A Phase II Study of the Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies
Phase: PHASE2
Conditions: EBV-induced Lymphomas, EBV-associated Malignancies, Transplant Patients With EBV Viremia at High Risk for Developing a Recurrent EBV Lymphoma
Sponsor: Atara Biotherapeutics

 
 
 
Page 1 of 41 
 
 
A Phase II Study of the Therapeutic Effects of Epstein-Barr Virus Immune T-Lymphocytes 
Derived from a Normal HLA- Compatible or Partially- Matched Third-Party Donor in the Treatment 
of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies 
 
PROTOCOL FACE PAGE FOR  
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
, M.D. 
Pediatrics, BMT 
Co-Principal 
Investigator(s)/Department: 
          
, M.D. 
 
Medicine, BMT 
 
Investigator(s)/Department: 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.B.B.S. 
, M.D. 
, M.D., Ph.D, 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D., Ph.D. 
, M.D., Ph.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, 
M.D., Ph.D. 
, M.D. 
, MD 
, M.D., Ph.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D., Ph.D. 
, M.D. 
, M.D. 
 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, Head & Neck 
Medicine, Head & Neck 
Medicine, Head & Neck 
 
Consenting Professional(s)/Department: 
, M.D. 
, M.D. 
, M.D. 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

 
 
 
Page 2 of 41 
, M.D. 
, M.D. 
, M.D. 
, M.B.B.S. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D., Ph.D. 
, M.D., Ph.D. 
, M.D., Ph.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, M.D. 
, 
M.D., Ph.D. 
, M.D 
, M.D., Ph.D. 
, M.D. 
, M.D. 
 
For Donor Consents and Patient 
Assessment Consents ONLY: 
 
 
 
 
 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
 
   Medicine, BMT 
Medicine, Head & Neck 
Medicine, Head & Neck 
Medicine, Head & Neck 
 
 
 
 
Medicine, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

 
 
 
Page 3 of 41 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 5 
3.0 
BACKGROUND AND RATIONALE ........................................................................................ 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................... 9 
4.1 
Design....................................................................................................................................... 9 
4.2 
Intervention ............................................................................................................................. 10 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS.............................................................................. 10 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY.............................................................................. 13 
6.1 
Subject Inclusion Criteria........................................................................................................ 13 
6.2 
Subject Exclusion Criteria ...................................................................................................... 15 
7.0 
RECRUITMENT PLAN .......................................................................................................... 16 
8.0 
PRETREATMENT EVALUATION ......................................................................................... 16 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 17 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 21 
11.0 
TOXICITIES/SIDE EFFECTS ................................................................................................ 23 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................... 25 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 26 
14.0 
BIOSTATISTICS .................................................................................................................... 27 
15.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 30 
15.1 
Research Participant Registration ......................................................................................... 30 
15.2 
Randomization........................................................................................................................ 31 
16.0 
DATA MANAGEMENT ISSUES............................................................................................ 31 
16.1 
Quality Assurance .................................................................................................................. 31 
16.2 
Data and Safety Monitoring.................................................................................................... 31 
17.0 
PROTECTION OF HUMAN SUBJECTS............................................................................... 32 
17.1 
Privacy .................................................................................................................................... 32 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................... 32 
17.2.1............................................................................................................................................... 32 
18.0 
INFORMED CONSENT PROCEDURES............................................................................... 35 
19.0 
REFERENCES ....................................................................................................................... 36 
20.0 
APPENDICES ........................................................................................................................ 41 
 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 4 of 41 
•Hematopoietic cell or solid organ 
allograft recipients with EBV lymphoma 
or EBV LPD. 
• Patients with or without pre-existing 
immune deficiency who develop EBV 
lymphoma, EBV LPD or other EBV-
associated malignancies. 
• EBV specific T-cells from transplant 
donor not immediately available.  
Consent to Treatment 
Selection of EBV-
specific T-cells from 
EBV-specific T- cell 
bank, based on 
partial HLA-match 
and whenever 
possible HLA 
restrictions. 
Treatment with at least 3 weekly doses of 
selected EBV-specific T-cell line. 
Assess response 
CR, PR or SD 
PD 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a single institution phase II trial designed to assess the therapeutic activity of Epstein-Barr 
Virus Immune T-lymphocyte lines derived from consenting EBV seropositive, partially HLA-
matched third party donors. These T cell lines are generated, maintained, and cryopreserved in 
an MSKCC Transplant Program-administered cell bank for the treatment of EBV+ lymphomas, 
EBV lymphoproliferative disease and other EBV-Associated Malignancies.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Normal EBV seropositive blood donors + and 
hematopoietic cell transplant donors. 
Consent to provide blood or leukapheresis for 
production of EBV T-cells to treat EBV 
lymphoma or other EBV malignancy in 
transplant recipients or other patients with 
EBV+ malignancies. 
Used to treat EBV 
Lymphoma in HSCT 
recipient 
Not used for 
designated HSCT 
recipient 
EBV-Specific T-cell Bank: a bank of HLA 
typed GMP grade T cell lines for use in 
adoptive therapy of EBV lymphoma, EBV 
LPD and EBV associated malignancies 
Eligible Patients 
Generation, Characterization + storage of 
EBV-Specific T- cell lines 
Treatment with at least one additional 
cycle of at least 3 weekly doses of 
selected EBV T-cell line if indicated and 
EBV-T-cells are available  
Treatment failure:  
Patient is candidate for 
a) Chemotherapy or other alternate treatment 
b) Treatment with EBV-specific T-cells from 
another donor whose EBV-specific T-cells are 
restricted by HLA-allele
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 5 of 41 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
PRIMARY 
1) To evaluate, in a Phase II single dose level trial, the therapeutic potential of adoptive 
immunotherapy with EBV-specific T-cells derived from HLA partially matched third-party donors in 
the treatment of EBV-induced lymphomas and EBV-associated malignancies including EBV+ 
Hodgkin’s and Non-Hodgkin’s disease, EBV+ nasopharyngeal carcinoma, EBV+ hemophagocytic 
lymphohistiocytosis, and EBV+ leiomyosarcoma. 
2) To establish a centralized bank of cryoperserved, GMP (Good Manurfacturing Practice) grade, 
EBV-specific T-cell lines from consenting donors of defined HLA type and HLA restriction which can 
serve as an immediately accessible source of HLA partially matched EBV-specific T-cells for 
adoptive therapy of EBV lymphomas, EBV lymphoproliferative disease and other EBV-associated 
malignancies. 
3) To estimate the overall survival, disease free survival, and probability of EBV relapse over time of 
patients who receive EBV-specific T-cells derived from HLA partially matched third-party donors. 
 
SECONDARY 
1) To evaluate the in vivo expansion and duration of engraftment of successive doses of transferred 
EBV-reactive lymphocytes within treated patients and to correlate these findings with the diseased 
patient’s T-cell populations and general immune function. 
2)  To determine the incidence, kinetics and durability of pathological and/or clinical responses of 
EBV-induced malignancies to treatment with infusions of EBV-specific T-cells derived from 
histocompatible or partially HLA-matched EBV-seropositive normal third-party donors.  
 
