed by these lymphomas.   
 
In a follow-up study we therefore determined whether anti-tumor activity could be 
improved by enriching CTL specific for LMP2, an immunologically subdominant 
antigen that is expressed on these tumor cells.52 We have manufactured and 
characterized 25 clinical grade LMP2 lines and infused them into 20 patients in a 
dose escalation study. After CTL infusion, no immediate or long-term toxicity was 
observed, and the frequency of EBV + LMP2-specific T cells increased (range 2 to 
17.6 fold). This increase persisted for up to 3 months, and represented a 1-3 log 
expansion of the infused cells in vivo53. Of eight patients in remission at the time of 
CTL infusion, seven remain in remission. Of the eight patients with disease, there 
were six complete responses, one very good partial response and one progressive 
disease. Four patients were also treated as adjuvant therapy post allogeneic 
transplant and only one progressed. 
 
Although these results were encouraging, we hypothesized that broadening the 
tumor-specificity of CTL would further increase the anti-tumor effect, since tumor 
antigen loss variants have been observed and the expression of LMP2 in tumors is 
heterogeneous. We therefore initiated a study in which we manufactured and 
infused both LMP1 and LMP2-specific CTL to 1) ensure that good CTL epitopes 
are available regardless of the patient’s HLA type and 2) generate a broader CTL 
response against the malignant cells.  
 
We have recently analyzed the combined results of the studies with LMP2 and 
LMP1/2 CTLs.  
Fifty patients have received autologous LMP CTLs (targeting LMP1/2 (n= 33) or 
LMP2 (n=17) for NHL or HL), plus an additional 15 patients received donor-derived 
LMP1/2-CTL (n=11) or LMP2-CTL (n=4) after allogeneic stem cell transplant.  In 
the 15 patients who received donor-derived (allogeneic) CTL, CTL infusions were 
well tolerated and no de novo GVHD was observed, although one patient developed 
dermatitis 4 weeks post CTL that has developed into a psoriatic rash of unknown 
etiology. Twelve of these 15 patients remain in remission for a median of 2 years 
post CTL (range 3 months-6 years). One patient with HL and 1 patient with NK/T 
cell lymphoma and 1 patient with T-cell CAEBV progressed within 3 months of T-
cell therapy. Of the 50 patients who received autologous LMP-CTL, no toxicity 
definitely attributable to CTL was seen. Twenty-eight of 29 high-risk or multiple-
relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at 
a median of 3.1 years after CTL infusion. None subsequently died as a result of 
lymphoma, but nine succumbed to complications associated with extensive prior 
chemoradiotherapy, including myocardial infarction and secondary malignancies. 
Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had 
clinical responses, including 11 complete responses. T cells specific for LMP as 
well as nonviral tumor-associated antigens (epitope spreading) could be detected 
in the peripheral blood within 2 months after CTL infusion, but this evidence for 
epitope spreading was seen only in patients achieving clinical responses. 

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3.6.2 Tumor-Specific CTL as Treatment for Other EBV+ Malignancies 
Because NPC, gastric cancer, leiomyosarcoma and other EBV+ malignancies 
are latently infected by EBV, and classified as Latency Types I, II or III, these 
cancers can also be targeted by EBV-specific CTLs. The expression of Type II 
latency viral proteins such as EBNA1, LMP1 and LMP2A/B in EBV-associated 
NPC forms the basis for it’s targeting by T cells specifically directed against 
EBV.36 Because NPC is highly associated with a latent EBV infection, almost all 
NPC patients’ blood contains a small population of EBV-specific T cells, which 
can be stimulated ex-vivo to expand into a large population that can be infused 
back into the patient. We and others have given EBV-specific CTLs to patients 
with EBV-positive lymphomas and NPC.41-43. Autologous EBV-specific CTLs 
generated from NPC patients’ own pool of T cells and directed against EBV 
antigens such as LMP1/2, as well as EBNA1 and BARF have been investigated 
by our group at Baylor College of Medicine  (NCT00516087, NCT02065362), 
without acute or long-term dose-limiting toxicities related to T-cell infusions. 41-43 
Specifically, we have treated 48 patients with EBV-specific CTLs at our center on 
three clinical studies. We observed no acute or long-term dose-limiting toxicities 
related to T-cell infusions.41-43 Of 30 patients treated with active 
resistant/relapsed disease, 14 patients (47%) had clinical benefit (5 CR, 2 PR, 7 
SD) resulting in a 2-year overall survival (OS) of 43.3%. In contrast, the median 
2-year OS for NPC patients with metastatic disease treated on 5 recent clinical 
studies with chemotherapy was 20%.54-58 Other groups including pharmaceutical 
companies have also investigated autologous EBV CTLs as a treatment for NPC 
even in a large multisite Phase III trial. 
 
To further validate the benefits of EBV-specific CTLs for NPC, we collaborated with 
investigators at the National Cancer Center in Singapore. NPC is the 6th most 
common cancer in Singapore and, as everywhere else, the outcome for patients 
with metastatic disease remains poor. In their study, patients with metastatic NPC 
received 4 cycles of chemotherapy followed by up to 6 infusions of EBV-specific 
CTLs. Of 35 patients receiving combined chemotherapy and T-cell therapy, the 2-
year OS was 67.2%.59  
 
Additionally, there have also been reports of safe and efficacious treatment of 
EBV-associated SMT/LMS with EBV-directed directed T cells (including those 
generated from allogeneic donors,60  (NCT01447056) making this therapeutic 
approach an option for refractory cases.  
 
Refining the CTL manufacturing strategy 
 
Although the previously mentioned LMP-CTLs have remarkable clinical efficacy, 
several problems with the current manufacturing strategy limit their broader 
application. The procedure is long (>12 weeks) and complex. Generation of the 
requisite EBV-LCL for each patient takes a minimum of 6 weeks, with longer culture 
required for patients who have received lymphotoxic chemotherapy, while 
production is impossible in patients who have received the B cell depleting CD20 
antibody rituximab, currently the standard of care for patients with B-cell lymphoma. 
Finally, the use of live EBV to generate LCLs and the requirement for Ad vectors to 
induce LMP1/2 overexpression both add undesirable cost, and complicate the 
regulatory process. We have recently been able to remove these viral and viral-

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vector components and have shown that T- cells specific for all four type 2 latency 
proteins can be prepared from healthy donors and lymphoma patients using 
dendritic cells (DCs) pulsed with peptide libraries (pepmixes) of 15mer amino acids 
overlapping by 11 that span the entire sequence of the antigens of interest. 
Responder T-cells can then be expanded by restimulation with the same pepmixes 
presented on autologous, activated T-cells (AATCs) together with HLA-negative 
K562 costimulatory cells (K562cs expressing CD80, CD86, CD83 and 4-1BB- 
ligand as transgenes) (gift from Dr. Carl June). ATCs upregulate HLA class II 
molecules and therefore can present peptides to CD4+ and CD8+ T-cells, while 
costimulation is provided in trans by K562cs. 
 
3.6.3 Limitations of stem cell donor-derived tumor specific CTL as treatment for 
Lymphoma 
 
Despite the successful use of stem cell donor-derived tumor specific CTL as 
treatment for EBV-positive lymphoma, there are some limitations to this approach.  
Despite the significant decrease in the amount of time it takes to manufacture EBV-
specific T-cell lines with our pepmix-based method (decrease from ~3 months to 
just 10 days), this time frame is still too long for patients with more fulminant disease.  
However, the previously recognized limitation from our VST studies that virus 
specific T lines cannot be generated from seronegative donors should not be an 
issue considering >90% of the population is EBV seropositive. 
 
3.6.4 Third-party T-cells 
 
Banked third-party “off-the-shelf” EBV-specific T-cells were first used in patients 
with refractory post-transplant lymphoproliferative disease (PTLD) after solid organ 
transplantation (SOT)61. Tumor responses were seen in 64% of recipients, with a 
CR in 42%.  Doubrovina et al62 extended this strategy to 25 patients with refractory 
leiomyosarcoma or PTLD following hematopoietic stem cell transplant (HSCT) or 
SOT.  Sixteen patients (64%) were responders; 9 had CRs and 5 had PRs, while 
the 2 with leiomyosarcoma had stable disease.  Failures occurred when the CTLs 
were matched with the recipient, but the tumors arose from HLA-mismatched grafts, 
and in patients with immunodeficiency, implying that reactivation of endogenous 
recipient T-cells contributes to tumor responses62.  
More recently our group evaluated third-party T-cells specific for EBV, 
cytomegalovirus and adenovirus in a multicenter trial for patients with therapy-
resistant viral infections after HSCT.  Lines were generated using adenovector-
pp65 transduced monocytes and EBV-LCL and were either retained from our prior 
donor-specific clinical study or were newly generated from donors with known 
antiviral activity, including HLA homozygous donors identified by the National 
Marrow Donor Program.  A total of 32 lines were produced and characterized, 18 
of which were administered to the 50 study patients.  The selection of lines for 
infusion was based on the specificity of the line for the target virus through a shared 
HLA allele, as well as the overall level of HLA match.   
 
From the bank of 32 virus specific T-cell lines, a suitable line was identified for 90% 
of the screened patients within 24 hours.  Of 50 recipients, 37 (74%) were partial or 
complete responders, even when the T-cells were HLA-matched at only a single 
allele.  This included responses in 6 of 9 patients with refractory EBV-PTLD.  Only 
4 responders had a recurrence or progression of their original disease.  Together, 
these results suggest that third-party T-cells can produce tumor/viral responses that 

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may be enhanced and sustained by the reactivation of endogenous tumor/virus-
specific T-cells.  Third-party banks can provide rapid access to virus-specific T-cells 
for almost any patient, circumventing the delays inherent in activation and 
expansion of autologous or stem cell donor-derived antigen-specific T-cells.   
 
Additionally, we and others have used third-party EBV CTLs to treat NPC and 
leiomyosarcoma, demonstrating safety and clinical responses in some patients in 
an ongoing trial.60, 62 
 
 
3.6.5 The Role of a Lymphodepleted Environment 
It is now well established that expansion of lymphocytes in vivo is subjected to 
homeostatic mechanisms that control their total numbers63.  Therefore, it has 
become apparent that a certain degree of lymphopenia will facilitate expansion of 
infused T cells. While lymphopenia will always be present after autologous stem 
cell transplantation (given the nature of the conditioning regimens, which are 
myeloablative and lymphodepleting) and in patients who are currently on 
chemotherapy, subjects who have been off chemotherapy for prolonged periods of 
time will most likely not be lymphopenic. In this case, induction of lymphopenia 
before T cell infusion is highly desirable, as evidenced by the much higher rate of 
complete responses achieved in studies in which high doses of cyclophosphamide 
and/or fludarabine preceded infusion of chimeric antigen receptor-modified T cells 
(CAR-T cells).64-66 We predict that lymphodepletion may be necessary for adequate 
T cell expansion in patients who have not recently received chemotherapy or 
undergone stem cell transplant. 
 
3.7 
Rationale for Current Protocol 
 
As these previous studies show that T cells directed against the Epstein Barr virus 
(EBV) latent cycle antigens, LMP1 and LMP2 can produce objective tumor 
responses in over 50% of recipients, we wish to develop this therapy to licensure.  
However, as discussed above, the current manufacturing strategy poses several 
impediments to the required pivotal studies. These include the requirement for live 
virus (EBV) and viral vectors (adenovirus), the complexity of the procedure and the 
difficulty or impossibility of generating EBV-transformed B cell line (LCL) for use as 
antigen-presenting cells (APCs) now that almost all lymphoma patients receive the 
B cell depleting CD20 antibody, Rituximab, as front-line therapy.   
 
Because of the above problems, we have modified our manufacturing process to 
eliminate the requirement for EBV-LCLs and adenoviral (Ad) vectors.  We have 
developed a 10-day GMP-compliant T cell production process to generate T cell 
lines specific for the EBV latent cycle antigens.  The first stimulation now uses 
PBMCs (or dendritic cells (DCs)) pulsed with overlapping peptide libraries 
representing the entire protein sequences of LMP1, LMP2, BARF 1 and EBNA1 
together with the cytokines IL-7 and IL-15. The peptide mixtures ensure that the 
antigen is effective for any HLA phenotype, and competition between peptides 
ensures that we select and expand only T cells of sufficiently high receptor avidity 
to bind to and kill tumor cells. The addition of cytokines to the culture mix prevents 
activation-induced T cell death by inducing anti-apoptotic molecules, thereby 
producing a broader antigen-specific T cell repertoire and a higher frequency of 
antigen-specific T cells. After activation cells are transferred to a G-Rex10 device 
for 9-11 days and cultured in media containing IL7 and IL15 to achieve maximal 

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expansion of antigen-specific T cells without carry-over of alloreactive T cells.67  To 
prevent compromising the repertoire of the T cells by HLA restriction or lack of 
CD4+ T cells, the second and subsequent stimulations require additional third-
party derived APCs. We use irradiated, third-party derived activated T cells (ATCs) 
that express both HLA class I and class II molecules, pulsed with the same peptide 
libraries, together with irradiated HLA-negative K562 cells genetically modified to 
express a broad range of costimulatory molecules (K562-cs). The responding T 
cells comprise CD4+ and CD8+ T cells with broad specificity, a high frequency of 
tumor antigen-specific T cells and a mixed effector phenotype.  
 
In an ongoing clinical trial, 12 patients have been treated with autologous 
EBNA1/BARF1/LMP specific CTLs manufactured with this method with no toxicity 
attributable to the infused cells. 
 
The establishment of a third-party “off the shelf” EBV specific CTL bank will directly 
address the previously recognized drawbacks associated with generating 
autologous or SCT donor-derived CTLs.  Our CTL bank will be generated from 
eligible HLA typed donors and characterized for specificity, HLA-restriction and 
function.  The banked lines will be chosen for each patient based on their ability to 
recognize lymphoma antigens through one or more shared HLA alleles.  These 
lines are readily available, and can provide rapid access to EBV-specific T-cells for 
almost any patient, circumventing the delays inherent in activation and expansion 
of autologous or stem cell donor-derived antigen-specific T-cell. 
 
3.8 Risks of Administrating LMP-specific CTL 
 
In our studies of LMP CTLs, over 60 patients received autologous LMP CTLs and 
no immediate or long-term toxicity was observed post CTL infusion.  
 
3.9 Risks of 3rd party CTL 
 
In a study at Memorial Sloan Kettering 35 patients received a median of 6 doses 
of third party virus specific T cells (VSTs) for EBV after HSCT for EBV LPD, most 
at 1 x 10^6 EBV-VST/kg/infusion, and all infusions were well tolerated.62   Updated 
data from the study was reported at the American Society of Blood and Marrow 
Transplantation BMT Tandem Meeting 2014, with now 28 patients after HSCT 
enrolled in this study.  Among the 28 patients one patient developed mild skin 
GVHD after infusion with 3rd party EBV-VSTs, but tolerated a subsequent infusion 
of EBV-VSTs from an alternate 3rd party donor, with no other incidences of GVHD 
reported.   
 
In our study of third party VSTs specific for three viruses (AdV, CMV and EBV) a 
total of 50 patients were infused with third party banked VSTs.  All of the infusions 
were well tolerated.  There were no immediate adverse effects, and despite the 
HLA disparity between the VSTs and recipients, de novo GVHD occurred in only 
2 patients (grade I in each case).  In the 8 patients in whom acute GVHD developed 
within 45 days of the first infusion (grade I in 6 patients, grade II in 1 patient, and 
grade III in 1 patient), 6 had a history of GVHD prior to receiving the VSTs.  An 
additional patient had a flare of chronic skin GVHD.  Two patients experienced 
transplant-associated microangiopathy, a complication that occurs in up to 10% of 
HSCT recipients, particularly in those receiving sirolimus68, as were both of our 

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patients.  Only 1 patient had secondary graft failure, concomitant with leukemic 
relapse.  
 
We have also treated 5 patients with third party LMP1/2 VSTs manufactured using 
our previous manufacturing methodology (with EBV LCLs and Ad-vectors) with no 
adverse effects. 
 
3.10 Risk of Cytokine Release Syndrome 
 
There have been several reported SAEs associated with cytokine release 
syndrome (CRS) in patients who received T cells69 or bispecific T-cell engagers70. 
The majority of CRS have been reported after the infusion of CAR T cells71-73, but 
CRS can also occur after the infusion of conventional antigen-specific T cells74 or 
tumor infiltrating lymphocytes75. Patients will be monitored closely as per study 
calendar and assessed for evidence of incipient CRS (onset of fever, malaise and 
dyspnea) and treated promptly. Management of CRS will follow published 
guidelines69,76, and is described in more detail in SOP F 05.11.XX and includes 
treatment options based on the clinical severity of the symptoms, such as 
oxygen, inotropic agents, IL-6 receptor antibody (4-8 mg/kg),TNF-α antibody (5-10 
mg/kg), and/or steroids (1-2 mg/kg/day of methylprednisolone or equivalent). 
3.11 Risks of Lymphodepleting Chemotherapy 
3.11.1 Cyclophosphamide 
Cyclophosphamide is commercially available. A list of toxicities is attached in 
Appendix I. 
3.11.2 Fludarabine 
Fludarabine is commercially available. A list of toxicities is attached in Appendix I. 
 