3.0 
BACKGROUND AND RATIONALE 
Epstein-Barr virus is a member of the herpes virus family of DNA viruses.  In normal individuals, 
primary infection occurs in early adolescents and initially involves the parotid and salivary glands 
giving rise to either an asymptomatic infection or infectious mononucleosis (1).  Following initial 
production of lytic virus, the virus infects and becomes latent in B-lymphocytes and remains so for 
the life of the individual.  Infection of the B-lymphocytes results in their transformation and 
immortalization. However, during latent infection, only a limited number of viral genes are expressed. 
These include the nuclear antigens EBNA1-5 and the latent membrane proteins, LMP1 and LMP2 
(2, 3). In normal seropositive individuals, 30-100/million circulating B-cells are transformed latently 
infected B-cells (4).  The immune response to EBV includes both the generation of antibodies and 
the production of antigen-specific T-cells.  However, control of latent infection depends upon the 
integrity of T-cell mediated immunity (5). Data from our own ( 6, 7 ) and other studies indicate that 
the principal effectors controlling EBV are HLA-class I-restricted CD8+ T-cells specific for latent EBV 
antigens, particularly EBNA-3 ( 8, 9 ).  EBV-specific HLA class II-restricted CD4+ T-cells stimulate 
the CD8+ T-cell populations but their role in controlling or eliminating EBV transformed cells is still 
controversial (10).   In a normal seropositive adult, 0.5-5% of the circulating T-cells can be shown to 
be EBV-specific by analyses of CD8+T-cells binding EBV peptide/HLA tetramer complexes.(11) 
Similarly, the frequencies of EBV reactive interferon-gamma positive T-cells and cytotoxic T-cell 
precursors range from 1/102-103 and 1/103-104 respectively ( 12 ). 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 6 of 41 
In immunocompromised, T-cell deficient human hosts, EBV may cause either lymphoproliferative 
disorders or outright lymphomas (13).  In addition, EBV latent infection has been implicated in the 
pathogenesis of up to 30 % of patients with Hodgkin’s disease (14), a high proportion of 
nasopharyngeal carcinomas developing in the Orient (15) and leiomyosarcomas developing in 
patients with advanced AIDS, genetic immunodeficiencies or states of immunosuppression resulting 
from drugs used to prevent rejection or GVHD following organ or hematopoietic stem cell transplants 
(16). 
EBV-LPD are particularly common among organ allograft recipients. Among renal allograft recipients 
their incidence ranges from 0.6 - 1% (17, 18). However, in more heavily immunosuppressed liver 
and heart allograft recipients, the incidences are 5% and 10-13% respectively (19, 20). The EBV-
LPD developing in these patients are most commonly polyclonal (21). Such polyclonal disorders 
may regress spontaneously if treatment with immunosuppressive drugs is curtailed (21, 22). 
Alternatively, treatment with interferon-, acyclovir or B-cell specific monoclonal antibodies may 
induce durable remissions in a proportion of cases refractory to this approach (23, 24, 25). However, 
for patients developing monoclonal EBV lymphomas, none of these approaches has been 
consistently effective. Furthermore, despite chemotherapy, the long term survival has been 
estimated at 25-60% (23).  
Recently, EBV-induced lymphomas have emerged as a significant complication of HLA non-identical 
related and matched related marrow allografts particularly when administered after selective 
depletion of T-cells (26, 27,32) or application of more intensive, T-cell targeted, cytoreductive 
regimens to ensure engraftment or prevent GvHD (28). These EBV-LPD resemble the EBV+ 
lymphomas in AIDS patients and differ from the benign B-cell hyperplasias and polyclonal 
lymphoproliferative disorders observed in most renal and cardiac allograft recipients in that they 
most often present as malignant high-grade diffuse large cell B-cell lymphomas which are 
monoclonal (29). Their clinical course is fulminant. Indeed, studies have demonstrated that the 
median survival for patients afflicted with EBV lymphomas emerging early after hematopoietic stem 
cell transplants is only 31 days (30).  Like EBV+ lymphomas which emerge in the context of profound 
cell mediated immune deficits, these lymphomas express not only EBNA1 but also EBNA2, EBNA3, 
4, 5 and LMP1 and 2.  However, a striking feature of EBV lymphomas emerging in marrow allograft 
recipients is that they are almost invariably of marrow donor rather than host origin (26, 31). 
Furthermore, they develop only in the interval between completion of pre transplant immunoblative 
therapy and the reconstitution of functional donor T-cell derived immunity, which is usually 6-8 
months post transplant (32).  These malignancies thus reflect the rapid emergence of EBV 
transformed B-cell clones from the marrow graft itself if not controlled by EBV-specific T-cells. 
Historically, treatment of systemic EBV lymphomas developing in patients with genetic immune 
deficiency, AIDS or organ grafts requiring chronic immunosuppression has entailed the use of 
combination chemotherapies similar to those used to treat non-Hodgkin’s lymphoma, such as 
CHOP, PROMACE-CYTOBOM or m-BACOD. However, while initial complete remissions have been 
recorded in 20-72% of such patients, these remissions have been invariably short-lived (33-37).  
Furthermore, intensive chemotherapy has been complicated by a high mortality ascribable to 
opportunistic infections.  As a consequence, median duration of survival post diagnosis of EBV 
lymphomas has ranged from 3-15 months. (33-37). For AIDS patients with EBV lymphomas of the 
central nervous system, which are consistently EBV+, median survival duration is only 2-3 months 
(38,39).   
More recently, the CD20 specific monoclonal antibody, Rituxan, has been employed to treat both 
EBV lymphoproliferative disorders and EBV lymphomas occurring in patients with genetic or 
acquired immunodeficiencies and in organ or hematopoietic stem cell transplant recipients.  Rituxan 
used alone has induced initial responses in up to 70% of organ allograft recipients and up to 50 % of 
patients developing lymphomas following hematopoietic cell transplants (40, 41).  However, 
responses overall have been sustained in no more than 50 % of patients (42).  In those who relapse 
or fail to respond to Rituximab, these lymphomas have been consistently lethal.   
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 7 of 41 
The importance of T-cell immunity to the control of EBV infection had initially been suggested by the 
studies of Moss et al in the early 1970s (43).  However, it was not until 1994 that the therapeutic 
potential of T-cells in the treatment of EBV lymphomas was formally demonstrated,   when, our 
group reported a series of 5 patients who developed monoclonal EBV lymphomas following T-cell 
depleted allogeneic hematopoietic cell transplants who achieved durable remissions of 
pathologically documented monoclonal EBV lymphomas following infusions of small numbers of 
donor lymphocytes (26).  In a subsequent study, we demonstrated that doses providing as few as 
1,000 EBV-specific CTLPs could induce durable and complete remissions of widespread disease 
(32). Groups in the United States and Europe have subsequently confirmed these observations (44, 
45).  Furthermore, Rooney et al demonstrated that infusions of EBV-specific T-cells propagated in 
vitro prevented the development of EBV lymphomas in a large cadre of patients at risk who had 
received T-cell depleted hematopoietic stem cell transplants (46).  In addition, our own group, the 
group at Baylor and a group in Milan have each demonstrated the capacity of such EBV-specific T-
cells to induce complete regressions of EBV lymphomas without risk of subsequent development of 
graft versus host disease (47-49). 
EBV specific T cells can also be effective in the treatment of other EBV associated malignancies. 
For example, recent clinical trials have demonstrated complete response rates in up to 20 % of 
patients with EBV+ Hodgkin’s disease who have received infusions of ex vivo propagated EBV-
specific autologous T-cells (50).  Similarly, a significant proportion of patients with EBV+ 
nasopharyngeal carcinoma have also responded to infusions of either unselected allogeneic HLA-
matched T-cells or in vitro propagated EBV-specific autologous T-cells (51, 69). 
Our current, ongoing study (95-024) is a phase I/II clinical trial evaluating the toxicity and therapeutic 
potential of EBV-specific T-cells generated from a hematopoietic stem cell transplant (HSCT) donor 
in the treatment of EBV+ lymphomas developing in recipients of such transplants.    This study 
initially concentrated on evaluation of EBV-specific T-cells generated from HLA disparate unrelated 
and related hematopoietic cell transplant donors. We have focused on these donor/recipient pairs for 
2 reasons: 1) These patients are at high risk of developing an EBV lymphoma, 2) These patients are 
also at the highest risk of developing severe acute and/or chronic graft vs. host disease if they 
receive unselected donor lymphocytes since these populations include significant frequencies of 
alloreactive T-cells capable of generating cytotoxic responses against major (HLA) as well as minor 
alloantigens. In Phase I of Protocol 95-024, a total of 18 marrow allograft recipients have received 
infusions of EBV-specific T-cells as treatment for documented monoclonal EBV lymphomas.  Of the 
18 HSCT recipients, 11 achieved complete and durable remissions of their EBV lymphomas 
following infusions of donor derived EBV-specific T-cells. No patient has developed acute or chronic 
GVHD.  
Subsequent to the initial 18 HSCT patients treated, 95-024 underwent an IRB/FDA approved 
expansion to include EBV CTL infusions from partially HLA-matched seropositive third party donors.  
Since that time, ten patients, who have received HSCTs, have been treated with EBV CTLs from 3rd 
party donors. All infusions were well tolerated without toxicity or adverse event ascribable to the T 
cell infusions. Furthermore, no patient has developed acute or chronic GVHD. Six (6) of these 
patients (including one who was treated on a single patient use IND according to 95-024) achieved 
durable complete remissions. The remaining 3 patients were treated with 3rd party EBV CTLs late in 
the course of their EBV lymphoma, and died of progressive disease. We have recently reported two 