 

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4. PATIENT ELIGIBILITY 
 
4.1  Eligibility for Screening 
 
4.1.1 
Inclusion 
4.1.1.1 Any patient regardless of age or sex, with diagnosis of either:  
 
-EBV positive Hodgkin’s lymphoma 
-EBV positive non-Hodgkin’s Lymphoma (regardless of histologic subtype)  
-EBV (associated)-T/NK-lymphoproliferative disease  
-Severe Chronic Active EBV (CAEBV)*  
 
- Other EBV positive malignancies (e.g. nasopharyngeal carcinoma, 
smooth muscle tumors, etc.) 
 
 
 
AND  
-in first or subsequent relapse   (Group A) 
-with active disease persisting despite therapy (Group B) 
-with active disease if immunosuppressive chemotherapy is 
contraindicated e.g. patients who develop Hodgkin disease after solid 
organ transplantation or if the lymphoma is a second malignancy e.g. a 
Richter's transformation of CLL. (Group C) 
 
* CAEBV is defined as patients with high EBV viral load in plasma or 
PBMC (>4000 genomes per μg PBMC DNA) and/or biopsy tissue positive 
for EBV  
 
4.1.1.2 EBV positive tumor (can be pending) 
 
4.1.1.3 Weighs at least 12kg 
 
4.1.1.4 Informed consent (and assent as applicable) obtained from 
patient/guardian. 
 
 
 
4.2 Eligibility Criteria at time of Treatment 
 
4.2.1 
Inclusion: 
4.2.1.1 Any patient regardless of age or sex, with diagnosis# of either: 
 
-EBV positive Hodgkin’s lymphoma  
-EBV positive non-Hodgkin’s Lymphoma (regardless of histologic 
subtype)  
-EBV (associated)-T/NK-lymphoproliferative disease  
-Severe Chronic Active EBV (CAEBV)*  
 
 -Other EBV positive malignancies (e.g. nasopharyngeal carcinoma, 
smooth muscle tumors, etc.) 
 
 
AND#  
-in first or subsequent relapse   (Group A) 

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-with active disease persisting despite therapy (Group B) 
-with active disease if immunosuppressive chemotherapy is 
contraindicated e.g. patients who develop Hodgkin disease after solid 
organ transplantation or if the lymphoma is a second malignancy e.g. a 
Richter's transformation of CLL. (Group C) 
 
 * CAEBV is defined as patients with high EBV viral load in plasma or 
PBMC (>4000 genomes per μg PBMC DNA) and/or biopsy tissue positive 
for EBV  
 
# The disease diagnosis and the Group must be noted on the eligibility 
checklist. 
 
4.2.1.2 EBV positive tumor  
 
4.2.1.3 Patients with life expectancy ≥ 6 weeks 
 
4.2.1.4 Patients with bilirubin ≤3x upper limit of normal 
 
4.2.1.5 AST ≤ 5x upper limit of normal 
 
4.2.1.6  Hgb ≥ 7.0 (may be a transfused value) 
 
4.2.1.7 Patients with a creatinine ≤ 2x upper limit of normal for age 
 
4.2.1.8 Pulse oximetry of > 90% on room air  
 
4.2.1.9 Patients should have been off other investigational therapy for 30 days 
prior to infusion.  
 
 

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4.2.1.10 
Patients with a Karnofsky/Lansky score of ≥ 50 as described below: 
 
Performance Status Criteria 
 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
Karnofsky 
Lansky 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor signs 
or symptoms of disease 
90 
Minor restrictions in physically 
strenuous activity 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less 
time spent in play activity 
60 
Required occasional assistance, but is able 
to care for most of his/her needs. 
60 
Up and around, but minimal active 
play; keeps busy with quieter 
activities. 
50 
Requires considerable assistance and 
frequent medical care. 
 
50 
Gets dressed, but lies around much of 
the day; no active play, able to 
participate in all quiet play and 
activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet 
activities 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed 
 
 
4.2.1.11 
Sexually active patients must be willing to utilize one of the more 
effective birth control methods during the study and for 6 months after 
the study is concluded.  The male partner should use a condom. 
 
4.2.1.12 
Informed consent (and assent as applicable) signed by 
patient/guardian.   
 
4.2.2 Exclusion  
 
4.2.2.1 
Pregnant or lactating 
 
4.2.2.2 
Severe intercurrent infection. 
 
4.2.2.3 
Current use of systemic corticosteroids >0.5 mg/kg/day 
 
4.2.2.4 
Patients who have received ATG, Campath, or other 
immunosuppressive T cell monoclonal antibodies within 30 days.  
 
 
 

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5. STUDY DESIGN  
 
 
5.1 Informed Consent 
 
The informed consent process will begin at recognition of subject eligibility and consent 
will be obtained per institutional practices before study therapy is initiated. Consent 
process will consist of two parts: a) screening consent and b) treatment consent 
 
 
1. Screening consent:  The screening portion consists of registering demographic data 
and patient eligibility data.  The search for a suitable matched EST line is initiated if 
the patient is eligible.  If an EST line is not available, the following data will be collected: 
demographic data, HLA type, and type of diagnosis. 
2. Treatment consent:  If a suitable matched EST line is available, the principal 
investigator or designee discusses the available line with the treating physician.  After 
enrollment in the treatment portion of the protocol the patient can then receive the 
identified EST line if eligibility criteria are still met. 
 
This protocol will be discussed with eligible patients and, when appropriate, with their 
guardians.  Patients who received their primary therapy at another institution will have the 
protocol discussed when they are referred either to TCH or HMH.  
 
Informed consent for generation of lines and participation in the study will be obtained 
from eligible third party donors on a separate protocol as denoted below. 
 
All cell culture manipulations will be carried out in the Center for Cell and Gene Therapy 
CGMP facility using current SOPs. After quality assurance testing is complete a certificate 
of analysis will be issued. 
 
5.2 Donor Eligibility 
 
 
The EBV specific T-cell lines that will be used in this third party study are manufactured 
for third party use from eligible donors with common HLA alleles.  Some of these 
individuals will be subjects who have been enrolled on our IRB approved research study 
(H -7634) to manufacture CTL lines from normal donors for third party use (including 
subjects chosen from our panel of highly characterized laboratory donors).  We may also 
collaborate with the National Marrow Donor Program, which is a registry of HLA-typed 
donors who have volunteered for transplant donation to obtain additional donors.  Those 
donors will be procured on a separate procurement protocol.  Alternatively, eligible related 
donors (parents, siblings) will comprise the remainder of our donor pool. 
 
For all third party lines, donors will be evaluated by the director of the donor center at BCM 
or an NMDP donor physician for NMDP donors.  Donors must meet standard eligibility 
criteria for donation of blood or marrow.  They will be screened with the standard blood 
bank donor questionnaire, medical history and testing for infectious disease markers by a 
physician who is experienced in screening transplant donors. Only donors who have 
cleared this process and are deemed to be eligible will have provided blood for EST 
generation.   
 
The results of the physician assessment and ID testing will be reviewed by a CAGT 
laboratory director who gave the final eligibility determination according to the SOPs for 
Donor Evaluation and Use of Third Party Lines. 
 

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5.3 Blood Procurement for CTL and antigen-presenting cell (APC) Generation 
 
5.3.1 CTL Lines selection 
Generation of LMP-specific CTL lines requires the generation of several different 
components from peripheral blood mononuclear cells (PBMC). The CTL line will 
be derived from third-party donor peripheral blood T cells, by stimulation with 
antigen-presenting cells (APCs) pulsed with overlapping peptide libraries 
representing the entire protein sequences of LMP1, LMP2, BARF 1 and EBNA1 
and the cytokines IL-7 and IL-15. The APCs used to stimulate and expand the 
EBV-specific T cells will be derived from donor mononuclear cells and T 
lymphocytes.  
 
Up to 120 mL of blood will be collected from the donor (subjects must be at least 
12 kg). The blood collection may be collected from the donor in 2 draws as needed. 
For donors <18 years, a maximum of 3mL/kg will be taken over an 8 week period. 
Peripheral blood mononuclear cells (PBMC) will be harvested using Ficoll 
gradients. Each component, T cells and dendritic cells, can be prepared from fresh 
or cryopreserved PBMC. A maximum of 30 mL from adults and 14mL from children 
will be collected for infectious disease testing (will be collected twice if blood is 
collected twice for CTL generation) and 9mL will be collected for HLA typing.  
 