of these patients who developed monoclonal EBV lymphomas following umbilical cord blood 
transplants which were successfully treated by sequential infusions of EBV specific T cells from an 
HLA-partially matched, consenting unrelated third party donor (70).  
The HSCT cohort of 95-024 (Group 1) remains open as a phase II study, accruing patients to an 
extension of its Phase I arm. 
In addition to HSCT recipients (Group 1), 95-024 is also designed to assess the toxicity and anti-
tumor activity of HLA-haplotype matched EBV-specific T-cells in patients who develop EBV 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 8 of 41 
lymphoma as a complication of the chronic immune suppression required to sustain an organ 
allograft or complicating AIDS (Group 2).  To date, 7 organ allograft recipients and one patient with 
AIDS with EBV lymphomas were treated with either ex vivo expanded autologous (N=1), haplotype 
matched, related (N=5) EBV specific T-cells, or partially HLA-matched seropositive third party 
donors (N=2). Of 7 organ allograft patients, 1 patient received EBV CTLs late in the course of his 
EBV LPD and died of progressive disease, 1 patient is in durable CR, 2 patients achieved durable 
partial responses (>3 years), and the remaining 2 are with stable disease for >2 years post 
treatment.  
The AIDS/organ allograft cohort of 95-024 (Group 2) remains open, and is accruing patients to its 
Phase I arm. 
Our preliminary successes with third party donor-derived EBV specific T cells are consistent with the 
findings of Haque et al (52, 53), who used pre-generated EBV- specific T-cells derived from normal 
partially HLA-matched seropositive third party donors for cellular immunotherapy of EBV+ 
lymphoproliferative disease in organ allograft recipients. In a phase II, multicenter trial conducted in 
Europe, HLA-partially matched EBV-specific T-cells were selected from a limited cryopreserved 
bank of EBV-specific predominantly CD8+ T-cell lines previously generated from normal EBV 
seropositive donors established by Crawford et al (54). The T-cells used for each patient were 
selected on the basis of partial HLA matching with the patient, EBV- specificity, and lack of reactivity 
against autologous or allogenic PHA-stimulated PHA blasts. A total of 33 transplant recipients were 
treated with an EBV lymphoproliferative disease that had progressed after discontinuation of 
immunosuppressive drugs.  While these EBV LPD were not characterized as to clonality, they did 
include 13 EBVLPD which were refractory to Rituxan and/ or chemotherapy.  There were 2 
recipients of allogenic hematopoietic stem cell transplant and 31 organ allograft recipients. 
Treatment consisted of weekly infusions of 2 x 106 EBV-reactive T-cells/kg x 4. In each case, the 
infusions were well tolerated without acute toxicities. Furthermore, no patient experienced either an 
allograft rejection response or, in the marrow transplant recipients, GVHD. At 5-week post infusion, 
64% had a significant response (12CR, 9 PR). At 6 months, these responses were sustained in all 
12 patients with CR and in 5/9 patients who achieved a PR, or 52% of the series. Only 5 patients 
were monitored for engraftment of the T-cells; they were detected for 7 days in only one patient.  
The use of partially HLA-matched seropositive third party donors in protocol 95-024, can obviate two 
central limitations to the broad application of EBV- specific T-cells for the adoptive immunotherapy of 
EBV-associated malignancies: the logistical difficulties in obtaining needed blood samples from 
donors and the prohibitively long time required to generate and isolate suitably EBV-specific T-cells 
in the numbers necessary for effective treatment. Without the use of third party cell lines, protocols 
rely on EBV- transformed B cell lines generated from the blood of the T-cell donor for in vitro 
immunization of the T- cells. Transformation of the B cells with the laboratory strain of EBV, B95.8 is 
very efficient. However, it takes 28-35 days before the transformed B cell line is sufficiently 
established and expanded to the numbers required for T-cell sensitization. Thereafter, an additional 
30 days is required to culture and expand T- cells that are adequately EBV-specific and cytotoxic 
against EBV- transformed cells. This period of culture is also required to deplete the T cell lines of 
alloreactive T-cells that could cause either GVHD in marrow transplant recipients or rejection in an 
organ allograft recipient. Since the total time required to generate such T-cells (60-65 days) exceeds 
the median survival of patients with such lymphomas (31 days) (30), the EBV-specific T-cells need 
to be generated before the onset of lymphoma if they are to be consistently effective. For patients, 
other than a transplant recipient, who develop other EBV associated malignancies, generation of 
autologous EBV- reactive T-cells has been attempted, but often fails. Furthermore, EBV- specific T-
cells generated from these tumor bearing hosts often fail to react against the limited spectrum of 
EBV antigens (LMP-1, LMP-2, EBNA-1) expressed by their tumors. 
In the course of our study, we have, whenever possible, attempted to generate EBV-specific T-cells 
for patients at risk for this complication prior to or at the time of transplant. As a result, over 300 
EBV-specific T-cell lines have been generated, characterized and cryopreserved for an individual 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 9 of 41 
patient’s use to treat an EBV lymphoma were it to develop. Fortunately, the incidence of EBV 
lymphoma in this patient group has been low (2-6%), and almost all of these patients have, by now, 
achieved reconstitution of functional T-cell immunity so that they are no longer at risk for developing 
an EBV lymphoma. As a result, we now have a significant number of HLA-typed, well characterized. 
HLA-restricted EBV-specific T-cell lines, generated under GMP conditions, which could be used for 
adoptive therapy of EBV lymphomas expressing shared HLA alleles, if the specific donors from 
whom they were generated provided second consent for their use in patients other than the specific 
individuals for whom they were transplant donors.  
Based on the studies of Haque et al (52, 53) and our own initial experiences with third party EBV-
specific T-cells, we propose 1) to test the clinical efficacy of such third party-derived EBV-specific T-
cells, when adoptively transferred for the treatment of EBV-associated malignancies, as measured 
by clinical and radiologic responses. 2) To continue growing a bank of cryopreserved HLA-typed 
EBV-specific T-cell lines generated under GMP conditions from the blood of consenting donors as a 
source of third party derived, HLA partially matched EBV-specific T-cells of desired HLA restriction 
for adoptive therapy. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a non-randomized, single institution phase II single dose trial, designed to evaluate the 
therapeutic activity of HLA partially matched, EBV-specific T-cell lines generated in vitro from normal 
EBV-seropositive third party donors when adoptively transferred into patients afflicted with an EBV 
lymphoma, an EBV+ lymphoproliferative disorder or another EBV-associated malignancy. 
Patients eligible for this trial will include: 
1) Recipients of allogenic hematopoietic cell (HSCT) transplants who develop an EBV lymphoma or 
EBV lymphoproliferative disease post transplant or who have rising levels of EBV DNA in the 
circulation following prior treatment of the EBVLPD with chemotherapy and/or Rituxan indicating that 
they are at high risk of developing a recurrent EBV lymphoma for whom EBV-specific T-cells from 
their HCT donor are not available 
2) Recipients of organ allografts who develop a biopsy-proven EBV+ lymphoma or 
lymphoproliferative disorder or recipients of organ allografts previously treated with chemotherapy 
and/or Rituxan who have persistent or recurrent elevations in levels of EBVDNA in peripheral blood 
mononuclear cells exceeding 500 copies/ml and are therefore at high risk for developing relapse of 
an EBVLPD 
3) Any immunocompromised or genetically immunodeficient patient who develops a biopsy proven 
EBV lymphoma or lymphoproliferative disease or  
4) Any patient afflicted with pathologically documented other EBV-associated malignancy (e.g. EBV+ 
Hodgkin’s and Non-Hodgkin’s disease, EBV+ nasopharyngeal carcinoma, EBV+ hemophagocytic 
lymphohistiocytosis or EBV+ leiomyosarcoma). 
The T cells to be used for adoptive therapy will be derived from T cell lines generated under GMP 
conditions from normal consenting EBV seropositive donors of defined HLA type. These T cell lines 
will be generated by repeated in vitro sensitizations with irradiated autologous B cells transformed 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 10 of 41 
with the laboratory strain of EBV B95.8, and expansion in culture for at least 21-28 days. After 
testing to insure EBV-specificity, absence of alloreactivity, absence of endotoxin and microbial 
sterility, these T cells will be cryopreserved and maintained in a designated EBV-specific T-cell bank 
for subsequent use. Selection of an EBV-specific T-cell line from this bank for the treatment of a 
patient consenting to enter this phase II trial will be based on: 1) the presence of HLA alleles on the 
T cell line that are also expressed by the patient (and/or, in the case of HSCT recipients, the 
transplant donor because EBV lymphomas in such patients are usually of donor origin) 2) the 
availability of EBV-specific  T cells in numbers adequate for treatment of the patient at the doses 
required and 3) ascertainment, whenever possible that the EBV-specific T-cell line is restricted by at 
least one HLA shared by the patient (and/or in the case of allogeneic HSCT recipients, the 
transplant donor).  
4.2 
Intervention 
For each course of therapy, the EBV-specific T-cells will be administered at a dose of 2x106 T-
cells/kg recipient weight once weekly (+/- 3 days) for three doses.  Each dose of T-cells will be 
infused intravenously over a period of 5 minutes.  Patients who achieve complete remission over the 
three weeks of treatment may require only one course of the T-cells.  Patients who have not 
experienced incremental grade III-IV toxicity following T-cell infusion who have not achieved a CR 
may receive additional courses of 3 weekly T cell infusions, each followed by 3 week periods of 
observation. 
 