To initiate the EBNA1/BARF1/ LMP-specific EST line, we will first manufacture  
PBMCs (or dendritic cells (DCs)) pulsed with overlapping peptide libraries 
representing the entire protein sequences of LMP1, LMP2, BARF1 and EBNA1 
and the cytokines IL-7 and IL-15. The peptide mixtures ensure that the antigen is 
effective for any HLA phenotype, and competition between peptides ensures that 
we select and expand only T cells with receptor avidity sufficient to bind to and kill 
tumor cells. The addition of cytokines to the culture mix prevents activation-related 
T cell death by inducing anti-apoptotic molecules. The consequence is a broader 
antigen-specific T cell repertoire and a higher frequency of antigen-specific T cells.  
 
For second and subsequent stimulations we will use irradiated, donor-derived 
activated T cells (ATCs) that express both HLA class I and class II molecules, 
pulsed with the same peptide libraries together with irradiated HLA-negative K562 
cells genetically modified to express a broad range of costimulatory molecules 
(K562-cs).  At the end of the EST culture period, the frequency of EBNA1, BARF1 
and LMP specific EST will be determined using tetramer reagents if available.    
 
The EST lines will also be checked for identity, phenotype and sterility, and 
cryopreserved prior to administration, according to SOPs.  To test the functional 
antigen specificity of the EST line we will use individual pepmixes spanning each 
of the viral antigens used in the initial stimulation as a stimulus in the IFN-Υ 
ELIspot.  Epitope mapping will be performed using known HLA epitope peptides 
or peptide mini-pools to identify novel immunogenic epitope peptides within our 
target antigens.   
 
Products that meet study specific release criteria, as detailed on the CofA, will be 
infused as per Section 6.0. 
 
If a positive sterility testing result is reported after the product is infused, the FDA 
and other relevant parties will be notified as per manufacturing SOP B01.03.XX  

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(Product Quality Assurance Program and Release and Return of Clinical 
GMP/GTP Products) and clinical research SOP J02.06.XX (Serious Adverse 
Experience and Unanticipated Problem Reporting).   Management of such a 
situation is further described in SOP F05.09.XX (Management of Culture Positive 
Cell Therapy Products).  
 
5.3.2 No Matched EST Line Available 
 
If no matched line is available the patient will be registered so that the feasibility of 
the approach can be assessed. 
 
5.3.3 EST Line Available but Patient Status Changes 
 
Patients with a clinical course that changes between screening and infusion and 
renders patients ineligible at time of infusion will not be given the ESTs.  
 
5.3.4 Criteria for Selection of EST Line 
 
In general, preference will be assigned to the infusion of a line with confirmed 
virus-specific activity against EBV-specific antigens through a shared HLA allele 
rather than the overall level of HLA match.  For example, a line that matches at 2 
loci but that has recognition of EBV mediated through those antigens would be 
preferable to a line matched at 3 loci but with no demonstrated activity against 
EBV.  Patients with a partial response or stable disease are eligible to receive up 
to 6 additional doses.  Additional doses may be from the same donor or a 
different donor. Decision to switch to a different donor can be made by the 
principal investigator based on factors that include non-response to a previous 
line and/or availability of a better matched or otherwise superior line.  
 
5.4 Administration and Monitoring 
 
Patients will be evaluated in the clinic and 2 doses of EST will be administered, as 
per section 6.2, with or without lymphodepleting chemotherapy (Cy/Flu) as 
outlined in section 6.1. The decision to administer lymphodepleting chemotherapy 
(Cy/Flu) will be based on absolute lymphocyte count (ALC) at the time of 
screening, timing of last chemotherapy and clinical status. Patients with 
lymphopenia (ALC < 500) due to current drug therapy may be infused at any time 
starting at least 24 hours after finishing their current cycle of chemotherapy. 
Patients who have not recently received chemotherapy and are not lymphopenic 
(ALC>500) may receive lymphodepleting chemotherapy per section 6.1. Patients 
are not required to reach a target ALC prior to T cell infusion. The decision to 
administer lymphodepleting chemotherapy will be based on the ALC criterion, but 
also will take clinical condition and ability to tolerate chemotherapy into account (at 
the discretion of the PI). Patients will be monitored for clinical toxicity by the NCI 
Common Toxicity Criteria Scale (Version 4.X located at http://ctep.cancer.gov) 
with the exception of CRS toxicities that are related to T-cell infusions. CRS 
toxicities will be graded according to Appendix II. We will also analyze 
immunological parameters in peripheral blood, including phenotype and EST 
frequencies by tetramer studies in patients who have HLA types for which such 
reagents are available. Functional analyses will use cytotoxicity or ELIspot assays. 
The levels of EBV DNA in peripheral blood before and following infusion will be 
compared. A time period of 8 weeks after the first dose will constitute the time for 

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clinical safety monitoring. If patients have had a partial response or have stable 
disease they will be eligible to receive up to 6 further doses of ESTs, each of which 
will consist of the same number or less (if there is not enough product available for 
the subject’s original dose) as their second infusion.  
 
6. TREATMENT PLAN  
 
6.1 Dose Levels 
 
The following dose levels will be evaluated.  All doses are based on total CD3+ 
cells/m2: 
 
 
 
Dose Level 1 
 
2x107 cells/m2   + 2x107 cells/m2 
 
Dose Level 2 
 
2x107 cells/m2 + 5x107 cells/m2 
 
Dose Level 3 
 
5x107 cells/m2   + 1x108 cells/m2 
 
 
 
 
In addition, in accordance with the rationale described in Section 5.4: 
(a) Patients with lymphopenia (ALC < 500) due to current drug therapy may be 
infused at any time starting at least 24 hours after finishing their current cycle 
of chemotherapy. 
(b) Patients who have not recently received chemotherapy and are not 
lymphopenic (ALC > 500) may receive 3 daily doses of cyclophosphamide (Cy: 
500 mg/m2/day) together with fludarabine (Flu: 30 mg/m2) to induce 
lymphopenia, finishing at least 24 hours before T cell infusion. Patients are not 
required to reach a target ALC prior to T cell infusion. Infusions should be given 
following hospital/pharmacy recommendations however at a minimum the 
cyclophosphamide should be infused over 1 hour and the fludarabine should 
be infused over 30 minutes.  Mesna, IV hydration and anti-emetics should also 
be provided following local institutional guidelines.  As stated in section 5.4, the 
decision to administer lymphodepleting chemotherapy will be based on the 
ALC criterion but also will take clinical condition and ability to tolerate 
chemotherapy into account (at the discretion of the PI).  
 
6.2 Dosing Schedules 
 
Three different dosing schedules will be evaluated. Two to four patients will be 
evaluated on each dosing schedule.  
 
Each patient will receive 2 infusions, 14 days apart, according to the following 
dosing schedules.  All doses are based on total CD3+ cells/m2: 
 
Dose Level One:  
 
Day 0  
2 x 107 cells/m2 
Day 14  
2 x 107 cells/m2 
 

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Dose Level Two:   
 
Day 0  
2 x 107 cells/m2 
Day 14  
5 x 107 cells/m2 
 
Dose Level Three: 
 
Day 0  
5 x 107 cells/m2 
Day 14  
1 x 108 cells/m2 
 
If patients with active disease have apparent clinical benefit (as determined by 
symptoms, physical exam, or radiological studies) at their 8 week post 1st infusion 
(6 weeks after 2nd infusion) or subsequent evaluations they are eligible to receive 
up to 6 additional doses of ESTs at intervals at least 6 weeks apart each of which 
will consist of the same cell number as their second injection or below the patient’s 
original dose if there is not enough product available for the subject’s original dose. 
Patients may receive lymphodepleting chemotherapy (Cy/Flu) prior to additional 
infusions based on guidelines in section 6.1. Patients will not be able to receive 
additional doses until the initial safety profile is completed at 6 weeks following the 
second infusion. 
 
6.2.1 Dosing At Lower Dose 
 
Patients may receive dosing at a level lower than the current dose schedule level 
if an insufficient number of cells have been manufactured and fewer than 4 
patients/arm have been treated at that lower level to be consistent with the mCRM 
statistical design. 
 
6.3 Administration Guidelines 
 
6.3.1 Patients may be premedicated with Benadryl (diphenhydramine) up to 0.25-0.5 
mg/kg IV (max 25mg) and Tylenol (acetaminophen) 10mg/kg po (max 650mg). 
 
6.3.2 Cell Administration: ESTs in an expected volume of 1-40cc will be given by 
intravenous injection over 1-10 minutes through either a peripheral or a central 
line. 
 
 
 
6.3.3 Monitoring will follow institutional standards for administration of blood products 
with the exception that the injection will be given by a physician. 
 
6.3.4 Patients will receive supportive care for acute or chronic toxicity. Such care will 
include blood components or antibiotics and other interventions as appropriate. 
 