Because of the potential of EBVLPD and EBV-associated malignancies to progress rapidly, patients 
who continue to show progression following the 3 week observation period will be considered for 
alternative therapy (e.g. chemotherapy) or continued treatment with EBV-specific T-cells. In some 
cases, patients with aggressive EBV in the absence of a grade 3-4 SAE related to treatment with 
cells may be treated with an additional cycle of cells as early as one week post completion of T-cell 
therapy.  
 
If the planned dose of EBV peptide sensitized T-cells (2x106 T-cells/kg) is not available, but the cells 
generated exhibit required levels of EBV specific cytotoxic activity and meet all other release criteria, 
patients may be treated at a dose level of 1x10^6 EBV specific T cells/kg. A +/- 20% variability of 
total cell dose is allowed. 
In certain cases, in order to avoid discarding a large fraction of a vial of the final product to achieve a 
specific dose level, which may affect viability, variability of each dose may exceed +/-20%. In such 
cases, care will be given to ensure that the total combined volume of the 3 doses does not exceed 
the planned dose.  
 
If there are insufficient cells and no other viable options, patients may be infused with all available 
cells in two doses or with three doses. If three doses are given each dose should be as close to 1 x 
106 T-cells/Kg as possible.  
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 Donors of EBV-Specific T-cells 
 
The EBV-specific T-cell lines to be used for treatment in this protocol and to be maintained 
cryopreserved under GMP conditions in the Adoptive Immune Cell Therapy Facility at MSKCC, will 
be derived from the 3 groups listed below: 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 11 of 41 
 
1) Normal, HLA-typed, EBV-seropositive donors of allogeneic hematopoietic progenitor cell or 
organ allografts, who previously consented and gave blood or leukocytes to establish EBV-
specific T-cells to be used to treat an EBV lymphoma were it to develop in the patient to 
whom they donated a hematopoietic cell graft or organ. Once that patient has reconstituted 
immune function and is no longer at risk of an EBV lymphoma, the donors will be informed 
of the purposes of this T-cell bank and will be asked for consent, in writing, to the addition of 
their EBV-specific T-cell line generated from their blood to the bank and to the use of these 
T-cells to treat an EBV lymphoma or EBV-associated malignancy in a patient other than the 
patient for whom they were originally intended. This group of previously established EBV-
specific T-cell lines currently constitutes a bank of approximately 300 separate donor-
derived lines.  
2) Normal, HLA typed, EBV-seropositive related and unrelated hematopoietic cell transplant 
donors who, from now on, are requested to consent to provide blood or blood white cells to 
make EBV-specific T-cells for treatment or prevention of an EBV-lymphoma in the recipient 
of their transplant will also be asked whether the EBV-specific T cell line generated can be 
transferred to the bank and used for another patient, at such time as the transplant recipient 
is no longer at risk for this complication.   
3) Normal, HLA typed, EBV-seropositive volunteer blood donors whose T cells would add to 
the HLA diversity of the T cells available in the Immune Cell Therapy Bank.  
Adequate health for donation is determined by institutional (related donor) or NMDP (unrelated 
donor) guidelines. Normal donors are evaluated for evidence of prior sensitization to EBV by EBV 
serology. They are also typed for HLA-A,B, C and DR.  
Clinical studies are obtained within 1 week of blood donation and include CBC with differential and 
platelet count. Results of tests must be within a range that would not preclude donating blood or 
undergoing leukapheresis.  Serologic testing for transmissible diseases will be performed as per 
each department’s guidelines or at the discretion of the treating attending. 
Because of the need to, at least, partially match the donor tissue type with the patient’s tumor, our 
goal is to have many 3rd party EBV CTL lines available. We estimate that a bank containing EBV-
immune T cells from about 300-500 donors of different types would be able to supply partially 
matched T cells for over 90% of patients who have EBV disease.  
Volunteer blood donors in Group 3 will be requested to provide the second of the two blood 
samplings listed below. The first sample may be provided, as well, if clinically feasible. Donors in 
Groups 1 and 2 will have already provided the two donations listed below upon initial consent to the 
T cell infusion protocol (IRB # 05-065, 07-055, 95-024, or 12-086) for the primary recipients of their 
allogeneic hematopoietic progenitor cell or organ allografts.  
i) 
An initial donation of 25 ml of heparinized blood-this blood is used to establish a B 
cell line transformed with the B95.8 laboratory strain of EBV, which is required for 
subsequent in vitro sensitization of the donor’s T-cells against EBV. The 
establishment and testing of an EBV transformed autologous B cell line suitable for T-
cell stimulation requires 4-5 weeks of in vitro culture.  
ii) 
A donation of a single standard 2 blood volume leukapheresis collected in standard 
ACD anticoagulant. If it is impossible to collect a leukapheresis from some of the 
donors, a unit of whole blood will be acceptable. However, the AICTF (Adoptive 
Immune Cell Therapy Facility manufacturing the clinical grade cell products under 
GMP conditions at MSKCC) may only be able to generate a limited number of T cells 
from a unit of blood. This blood is required for isolation of the T-cells to be sensitized 
with the donor’s EBV B cell line and propagated in vitro. In addition, it is required to 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 12 of 41 
provide autologous feeder cells essential to sustain T- cell growth without the risk of 
stimulating the growth of alloreactive T-cells capable of inducing GVHD. 
In addition to providing written consent to these donations of blood for the purpose of generating 
EBV- specific T-cells for potential use in the treatment of an EBV lymphoma, volunteer donors in 
Groups 2 and 3 will be informed of the following potential applications of the blood cells donated:  
The use of a fraction of the cells isolated to generate:  
a) immune T-cells specific for another virus, called cytomegalovirus, that can cause lethal 
infections in transplant recipients  
Such T-cells could be used, under separate protocols to treat CMV infection (IRB # 12-086).  
Inclusion of the use of blood cells for the purpose of also generating T cells against CMV can 
obviate the need for an additional leukapheresis or unit of blood for this purpose. T-cells will be 
stored and maintained cryopreserved under GMP conditions in the Adoptive Immune Cell Therapy 
Facility at MSKCC, to be used for the treatment of patients in whom these cells may be therapeutic.  
 