6.3.5 All treatments will be given at the Center for Cell and Gene Therapy, in Texas 
Children’s Hospital or Houston Methodist Hospital.  
 
6.3.6 Patients should not receive other treatment for their cancer between the first and 
second EST doses or for at least 6 weeks post EST (for purposes of evaluation). 
If a patient receives other treatment for their cancer between the first and 
second EST doses, that patient will be taken off treatment and will need to be 
replaced. 
 
6.3.7  If a patient who has had apparent clinical benefit (based on their 8 week post-
infusion or subsequent evaluation) receives additional EST doses on the 

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extended dosing regimen, they should not receive other treatment for their 
cancer for at least 6 weeks post EST.  If a patient receives other treatment for 
their cancer during this time period, they will be taken off treatment.   
 
 
 
 
7. PATIENT EVALUATION 
 
7.1 Routine Laboratory Investigations 
 
7.1.1 A complete history and physical examination is necessary prior to administration 
of chemotherapy (if applicable) and ESTs. 
 
7.1.2 The following investigations will be obtained pre-infusion, at 1*, 2, 4 and 6 
week(s) post-infusion and then at 3, 6, 9, and 12 months:  
 
CBC and differential, BUN, creatinine, bilirubin, SGOT, SGPT, Na, 
K, Cl, CO2, albumin. 
 
Pregnancy testing is required for female patients of childbearing 
potential (pre-infusion of chemotherapy or T-cells as applicable).  
* At week 1, only a CBC is required.  
 
7.2 Diagnostic Imaging 
 
 
Diagnostic imaging (CT scans, MRI, nuclear imaging) and/or blood tests (EBV 
viral load) to document measurable disease and response to therapy will be 
performed pre-infusion (within 4 weeks prior) and 6 weeks following the second 
infusion (8 weeks after the first infusion). If diagnostic imaging studies are 
performed at other times either during or after treatment on this study, that data 
will be collected and information gained will be used for this study. If the patient 
receives extended dosing, imaging will be done 1-3 months after the final infusion. 
 
7.3 Immune Function and Persistence Studies 
 
7.3.1 The following investigations will be obtained pre-infusion, at 3-4 days post 
infusion (optional depending on patient preference), 1, 2, and 6 weeks post-
infusion and then at 3, 6, 9, and 12 months. 
 
Peripheral blood is collected in preservative free heparin and ACD (acid citrate 
dextrose) anticoagulant (20-50ml).  This blood will be used for phenotyping of 
peripheral blood T cells and analysis of specificity of the EST response, using 
HLA-peptide tetramer analysis and immune function assays including ELISPOT 
and cytotoxicity assays where appropriate reagents are available. PCR for EBV-
DNA will be used to monitor the viral load. 
 
7.3.2 If the patient has additional injections of cells after the first two infusions, the 
above tests will also be obtained pre each infusion, 3-4 days post each infusion 
(optional depending on patient preference), and at 1, 2, and 6 weeks post each 
infusion. Follow up will continue every 3 months until 12 months after the last 
infusion, then yearly thereafter for 5 years. No study specific blood tests will be 

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collected after one year (if the patients have had additional injections) but we will 
remain in contact with patients to follow long term disease responses. 
 
7.4    Other Tissues  
 
7.4.1 Should the patient require a tumor biopsy at any stage during the first year, a 
sample of this will be used to assess EBV-DNA status.  
 
7.4.2 If a patients’ hemoglobin is less than 7.0g/dl, from a previous blood draw, at any 
of the evaluation times, the amount of blood drawn for the evaluation will be 
reduced and may be obtained over more than one venipuncture, if necessary. 
 
 

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7.5  
Study Calendar 
 
A summary of monitoring studies is provided in the following tables: 
 
7.5.1 For subjects who will not receive lymphodepleting chemotherapy as per guidelines in section 6.1.   
 
Study Procedure 
Pre-Study 
Treatment 
Follow-Up 
Day 0 
Day 
3-4 
Wk 1 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
M3 
M 6 
M 9 
M 12 Years 
2-5 
STUDY DRUG ADMINISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EST infusiona 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
DATA/TESTS/SPECIMENS TO BE OBTAINED 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hx 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PEb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood Tests [Hematology, clinical chemistry]d 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Imaging studies e 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Immune function studiesf 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
EBV Viral Load (PCR for EBV) f 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
DATA REVIEW 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment for Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment for Therapy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
AE Assessment 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
DLT Assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Response Assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Follow-up 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
a- Second EST infusion is planned on Day 14, however a delay of up to 2 weeks is allowed if necessary based on clinical status. 
b- After initial period of adverse event evaluation patients are followed based on standard of care practice. For the purposes of follow up, after week 8 patients may be followed in clinic or  follow up visits may 
be conducted at the subject’s local physicians office with appropriate documentation provided to the research team 
c- Pregnancy testing will be done pre-infusion in patients of childbearing potential.  
d- Hematology labs for CBC with differential; Clinical chemistry panel includes sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, total bilirubin, aspartate transaminase, alanine 
transaminase, albumin. 

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e- Evaluations of tumor size will be performed within 4 weeks of beginning treatment and 6 weeks after the second injection to occur anytime between week 6 and week 8.  
f- Blood will be used for immune function assays including ELISPOT assays (the day 3-4 post infusion sample is optional) 
g- Adverse Events are assessed throughout the clinical safety monitoring timeframe 
 
 
 
          Additional Treatment 
Study Procedure 
Treatment 
Follow-Up 
Day 
0 
Wk 
1 
Wk 2 
Wk 4 
Wk 6 
M 3 
M 6 
M 9 
M 12 
STUDY DRUG ADMINSITRATION 
EST infusion 
X 
 
 
 
 
 
 
 
 
 
DATA/TESTS/SPECIMENS TO BE OBTAINED 
 
 
 
 
 
 
 
 
 
 
Hx 
X 
 
X 
X 
X 
X 
X 
X 
X 
PEa 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Testb 
X 
 
 
 
 
 
 
 
 
 
Blood Tests [Hematology, clinical chemistry and lipase]c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging studiesd 
 
 
 
 
 
 
 
 
 
 
Immune function studiese 
X 
X 
X 
 
X 
X 
X 
X 
X 
EBV Viral Load (PCR for EBV) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DATA REVIEW 
 
 
 
 
 
 
 
 
 
 
AE Assessment 
Xf 
 
 
 
 
 
 
 
 
 
Response Assessment 
 
 
 
 
Xd 
 
 
 
 
 
Follow-up 
 
 
 
 
 
 
X 
X 
X 
X 
 
a- After initial period of adverse event evaluation patients are followed based on standard of care practice. For the purposes of follow up, after week 8 patients may be followed in clinic or 
follow up visits may be conducted at the subject’s local physicians office with appropriate documentation provided to the research team 
b- Pregnancy testing will be done pre-infusion in patients of childbearing potential. Either serum or urine is acceptable 
c- Hematology labs for CBC with differential WBC count; Clinical chemistry panel includes sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate transaminase, alanine transaminase, total protein, and Lipase. 
d- Imaging will be done 1-3 months after the final EB-VST infusion. 
e- Blood will be used for immune function assays including ELISPOT assays  
f- Adverse Events are assessed until 6 weeks after the last dose of study drug 
 
 
 
 

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7.5.2 For subjects who will receive lymphodepleting cyclophosphamide and fludarabine (as per guidelines in section 6.1). 
 
Study Procedure 
Pre-Study 
Treatment 
Follow-Up 
Day -4 
Day 0 
Day 
3-4 
Wk 1 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
M3 
M 6 
M 9 
M 12 Years 
2-5 
STUDY DRUG ADMINISTRATION 
Cytoxan/Fludarabine 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EST infusiona 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
DATA/TESTS/SPECIMENS TO BE OBTAINED 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hx 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PEb 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Tests [Hematology, clinical chemistry]d 
 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Imaging studies e 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Immune function studiesf 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
EBV Viral Load (PCR for EBV) g 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
DATA REVIEW 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment for Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment for Therapy 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
AE Assessment 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
DLT Assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Response Assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Follow-up 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
a.      Second EST infusion is planned on Day 14, however a delay of up to 2 weeks is allowed if necessary based on clinical status. 
b. 
After initial period of adverse event evaluation patients are followed based on standard of care practice. For the purposes of follow up, after week 8 patients may be followed in clinic or follow up visits 
may be conducted at the subject’s local physicians office with appropriate documentation provided to the research team 
c. 
Pregnancy testing will be done pre-infusion in patients of childbearing potential.  
d. 
Hematology labs for CBC with differential; Clinical chemistry panel includes sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, total bilirubin, aspartate transaminase, 
alanine transaminase, albumin. 
e. 
Evaluations of tumor size will be performed within 4 weeks of beginning treatment and 6 weeks after the second injection to occur anytime between week 6 and week 8.  
f. 
Blood will be used for immune function assays including ELISPOT assays (the day 3-4 post infusion sample is optional) 
g. 
Adverse Events are assessed throughout the clinical safety monitoring timeframe 

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     Additional Treatment 
Study Procedure 
Treatment 
Follow-Up 
Day  
-4 
Day 
0 
Wk 1 
Wk 2 
Wk 4 
Wk 6 
M 3 
M 6 
M 9 
M 12 
STUDY DRUG ADMINSITRATION 
Cytoxan/Fludarabine 
X 
 
 
 
 
 
 
 
 
 
EST infusion 
 
X 
 
 
 
 
 
 
 
 
DATA/TESTS/SPECIMENS TO BE OBTAINED 
 
 
 
 
 
 
 
 
 
 
Hx 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PEa 
X 
X 
 
 
 
 
 
 
 
 
Pregnancy Testb 
X 
 
 
 
 
 
 
 
 
 
Blood Tests [Hematology, clinical chemistry and lipase]c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging studiesd 
 
 
 
 
 
 
 
 
 
 
Immune function studiese 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
EBV Viral Load (PCR for EBV) e 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DATA REVIEW 
 
 
 
 
 
 
 
 
 
 
AE Assessment 
Xf
 
 
 
 
 
 
 
 
 
Response Assessment 
 
 
 
 
 
Xd 
 
 
 
 
Follow-up 
 
 
 
 
 
 
X 
X 
X 
X 
a- 
After initial period of adverse event evaluation patients are followed based on standard of care practice. For the purposes of follow up, after week 8 patients may be followed in clinic or 
follow up visits may be conducted at the subject’s local physicians office with appropriate documentation provided to the research team 
b- 
Pregnancy testing will be done pre-infusion in patients of childbearing potential. Either serum or urine is acceptable 
c- 
Hematology labs for CBC with differential WBC count; Clinical chemistry panel includes sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, total bilirubin, 
alkaline phosphatase, aspartate transaminase, alanine transaminase, total protein, and Lipase. 
d- 
Imaging will be done 1-3 months after the final EB-VST infusion. 
e- 
Blood will be used for immune function assays including ELISPOT assays  
f- 
Adverse Events are assessed until 6 weeks after the last dose of study drug 
 
 
   

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8. EVALUATION DURING STUDY  
 
8.1 Follow up Interval 
 
Patients shall be evaluated (seen in clinic or contacted by research coordinator) at 
two-week intervals for the first eight weeks, then at 3, 6, 9 and 12 months, then yearly 
for 5 years. Additional visits will be obtained as clinically indicated or if the patient is 
having more than 2 infusions. 
 
8.2 Early Termination of Study and Modifications of Drug Dosages 
 
8.2.1 The study will be completed when all dose levels have been safely studied (see 
Section 9) in each group, OR the study has reached the maximum tolerated 
dose lower than dose level 3. 
 
8.2.2 The criteria listed in the NCI Common Toxicity Criteria Scale will be used in 
grading toxicity. (Version 4.X located at http://ctep.cancer.gov) with the 
exception of CRS toxicities that are related to T-cell infusions. CRS toxicities will 
be graded according to Appendix II. 
 
8.2.3 A 6-week period after the second infusion (8 weeks after the first infusion) will 
constitute a course, which will be evaluated for critical toxicity and evaluation for 
antitumor activity. If a patient receives other treatment for their cancer between 
the first and second EST doses, we will discontinue study agent administration. 
In that case, our study follow up will be limited to long term outcome. 
 
8.3 Measurement of Effect 
 
 
Although response is not the primary endpoint of this trial, patients with measurable 
disease will be assessed by standard criteria. Evaluations of tumor size will be 
performed within 4 weeks of beginning treatment and 6 weeks after the second 
injection (8 weeks after the 1st infusion).  All patients who receive the first infusion will 
be evaluable for response (aside from those who receive chemotherapy between the 
first and second infusion).  
 
 
8.3.1 Measurement of Disease 
 
This study will use the International Working Group Criteria (Cheson BD, Annals 
Oncol 2008;19(Suppl 4):iv35) for measurement of disease in patients with 
lymphoma. 
 
The response criteria are defined below 
 
Response 
Definition 
Nodal masses 
Spleen/liver 
Bone Marrow 
Complete 
remission 
(CR) 
Disappearance 
of 
all evidence of 
disease 
(a) FDG avid or 
PET+ before 
therapy: mass of 
any size 
permitted if PET–
; 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy, if 
indeterminate 
by morphology 
immunohistochemistry 
should be negative 

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(b) variably FDG 
avid or 
PET–: regression 
to normal 
size on CT 
Partial 
remission 
(PR) 
Regression of 
measurable 
disease and no 
new sites 
‡50% decrease 
in SPD of up to 
six largest 
dominant 
masses. No 
increase in size 
of other nodes 
 
(a) FDG avid or 
PET+ before 
therapy: one or 
more PET+ at 
previously 
involved site; 
(b) variably FDG 
avid or PET–: 
regression on CT 
‡50% 
decrease in 
SPD of  
nodules (for 
single nodule 
in greatest 
transverse 
diameter), no 
increase in 
size of liver 
or spleen 
Irrelevant if positive 
before therapy, cell 
type should be 
specified 
Stable 
disease (SD) 
Failure to 
attain 
CR/PR or PD 
(a) FDG avid or 
PET+ prior to 
therapy: PET+ at 
prior sites of 
disease and no 
new sites on CT 
or PET; 
(b) variably FDG 
avid or PET–: no 
change in size of 
previous lesions 
on CT 
 
 
Relapsed or 
progressive 
disease 
Any new lesion 
or increase 
from nadir by 
‡50% of 
previously 
involved sites 
Appearance of a 
new lesion>1.5 
cm in any axis 
‡50% increase in 
the longest 
diameter of a 
previously 
identified node 
>1 cm in short 
axis or in the 
SPD of more 
than one node; 
lesions PET+ if 
FDG-avid 
lymphoma or 
PET+ before 
therapy 
‡50% 
increase from 
nadir in the 
SPD of any 
previous 
lesions 
New or recurrent 
involvement 

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In patients with CAEBV, response and progression will be evaluated by decreases in EBV viral 
load in blood and other tissues as applicable. 
 
This study will use the international criteria proposed by the Response Evaluation 
Criteria in Solid Tumors (RECIST) Committee77 for measurement of disease in 
patients with solid tumors (NPC, leiomyosarcoma, SMT). 
 
Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria.  Measurable lesions are defined as those 
that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm 
with spiral CT scan.  The investigator will identify up to 10 measurable lesions to 
be followed for response. Serial measurements are to be done with CT or MRI.  
The same method of assessment is to be used to characterize each identified and 
reported lesion at baseline and during follow-up. 
 
Complete Response:  Disappearance of all target lesions 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 
 
 
9. STATISTICAL CONSIDERATIONS  
 
9.1 Study Design Synopsis 
 
This protocol is designed as a phase I study to evaluate the safety and clinical 
response of 2 IV injections of rapid EBV Specific T cells (ESTs) in patients with 
EBV-associated Hodgkin’s Disease, lymphoma, CAEBV, or other EBV-associated 
malignancies. This is a phase-I dose-escalation trial to determine the maximum 
tolerated dose (MTD) level. The three dose levels of interest are discussed in 
Section 6.2. The dose escalation procedures will be operated separately and 
concurrently for the following 3 patient groups 
 
Group A: 
Patients in first or subsequent relapse 
 
Group B:    
 
Patients with persistent active disease despite therapy 
 
Group C: 
Patients with active disease if immunosuppressive chemotherapy is 
contraindicated e.g. patients who develop Hodgkin disease after solid organ 
transplantation or if the lymphoma is a second malignancy e.g. a Richter’s 
transformation of CLL.  

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We expect the safety profile to be similar across the different disease types, 
including NPC, leiomyosarcoma, and other smooth muscle tumors, as EBV-
specific T cells have been used in the past in these disease groups. We therefore 
do not feel the addition of patients with other EBV+ malignancies in the middle of 
the dose escalation will change the safety profile. As of the date of this 
amendment, all groups have finished dose level 1 without any DLT. The addition 
of patients with non-lymphoma EBV-associated malignancies will start with dose 
level 2 in group B.  
 