 
5.2 Generation of EBV-Specific T-Cells From the Blood of Selected Donors 
For the generation of EBV-specific T-cells, 25 ml of heparinized blood is initially drawn and used to 
prepare an EBV transformed B-cell line. To prepare these lines, Ficoll-Hypaque separated 
mononuclear cells are washed and exposed to filtered bacterial, fungal and mycoplasma-free 
supernatants of the EBV secreting B95-8 marmoset cell line. The B95-8 cell line used is negative for 
retroviruses and other animal viruses. After exposure, the cell lines are propagated in RPM1-1640 
with glutamine and 10% pooled, screened fetal calf serum. After transformation of the B cells by 
EBV, the EBV transformed cell line is expanded in the same medium together with acyclovir to 
prevent generation of infectious EBV. Theses cell lines can then be used as a stimulus for the 
generation of T-cells from the same donor. Prior to use as stimulators, the EBV transformed cells 
are also irradiated to 9,000 rad to eradicate the capacity of these lines to grow within the co-cultures 
used to propagate EBV-specific T-cells. A calibrated, certified blood irradiator will be used for 
irradiation of these targets. 
EBV-specific T-cell lines will be generated from cultures of purified peripheral blood T-lymphocytes 
sensitized with the EBV transformed B-cells. Effector T cells can be generated from 50 cc of blood 
from an EBV-seropositive donor. However, in order to have adequate numbers of irradiated 
autologous mononuclear cells as feeder cells during the propagation of the EBV-specific T cells, a 
standard 2.0 blood volume leukapheresis or a unit of blood obtained from the donor is required. 
Peripheral blood mononuclear cells will be separated from the leukapheresed cells by density 
gradient centrifugation on Ficoll-Hypaque. An aliquot of these cells will be depleted of monocytes by 
incubation on plastic surfaces to remove adherent cells (or by immunoadsorption with CD14 
microbeads if frozen/thawed sample is used, so as to prevent clumping and loss of the cells during 
the depletion procedure). T-cells will then be enriched and purified by removal of NK cells and B-
cells with magnetic beads coupled with CD56 and CD19 clinical grade microbeads. Purified 
peripheral blood T-lymphocytes (1x106 cells/ml) will then be stimulated with 5x104 irradiated (9,000r) 
autologous EBV transformed B-cells. The T-cell: EBV+ BLCL ratio is therefore 20:1, a condition 
which favors development of EBV-reactive T-cells. These cells are propagated without added 
cytokine for 10 days, and thereafter, expanded by growth in medium supplemented with clinical 
grade recombinant IL-2 (concentration 10 units/ml) and IL-15 (concentration 10ng/ml). Feedings with 
medium and IL-2 are administered at 3 day intervals. IL15 is added weekly. 
The activity of the anti-EBV specific T-cells will be assayed at ~28-42 days of culture as soon as the 
number of cells sufficient for the treatment dose is obtained. Included in these assays will be 
analyses of the cytolytic activity of the T-cells against the autologous BLCL and against autologous 
donor and allogeneic host derived PHA blasts. After in vitro propagation for 28-42 days, populations 
of T cells exhibiting cytolytic activity against autologous EBV B cell lines and appropriate specificity 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 13 of 41 
will be selected for use as effectors for adoptive immunotherapy. The criteria for selection of effector 
cell populations appropriate for adoptive immunotherapy will include: 
1) 
The EBV-specific T cell populations must be culture negative for bacteria, fungi, mycoplasma 
and must be tested and shown to contain ≤ 5 EU/ml cell dose of endotoxin. 
2) 
The EBV-specific T cell populations must exhibit high levels of specific lysis of EBV-
transformed autologous B cell lines (>25% specific lysis at effector target ratios of 25:1), but not 
against autologous PHA blasts (<10%) in standard 51Cr release assays.  
3) 
The EBV-specific T cells must not exhibit significant cytotoxicity against the patient's PHA 
blasts or against HLA-mismatched EBV transformed B cell lines in standard 51Cr release assays. 
5.3  
Cryopreservation and Storage 
Prior to use, these EBV- specific T-cells may be cryopreserved at a concentration of up to 30 x 106 
cells/ml in 10% DMSO, 16% human serum albumin and normal saline for intravenous infusion in 
cryovials labeled with the unique identifier number and unique bar code of the donor, name of the 
initially intended transplant recipient, MSKCC MRN of the recipient, component AICT#, component 
name, date the component was started, date the component was frozen and the number of cells 
frozen per container.   Cryovials will be stored in the vapor phase of a monitored liquid nitrogen 
freezer designated for this purpose in the AICT cell manufacture facility at MSKCC.  
5.4 
 A Central Bank of Cryopreserved EBV- Specific T-cells for Adoptive Cell 
Therapy 
The MSKCC Bank of Cryopreserved Immune T-cells for Adoptive cell Therapy will be maintained in 
monitored liquid nitrogen freezers designated for this purpose in the AICT Cell Manufacture Facility 
at MSKCC. Each T-cell line accrued to this Bank will be logged in a computerized registry recording 
the donor providing the T-cells, the donor’s eligibility, the donors written consent, the donor’s unique 
AICT number and the Q/A testing specifications described above under Generation of EBV- specific 
T-cells. Each sample will be labelled as described above under Cryopreservation and Storage. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
 
6.1.1 Subject Inclusion Criteria 
 
Pathologically documented EBV antigen positive lymphoproliferative disease, lymphoma or 
other EBV-associated malignancy.  
OR 
 
Evaluable disease as demonstrated by clinical and/or radiologic studies with current or prior 
elevated blood levels of EBVDNA exceeding 500 copies/ml by quantitative real time pcr. 
 OR 
 
Persistent or recurrent elevations in levels of EBVDNA exceeding 500 copies/ml in patients 
previously treated for EBVLPD with chemotherapy and/or Rituxan who do not yet have 
clinically or radiologically evaluable disease but are at high risk of disease recurrence.  
 
EBV-specific T-cells from donor of the patient’s transplant are not available.  
 