9.2 Sample Size and Design Characteristics 
 
Dose escalation in each patient group will be guided by a modified continual 
reassessment method (mCRM) to determine the MTD described as follows. The 
toxicity will be evaluated as per the NCI CTC Version 4.X and Section 8.2 of the 
protocol.  Dose limiting toxicity (DLT) is defined in Section 9.3. MTD is defined as 
the highest dose level at which the probability of DLT is at most 20%.  
 
Based on our previous trials, we expect the risk of toxicity due to EST infusion to 
be very low. To find the MTD with the targeted probability of 20%, we will 
implement the CRM method to guide the dose escalation, which has been shown 
in the literature to be superior to the standard 3+3 method designed for the targeted 
MTD probability 33.3%. To reduce the probability of treating patients at 
unacceptable toxic dose levels, we also employ some modifications to the original 
CRM. Specifically, the modifications are: (1) the first patient starts at the lowest 
dose level, (2) more than one patient can be treated at the same dose level, (3) 
there will be no jumps over a dose level and the dose is escalated according to the 
pre-specified levels, and (4) if a patient experiences a DLT, then there is no dose 
escalation for the immediate next patient. The modified CRM phase-I design has 
been studied extensively in the literature. Compared to the 3+3 design, mCRM 
provides better estimates of the MTD, affords smaller number of patients accrued 
at lower and more likely ineffective dose levels, and treats more patients at the 
MTD level.78-80  
 
During the dose escalation, each patient will be followed for 6 weeks post the 2nd 
EST infusion for the evaluation of DLTs. Two patients can be treated concurrently 
at the same dose level while the maximum number of patients in each dose level 
is 4. As we expect the risk of DLT due to EST infusion to be very low, we feel 
comfortable with the slightly accelerated dose-escalations (2 subjects in each 
cohort) without compromising patient safety. Depending on DLT data at each dose 
level, maximum 14 patients will be accrued for each patient group, where we will 
enroll 6 patients at the MTD dose level to ensure its safety.  
 
The dose escalation guided by a model-based mCRM will be based on a logistic 
model for the probability of toxicity Prob(Tox|d)=1/{1+exp(0.41- θ log[(da+db)/α]}, 
where da+db is the sum of 2 IV injected cells (0.4x108, 0.7x108, 1.5x108, 
respectively), α=3x108 is a scaling constant, and θ is the unknown parameter. We 
will implement a Bayesian version of the CRM and assume a non-informative 
uniform prior for θ.  Based on our previous trials, we expect a shallow dose-toxicity 
curve. The prior predictive probability is chosen conservatively to be 8.6%, 11.8%, 
and 21% for the three dosing schedules, respectively. 
 

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Two patients will be initially enrolled to the lowest dose level. Based on the 
observed toxicity data from the two subjects, we will update θ by computing its 
posterior distribution. The predictive probability of DLT under the current dose level 
and the next dose level are then evaluated. DLTs that occur during the 8 weeks 
following the initial injection will be factored into the CRM calculations to determine 
the predictive probability, so the next cohort of patients in each patient group will 
wait until the completion of the 8 weeks DLT evaluation. During the study, real-
time monitoring of patient toxicity outcome will be performed in order to estimate 
the dose-toxicity curve.  
 
The following rule will be applied independently to each patient group. If the 
predictive probability of DLT of next dose levels is  20%, then a new cohort of 2 
patients will be enrolled at the next dose level. If the probability of DLT of next dose 
level is > 20% but at the current dose level is  20%, then two more patients will 
be enrolled at the current dose level. If the probability of DLTs at the current dose 
level is > 20%, the dose will be de-escalated to the highest dose level with 
predictive probability of DLT  20%. The trial will be stopped if the predictive 
probability of DLT of all dose levels is > 20% after 4 patients have been studied at 
current or lower dose levels. The procedure continues until the dose has reached 
the highest dose level or stopped. If the probability of DLT under at the lowest dose 
level is > 20% after 4 patients, then the trial will be stopped and no MTD will be 
declared. If the trial reached the highest dose level with the predictive probability 
of DLT is  20% and 4 patients have been studied, then this dose level is tentatively 
defined as the MTD. Two more patients will be enrolled at this dose level (total 6 
at the MTD dose level).  
 
For each patient group, the final MTD will be the highest dose with toxicity 
probability lower than the target 20%. To ensure safety, we will treat a total 6 
patients at the MTD level.  As mentioned, the EST is safe and we do not anticipate 
seeing any EST-related DLTs. Hence, upon completion of the dose escalation, we 
anticipate that 10 patients will be treated with total 6 patients accrued at the MTD 
level for each patient group. If there are indeed one or more DLT events, we expect 
that at most 14 patients will be enrolled in the phase-I trial for each of three patient 
groups (total 42).  If there is any death possibly or probably related to EST infusion, 
then the study will be halted for patient accrual for the respective patient group, 
and the data will be discussed with the FDA. 
 
 
9.3 Dose Limiting Toxicity 
 
Except as noted below, a dose limiting toxicity is defined as any toxicity that is 
considered to be primarily related to the EST infusion that is irreversible, life 
threatening or a non-hematologic Grade 3-5.   
 
Grade 3 and 4 expected reactions seen with the use of T cell-based immunotherapy, 
such as fever and hypotension requiring pressor support, will not be considered 
DLTs. Any other grade 3 or greater toxicity felt to be related to or resulting from 
Cytokine Release Syndrome (CRS) is included in the definition of DLT. Grade 3 and 
4 CRS infusion reactions that are persistent beyond 72 hours will be reported to the 
FDA in an expedited fashion, and will be considered a treatment-limiting toxicity. 
 

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9.4 Data Analysis 
 
9.4.1 Safety Analysis of Adverse Event Data 
 
All patients who received EST infusions will be included in the safety analysis. All 
analyses will be performed separately for the three patient groups in this study. 
Safety and toxicity outcomes will be summarized for the overall patient group and 
by dose levels. Adverse event data and corresponding toxicity grades six weeks 
after EST infusions and during long-term follow-up will be summarized in the form 
of tables. Incidence tables will be generated to summarize incidence of patients 
reporting at least one episode of each specific adverse event, incidence of adverse 
events causing withdrawal and incidence of serious adverse events. The total 
number of episodes for each event reported (Frequency Table), and the severity 
and attribution to study therapy of each episode reported (Severity Table and 
Attribution Table) will also be displayed. 
 
Listings of adverse events by patients will include the time to onset, the duration 
of each event, the severity of each event, and the relationship of the event to study 
therapy, whether it was a serious event, and whether it caused withdrawal. Safety 
data will be summarized.  
 
9.4.2 Clinical response data 
 
For each patient group, response rates will be estimated as the percent of patients 
whose best response is either complete remission or partial remission (see 
Section 8.3) by combining the data from the three patient groups. To compare 
with historical data, a 95% confidence interval will be calculated for the response 
rate. 
 
The analysis of time to progression will include all patients who are considered 
evaluable for response. The probability of progression free survival at 6 months 
will be summarized.  Time to progression will be estimated using the product-limit 
method of Kaplan and Meier, and their associations with biologic biomarkers will 
be studied by the Cox regression in an exploratory way.  Time to progression is 
defined as the number of days from enrollment to: (1) disease progression; (2) 
death because of treatment complications; or (3) last patient follow-up whichever 
is first. Patients will be considered to have experienced a progression event if (1) 
or (2) occurs. Otherwise, the patient will be considered censored for time to 
progression. 
 
9.4.3 Safety Analysis of Laboratory Data 
 
Descriptive statistics (means, standard deviations, medians and ranges) at pre-
infusion and at 1, 2, and 6 and 8 weeks post-EST infusion will be calculated.  
Laboratory data collected at 3-month intervals for the first year will also be 
summarized. Scatter plots depicting laboratory values at each time point for each 
patient will also be generated. In order to analyze changes in laboratory values, a 
shift table with Stuart-Maxwell chi-square analysis of the change in the normal 
range from pre-infusion to post infusion time points (using high, normal, low) will 
be performed.  When appropriate, these tables are collapsed and the McNemar’s 
test applied in place of the Stuart-Maxwell test. 
 

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9.4.4 Analysis of Expansion and Persistence of ESTs 
 
Despite the small patient numbers, a data-dense study will be generated due to 
the repeat measurements on proliferation, immune function, etc. on each patient. 
Descriptive statistics using mean ± SD, medians and ranges will be calculated to 
summarize repeated measurements of EST expansion (increasing EST levels in 
the peripheral blood over time), persistence (infused ESTs continuing at detectable 
levels over time), and function (ability to respond to viral antigens) following 
infusion. Immune response to viral antigens measured by interferon-γ (IFNγ) 
ELISPOT will be analyzed. Plots of growth curves will be generated to graphically 
illustrate patterns of survival and expansion of ESTs as well as immune response. 
The validity of the normality assumption on these data will be tested and 
appropriate transformations will be considered whenever indicated. 
 