EBV-specific T-cells are available for adoptive immune cell therapy from a consenting third 
party donor. The third party EBV CTLs to be administered will be selected on the basis of 
two criteria: 1) that they are matched for at least 2 HLA antigens and 2) that they are 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 14 of 41 
restricted by an allele shared with the EBV+ malignancy (if known), or with the donor in 
HSCT recipients, or patient in organ transplant or immunodeficient patients.  
 
KPS or Lansky score ≥ 20. 
 
A life expectancy of at least 6 weeks. 
 
Adequate bone marrow, heart, lung, liver and kidney function at the time treatment with 
EBV-specific T-cells is initiated, including: 
a) Absolute neutrophil count (ANC) ≥ 1K/mcL, with or without GCSF support 
b) Platelets ≥ 20K/mcL 
c) Creatinine ≤ 2.0mg/dl 
d) ALT, AST < 3.0x and total bilirubin < 2.5x the institutional ULN 
e) Stable blood pressure and circulation not requiring pressor support  
f) Adequate cardiac function as demonstrated by EKG and/or echocardiographic 
evidence (may be performed within 30 days prior to treatment)  
However, abnormalities of specific organs will not be considered grounds for exclusion if they 
are the result of the EBV+ malignancy or its treatment (e.g. a renal allograft recipient with an 
EBVLPD may be on dialysis because the allograft was rejected when the immune 
suppression was stopped as a first approach to treatment of the EBVLPD). At the discretion 
of the investigator, patients with elevated but stable creatinine will not be precluded from 
treatment on study.   
 
There is no age restriction to eligibility for this protocol.  
It is expected that five types of patients afflicted with EBV-associated lymphomas, 
lymphoproliferative diseases or malignancies will be referred and will consent to participate in this 
trial. These are: 
1) 
Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic 
hematopoietic progenitor stem cell transplant (HSCT) (ie: marrow, PBSC, or umbilical cord blood). In 
these cases, the HSCT donor, if EBV-seropositive, will be used as the donor of EBV-specific T-cells 
for adoptive immunotherapy wherever possible, because the EBV-LPD are almost invariably derived 
from that marrow donor. These patients will be enrolled onto protocol # IRB 95-024.  However, if the 
HSCT donor is EBV seronegative or not readily available (e.g. a cord blood transplant), the patient 
will be a candidate to receive EBV- specific T-cells generated from a third party seropositive donor 
that have been generated and stored in the MSKCC bank of cryopreserved immune T-cells for 
adoptive cell therapy. For these patients, the third party donor derived T cells to be used will be 
selected primarily on the basis of 1) matching for, at least, 2 HLA antigens and 2) one restricted 
allele shared by the transplant donor and recipient. However, priority is given to T cells partially HLA 
antigen matched with, and restricted by, HLA alleles of the transplant donor, since EBV + 
lymphomas in HSCT recipients are usually (but not always) derived from the transplant donors’ cells.  
 
2) 
Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic 
organ transplant. In these cases, the lymphoma is usually of recipient origin. EBV-specific T-cells will 
be selected from the MSKCC Bank expanded from an EBV-seropositive normal donor who is at 
least matched for 1) 2 HLA antigens and 2) one restricted allele with the EBV lymphoma. If the origin 
of the lymphoma is unknown, T-cells partially matched with the transplant recipient will be used, 
since these lymphomas are usually of host origin. Using this approach to donor selection, it is 
expected that the EBV-specific, HLA restricted cytotoxic T-cells expanded from the HLA partially-
matched donor would be able to recognize and kill lymphoma cells presenting EBV antigens in the 
context of an appropriate HLA restricting element. Priority will be given to the use of partially 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 15 of 41 
matched EBV specific T cells known to be restricted by an HLA allele shared by the lymphoma (or, if 
unknown, the patient).  
 
3) 
Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a 
consequence of the profound acquired immunodeficiency induced by HIV. For such patients, EBV 
specific T-cells from third party seropositive donors who are HLA compatible in 1) at least 2 HLA 
antigens and 2) one restricted allele shared by the patient will be used. Selection of T cells known to 
be restricted by an HLA allele shared by the patient will be given priority.  
 
4) 
Patients who develop EBV lymphomas or lymphoproliferative diseases or other EBV-
associated malignancy as a consequence of profound immunodeficiencies associated with a 
congenital immune deficit or acquired as a sequela of anti-neoplastic or immunosuppressive 
therapy. For these patients, normal, EBV specific T-cells from third party seropositive donors who 
are HLA compatible in 1) at least 2 HLA antigens and 2) one restricted allele shared by the patient 
will be used. Again, selection of T cells known to be restricted by an HLA allele shared by the patient 
will be given priority. 
 
5) 
Patients who develop other EBV-associated malignancies without pre-existing immune 
deficiency, including: EBV+ Hodgkin’s and Non-Hodgkin’s disease, EBV+ nasopharyngeal 
carcinoma, EBV+ hemophagocytic lymphohistiocytosis, or EBV+ leiomyosarcoma. Normal, EBV 
specific T-cells from third party seropositive donors who are HLA compatible in 1) at least 2 HLA 
antigens and 2) one restricted allele shared by the patient will be used. Again, selection of T cells 
known to be restricted by an HLA allele shared by the patient will be given priority. 
6.1.2 Donor Eligibility 
Donors in Groups 1 and 2 (Section 5.1) would have already been determined to be eligible and will 
have donated blood or leukocytes to establish EBV-specific T-cells under IRB # 05-065, 07-055, 95-
024, or 12-086. There are no additional eligibility requirements for these donors. 
Donors in Group 3 (section 5.1), however, will need to meet the following eligibility requirements 
prior to donation: 
a) Donors must satisfy the criteria specified in FDA 21 CFR 1271. 
b) Donors must be typed for HLA-A, B, C and DR 
c) Donors must have a hemoglobin value > 10g/dl 
d) Donors must be capable of undergoing, at least, a single standard 2 blood volume 
leukapheresis or a donation of one unit of whole blood 
6.2 
Subject Exclusion Criteria 
6.2.1 Patient Exclusion Criteria 
The following patients will be excluded from this study: 
a) 
Patients with active (grade 2-4) acute graft vs. host disease (GVHD), chronic GVHD or an 
overt autoimmune disease (e.g. hemolytic anemia) requiring high doses of 
glucocorticosteroid (>0.5 mg/kg/day prednisone or its equivalent) as treatment 
 
b) 
Patients who are pregnant  
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 16 of 41 
c) 
Patients with severe comorbidities, not related to their EBV-associated malignancy, that 
would be expected to preclude their survival for the 6 weeks required to assess response 
of T cell therapy 
 
d) 
Patients eligible for MSK protocol # 16-803 (EBV-CTL-201).  
 
6.2.1 Donor Exclusion Criteria 
a) HTLV/HIV(+) or Hepatitis B or C antigen(+) donors 
b) Donors who are known EBV seronegative 
 
7.0 RECRUITMENT PLAN 
 
7.1 Patient Recruitment 
 
Patients with EBV lymphoproliferative diseases, lymphomas or other EBV-associated malignancies 
will be referred from (but not limited to) the Allogeneic Marrow Transplant program at MSKCC, the 
marrow and organ transplant programs at other centers in New York, New Jersey and Connecticut 
and from transplant centers participating in the national BMT Clinical Trials Network. We are also 
establishing collaborations with the organ transplant programs at Weill-Cornell Medical Center, 
Columbia Presbyterian Hospital and Mount Sinai Hospital to refer patients that develop a PTLD to 
our center as potential candidates for this trial.  
 
 
7.2 Donor Recruitment 
Volunteer donors will be recruited from the Allogeneic Marrow Transplant program at MSKCC. 
Other donors would have already been enrolled onto a previous MSKCC/NMDP IRB approved study 
(ie: MSKCC IRB # 95-024, 05-065, 07-055, and 12-086) and have already provided blood donations 
under those protocols. These donors will be asked to provide separate consent for transfer of their 
cells to the third party bank for potential use in patients enrolled onto this protocol. Because these 
donors were only under the care of MSKCC for the period in which they donated cells for their 
primary recipients and have since returned home, they will be mailed a copy of the consent form to 
review during the consent discussion, which will occur over the phone. If they agree to 3rd party use 
of their cells, the consent will be signed and sent back via MSKCC provided pre-paid/addressed 
envelope. 
 
8.0 
PRETREATMENT EVALUATION 
8.1 Patient Pretreatment Evaluation 
The following evaluations will be performed within approximately 30 business days prior to 
treatment on study, with the exception of EBV DNA and blood samples, which will be drawn 
within approximately 3 business days prior to beginning treatment. Certain tests may be held 
at the discretion of the treating physician: 
 
EBV DNA will be quantitated in peripheral blood mononuclear cells, using a quantitative pcr-
amplified assay incorporating appropriate controls to define EBV DNA copy number/ml of 
blood.   
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 17 of 41 
 
Radiographic analyses, if clinically indicated, including PET/CT scans and/or MRI scans to 
define extent of disease will be obtained and any lesions quantitated as to size by three-
dimensional measurements.   
 
Biopsy of affected or suspicious tissue will be obtained when clinically feasible. For 
immunocompromised patients with significant levels of circulating EBV DNA, who are at high 
risk of an EBV lymphoma, no suspicious lesions may be detected or appropriate for biopsy.  
However, patients who have clinically overt EBV LPD, or other EBV associated malignancy, 
will usually have tumor or lymph nodes assessable for such biopsies. The purpose of these 
biopsies is to obtain viable tumor cells. These cells will be analyzed to determine the genetic 
origin of the EBV-LPD in transplant recipients (donor or host) by ascertainment of HLA type 
or definition of donor or host unique autosomal or sex chromatin polymorphisms by pcr-
amplified RFLP analyses. They will also be evaluated for the clonality of the lymphoma as 
defined by evaluation of immunoglobulin VDJ rearrangements and the structure of EBV 
episomal DNA genomic termini.  For patients with other EBV associated malignancies, the 
tumor cells can be analyzed for their expansion of EBV antigens and for EBV type by DNA 
sequence. Pathologically confirmed lymphomas will be characterized by histopathologic and 
immunohistochemical analysis for immunophenotype and expression of EBV-associated 
RNAs (EBERs) and proteins such as EBNA-1, EBNA-2 and/or LMP-1. Whenever possible, 
an aliquot of cells will be cryopreserved.   
 
Pregnancy Test for women of childbearing age 
Patients will also have blood samples drawn to evaluate: 
 
General immune function. These studies will include quantitation of T- and B-cells and their 
subsets by immunophenotypic analysis and quantitation of the capacity of T-cells to respond 
to mitogens, antigens, and allogeneic cells. 
 
EBV-specific immunity. Peripheral blood mononuclear cells isolated from the patients will be 
evaluated for their capacity to proliferate and to generate cytotoxic T-cells specifically 
reactive against autologous EBV-transformed B-cells. In addition, limiting dilution analyses 
will be performed to ascertain the frequency of CTL precursors in the peripheral blood T-cell 
population which exhibit specific reactivity against EBV as well as the frequency of T-cells 
exhibiting a capacity to react against a third party allogeneic stimulus. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Each patient consenting to participate in this Phase II trial will be treated with in vitro expanded EBV-
specific T-cells. Patients will be initially stratified into two groups.  
Group 1 will consist of: 
A. Allogeneic marrow graft recipients who are severely immunocompromised and may have 
more prolonged or sustained T cell engraftment and, therefore, could be at risk for GvHD 
B. Patients with severe congenital or antineoplastic drug induced immunodeficiency who 
could be durably engrafted and are therefore at risk for GvHD 
Group 2 will consist of: 
A. Organ allograft recipients. Although immunocompromised, these patients can reject third 
party blood cells. Thus, the risk of sustained engraftment or GvHD is low 
B. AIDS patients who will almost invariably reject the infused T-cells and are therefore at 
very low risk of GvHD 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 18 of 41 
C. Patients who develop other EBV-associated malignancies without pre-existing immune 
deficiency who are also expected to reject the infused T cells and are at low or no risk of 
GvHD 
9.1 
Treatment for Patients in Group 1 
Patients in Group 1 will each receive a course of three weekly infusions of EBV-specific T-cells. 
Each weekly dose will provide 2 x106 T-cells/Kg recipient weight (+/- 3 days) from the donor’s EBV-
specific T-cell line. After the third dose, patients will be observed for approximately 3 weeks. If only 
grade 0-2 toxicity related to the infusion has been observed and GVHD has not developed or 
exacerbated, patients in CR, PR, or SD may be treated with a second course of 3 weekly infusions 
of EBV-specific T-cells. After the second 3 week course of cell infusions, responses will be graded if 
there is a change in response. If at that time, only 0-2 toxicity related to the infusion has been 
observed and GVHD has not developed or exacerbated, and no further progression of the EBV LPD 
or malignancy has been detected, these patients may be treated with additional infusions of EBV-
specific T-cells at the same dose level. If, on the other hand, the patient has already achieved a CR 
of the EBV LPD or malignancy, the secondary infusions may be either administered or electively 
held or postponed. If at any time in the course of these infusions a grade 3-4 toxicity related to the 
infusion has been observed, no further doses of cells will be administered. 
Because of the potential of EBV LPD and EBV-associated malignancies to progress rapidly, patients 
who continue to show progression following the 3 week observation period will be considered for 
alternative therapy (e.g. chemotherapy) or treatment with additional EBV-specific T cells. Patients 
may receive treatment from a different third party donor that is specific for EBV but restricted by a 
different HLA allele shared by the EBVLPD.  
The rationale for using such EBV-CTL from a second HLA partially matched third party donor is 
based on our prior experience (72, 73) and that of Gottschalk et al (74) indicating that failures of 
adoptive therapy in the treatment of EBVLPD are usually due to failure of T-cells generated against 
EBV strain B95.8 to recognize the tumor cells transferred with the endogenous EBV in the patient. 
This failure is often caused by EBV virus mutations that result in deletions or alterations in the amino 
acid sequence of immunodominant peptide epitopes of an immunogenic latent protein like EBNA 3C 
targeted by the T-cells. Because T-cells restricted by a different HLA can be expected to be specific 
for a different, and potentially non-mutated epitope, adoptive transfer of such T-cells from a separate 
donor could provide an alternative and potentially effective approach to the treatment of EBVLPD 
transfused by a mutated EBV strain of this type.  
In some cases, patients with aggressive EBV, in the absence of a grade 3-4 SAE related to 
treatment with cells, may be treated with an additional cycle of cells as early as one week post 
completion of T-cell therapy. 
 
If the initial planned doses of EBV peptide sensitized T-cells (2 x106 T-cells/Kg) are not achieved or 
available, but the cells generated exhibit required levels of EBV specific cytotoxic activity and meet 
all other release criteria, patients may be treated at a dose level of 1 x106 T-cells/Kg recipient 
weight. A +/- 20% variability of total cell dose is allowed. 
 
In certain cases, in order to avoid discarding a large fraction of a vial of the final product to achieve a 
specific dose level, which may affect viability, variability of each dose may exceed +/-20%. In such 
cases, care will be given to ensure that the total combined volume of the 3 doses does not exceed 
the planned dose.  
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 19 of 41 
 
If there are insufficient cells and no other viable options, patients may be infused with all available 
cells in two doses or with three doses. If three doses are given each dose should be as close to 1 x 
106 T-cells/Kg as possible.  
 