To compare the persistence of ESTs among the three dose levels, we will calculate 
the area under the growth curves (AUC) over time for EST frequencies.  After 
appropriate log-transformation, ANOVA and t-test will be used to compare the 
AUCs with Tukey adjustment for multiple comparisons. Alternative strategies such 
as repeated measurement models will be applied to compare immunological and 
virological efficacy across dose levels. We will use a type-I error of 10% in the 
analysis because of the small sample size.  
  
The modeling strategies proposed here are amenable to these types of data but 
will however be considered exploratory and interpreted with caution due to limited 
study power and high type-I error. The results of this study will not be definitive but 
only exploratory. 
 
 
10.  MODIFIED FOLLOW - UP and OFF-STUDY CRITERIA  
 
10.1 Modified Follow-Up Criteria:  
The following criteria will result in the patient being ineligible for further treatment     
on the protocol, although response data will continue to be collected as 
applicable: 
 
10.1.1 Any patient who develops irreversible, life threatening or non-hematologic 
Grade 3 to 5 toxicity considered to be primarily related to EST infusion. In 
such patients the toxicities will be followed until resolution or until their off 
study date. 
10.1.2 Any patient who receives any other hematopoietic cell product.  In such 
patients adverse event data collection will cease.  
10.1.3 Any patient who receives therapy for relapse of their primary malignancy. 
In such patients adverse event data collection will cease,  
10.1.4 Any patient who experiences Grade 3 or 4 cytokine release syndrome 
that persists beyond 72 hours. In such patients, the toxicity will be 
followed until resolution or until their off study date. 
10.1.5 Any patient who receives other treatment for their cancer between the 
first and second EST doses will be taken off treatment and will need to be 
replaced. 
  
 
Patients who meet modified follow up criteria remain on long term follow-up as 
per study calendar (Section 7.5).  
 

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37 
 
10.2 Off Study Criteria 
 
Patients are considered to be off study if they meet the following criteria:  
10.2.1 Completion of study specified procedures  
10.2.2 Refusal of further study follow up by patient or legal guardian 
10.2.3 Lost to follow up 
10.2.4 Death 
 
  
Any questions regarding patients on this study should be addressed to Dr. Rouce at 
832-824-4716. 
 
11. RECORDS TO BE KEPT  
 
The CAGT research nurse/coordinator will maintain a database documenting on study 
information, adverse events, off study notification and death information. The dates and 
doses of therapy as well as clinical chemistries, hematologic parameters, the clinical 
status and occurrence of any adverse events and subsequent interventions are to be 
kept on all patients. 
 
 
Imaging reports 
 
Surgical summaries 
 
Autopsy summaries, where appropriate 
 
Informed consent documents 
 
All required clinical evaluation records will be the responsibility of Dr. Rouce, who will 
also be responsible for analysis of the clinical outcome and toxicity. 
 
The laboratory evaluation of immunological efficacy and EBV DNA persistence will be 
the responsibility of Dr. Rooney. 
 
 
 
12. REPORTING REQUIREMENTS  
 
12.1 Registration 
 
 
Register all patients with Cell and Gene Therapy Research Coordinator. 
 
 
Enter all patients by phoning Dr. Rouce. The following data should be 
collected: 
 
Eligibility 
On study 
Concomitant medications 
Off study 
Flow sheets 
Adverse events  
CRS adverse event (as applicable) 
Death (if applicable) 
 
12.2 Drug Toxicity and/or Adverse Reactions 
 
12.2.1 Adverse events will be collected as per SOP J 02.05.XX and SOP J 02.75.XX.  
Data on adverse experiences/toxicities regardless of seriousness, must be 

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38 
 
collected for documentation purposes only for 6 weeks after the last dosing of 
study drug/biologic. 
 
12.2.2 Serious adverse events will be collected for 1 year post-last infusion as per SOP 
J 02.06.XX.   
 
13. INFORMED CONSENT  
 
All patients and/or their legal guardian must sign a document of informed consent 
consistent with local institutional and Federal guidelines stating that they are aware of the 
investigational nature of this protocol and of the possible side effects of treatment. 
Further, patients must be informed that no efficacy of this therapy is guaranteed, and that 
unforeseen toxicities may occur. Patients have the right to withdraw from this protocol at 
any time. No patient will be accepted for treatment without such a document signed by 
him or his legal guardian. Full confidentiality of patients and patient records will be 
provided according to institutional guidelines. 
 
14. CLINICAL TRIAL OVERSIGHT AND MONITORING 
 
This protocol will be conducted in accordance with the Cell Therapy Monitoring Plan on 
file with the FDA.   
 
This protocol will be monitored in accordance with the current Data Safety Monitoring 
Plan of the Dan L Duncan Cancer Center at Baylor College of Medicine. 
 
The conduct of this clinical trial will be evaluated in accordance with the Texas 
Children's Cancer Center and Center for Cell and Gene Therapy Quality Assurance 
Policy and Procedure Plan.  
 
 
 
 

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Appendix I 
 
Potential Side Effects of Lymphodepleting Chemotherapy 
 
 
 
Risks and side effects related to CYCLOPHOSPHAMIDE include those which are: 
Likely 
Less likely 
Rare but serious 
 
Loss of appetite 
 
Nausea 
 
Vomiting 
 
Fewer white blood cells 
 
in the blood. 
 
A low number of white blood 
cells, which may make it 
easier to get infections. 
 
Hair loss 
 
Decreased ability of the body 
to fight infections 
 
Absence or decrease in the 
number of sperm, which may 
be temporary or permanent 
which may decrease the 
ability to have children 
 
Abnormal hormone function 
which may lower the level of 
salt in the blood 
 
Abdominal pain 
 
Diarrhea 
 
Fewer red blood cells and 
platelets in the blood 
 
A low number of red blood 
cells may make you feel tired 
and weak. 
 
A low number of platelets 
may cause you to bruise and 
bleed more easily. 
 
Bleeding and inflammation of 
the urinary bladder 
 
Absence 
or 
decrease 
monthly periods which may 
be temporary or permanent 
and which may decrease the 
ability to have children 
 
Temporary blurred vision 
 
Nasal stuffiness with IV 
infusions 
 
Skin rash 
 
Darkening of areas of the 
skin and finger nails 
 
Slow healing of wounds 
 
Infections 
 
Heart muscle damage which 
may occur with very high 
doses and which may be 
fatal. 
 
Abnormal heart rhythms 
 
Damage and scarring of lung 
tissue which may make you 
short of breath 
 
A new cancer or leukemia 
resulting from this treatment. 
 
Damage 
or 
scarring 
of 
urinary bladder tissue 
 
Severe 
allergic 
reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 
rate chills and fever  
 
Infertility, 
which 
is 
the 
inability to have children 
 

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Risks and side effects related to FLUDARABINE (IV) include those which are: 
 
Likely 
(May happen in more than 
20% of patients) 
Less Likely 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
(May happen in fewer than 2% 
of patients) 
 
Low number of red 
blood cells (anemia) 
 
Low number of white 
blood cells 
 
Low number of blood 
platelets 
 
Feeling tired 
 
Nausea (feeling sick to 
your stomach) 
 
Throwing up (vomiting) 
 
Weak immune system 
 
Pneumonia 
 
Infection 
 
Bleeding 
 
Pain 
 
Electrolyte imbalance 
 
Diarrhea 
 
Mouth sores 
 
Skin rash 
 
Fever 
 
Swelling of hands and 
feet 
 
Numbness and tingling in  
hands and/or feet  
 
Loss of appetite 
 
Changes in vision 
 
Feeling nervous or anxious 
 
Confusion 
 
Cough 
 
Difficulty breathing 
 
Feeling weak 
 
Severe brain injury which 
can lead to death 
 
Kidney damage that could  
require dialysis 
 
Coma 
 
New (secondary) cancers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix II CRS Grading Scale 
 
 
Grade 
Symptoms 
1 
 Symptoms are not life threatening and require symptomatic treatment only 
(e.g. fever, nausea, fatigue, headache, myalgia, malaise)  
2 
 Symptoms require and respond to moderate intervention  
 Oxygen requirement <40% or hypotension responsive to fluids or  
 low dose of one vasopressor or Grade 2 organ toxicity  
3 
 Symptoms require and respond to aggressive intervention  
 Oxygen requirement ≥ 40% or  
hypotension requiring high dose or multiple vasopressors or  
 Grade 3 organ toxicity or Grade 4 transaminitis  
4 
 Life-threatening symptoms 
 Requirements for ventilator support or  
Grade 4 organ toxicity (excluding transaminitis)  
5 
 Death