 
 
9.2 
Treatment for Patients in Group 2 
 
Patients in Group 2 will also receive 3 weekly intravenous infusions of 2 x 106 EBV-specific T-
cells/kg recipient weight (+/- 3 days). After the third dose, patients will be observed for at least 3 
weeks. If only grade 0-2 toxicity related to the infusion has been observed and GVHD has not 
developed or exacerbated, patients in CR, PR, or SD may be treated with a second course of 3 
weekly infusions of EBV-specific T-cells. After the second 3 week course of cell infusions, responses 
will be graded if there is a change in response. If at that time, only 0-2 toxicity related to the infusion 
has been observed and no further progression of the EBV LPD or malignancy has been detected, 
these patients may be treated with additional infusions of EBV-specific T-cells at the same dose 
level OR at a dose of 1 x 107 T-cells/kg/dose. If, on the other hand, the patient has already achieved 
a PR or CR of the EBV LPD or malignancy, the secondary infusions may be either administered or 
electively held or postponed. If at any time in the course of these infusions a grade 3-4 toxicity 
related to the infusion has been observed, no further doses of cells will be administered. 
This five-fold increment in dose planned for the secondary courses, to be administered to patients in 
Group 2 is based on these considerations: 1) the expected low incidence of toxicity and 
complications of the T-cell infusions; 2) the expectations that patients in Group 2, once sensitized, 
will eliminate secondary doses of T-cells too rapidly to permit them to have an effect if the initial 
dose is again used. This reactivity against donor cells will also likely limit their effectiveness beyond 
two courses of therapy. 
Because of the potential of EBV LPD and EBV-associated malignancies to progress rapidly, patients 
who continue to show progression following the 3 week observation period may be considered for 
alternative therapy (e.g. chemotherapy) or treatment with additional EBV-specific T cells. Patients 
may receive treatment from a different third party donor that is specific for EBV but restricted by a 
different HLA allele shared by the EBVLPD. In some cases, patients with aggressive EBV in the 
absence of a grade 3-4 SAE related to treatment with cells may be treated with an additional cycle of 
cells as early as one week post completion of T-cell therapy. 
If the planned dose of EBV peptide sensitized T-cells (2 x106 T-cells/Kg and/or of 1 x 107 cells/kg) is 
not achieved, but the cells generated exhibit required levels of EBV specific cytotoxic activity and 
meet all other release criteria, patients may be treated at a dose level of 1 x106 T-cells/Kg recipient 
weight. A +/- 20% variability of total cell dose is allowed. 
 
In certain cases, in order to avoid discarding a large fraction of a vial of the final product to achieve a 
specific dose level, which may affect viability, variability of each dose may exceed +/-20%. In such 
cases, care will be given to ensure that the total combined volume of the 3 doses does not exceed 
the planned dose.  
 
If there are insufficient cells and no other viable options, patients may be infused with all available 
cells in two doses or with three doses. If three doses are given each dose should be as close to 1 x 
106 T-cells/Kg as possible.  
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 20 of 41 
Initial published studies and our own experience using third party, HLA partially matched virus-
specific T-cells, generated in vitro, for adoptive immunotherapy or prophylaxis against CMV or EBV 
suggest that the toxicity associated with the T-cell infusions will be minimal (29, 46, 52, 53). Because 
of the in vitro selection for T-cells reactive against EBV, the frequency of alloreactive T-cells capable 
of inducing GvHD or, in organ allograft recipients, an organ rejection episode should also be 
extremely low. Nevertheless, the risks of fostering GvHD in marrow allograft recipients must be 
considered substantive, since these patients will already have been engrafted with an allogeneic 
donor-derived marrow and lymphoid progenitors. On the other hand, AIDS patients, organ graft 
recipients, and otherwise normal patients with other EBV associated malignancies, even in the 
extremes of virus or drug induced immunosuppression, retain the capacity to reject foreign 
hematopoietic cells and do not develop GvHD even when repeatedly transfused with unirradiated 
blood (39). Thus, these patients who constitute group 2would be expected to be at low risk for GvHD 
even if substantial numbers of alloreactive T-cells were to be transfused in the EBV-specific T-cell 
inoculum. 
9.3. 
Use of Other Medications and Treatments During the Trial of EBV-Specific T-
Cell Infusions 
1) 
Graft Versus Host Disease Prophylaxis and Treatment 
Following the infusions of third party donor-derived EBV-specific T-cells, no additional drug 
prophylaxis will be given to prevent GvHD. In patients who do develop GvHD, standard clinical and 
pathological criteria will be used to establish the diagnosis. GvHD will be graded according to BMT-
CTN and IBMTR systems clinical criteria as defined by Rowlings, et al (66). A patient who develops 
significant (grade II or greater) GvHD following infusion of third party donor-derived EBV specific T 
cells will be considered for treatment with high-dose methylprednisolone. Refractory grade II or 
progressive grade III or IV GvHD will be treated according to separate protocols. 
2) 
Concurrent Medications 
a) 
Any non-cytotoxic, non-chemotherapeutic medications needed in the management of the 
patient or the prevention and treatment of bacterial, fungal or parasitic infection are allowed. Since 
Rituxan is being used to treat EBV+ B cell lymphomas, and most patients referred for treatment with 
EBV CTLs are those whose disease continues to progress despite Rituxan, ongoing treatment with 
Rituxan will also be permitted.  
b) 
Marrow transplant recipients receiving, steroids, or antimetabolite drugs as 
immunosuppressive agents for prophylaxis against GvHD should, whenever possible, have these 
agents discontinued at least one week prior to initiation of treatment with EBV-specific T-cells. 
Patients requiring these agents as treatment for acute or chronic GvHD or as essential prophylaxis 
against organ graft rejection may continue maintenance therapy with cyclosporine, tacrolimus or 
sirolimus since data from our own and other centers suggest that these agents do not preclude the 
viability or antigen-specific cytotoxic function of pre-sensitized and expanded memory T-cells. 
However, treatment with systemic steroids, anti-thymocyte globulin, and/or Imuran should be 
discontinued whenever possible prior to initiation of T-cell infusions since theses agents will 
eliminate the infused T cells or severely compromise their capacity to grow in the treated patient. It is 
recognized, however, that clinical circumstances may mandate maintenance of treatment with 
steroids (e.g., GVH treatment in patients who, by virtue of kidney or liver toxicity, cannot tolerate 
cyclosporine, or patients to be treated for EBV lymphomas of the brain who may require steroids to 
reduce neurologic symptoms induced by edema surrounding the tumor). In such cases, doses will 
be maintained at as low a level as considered clinically safe and appropriate prior to initiation of 
infusions of EBV specific T cells. 
c) 
Organ transplant recipients receiving immunosuppressive agents to prevent organ allograft 
rejection may continue maintenance therapy with cyclosporine, tacrolimus or sirolimus. Of these, 
sirolimus is preferred since this MTOR inhibitor may, itself, inhibit growth of EBV transferred cells 
(71). If possible, treatment with systemic steroids should be discontinued prior to initiation of T-cell 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 21 of 41 
infusions. Anti-thymocyte globulin and/or Imuran should not be given. Since polyclonal EBV-
lymphoproliferative diseases may regress following cessation of immunosuppression, cessation of 
agents other than cyclosporine, tacrolimus or sirolimus should ideally be completed two weeks prior 
to initiation of infusions of EBV-specific T-cells to permit assessment of the effect of altered 
immunosuppression on the progress of the EBV lymphomas to be treated. As for marrow graft 
recipients, clinical circumstances may preclude cessation of steroids. In such cases, doses should 
be reduced to as low a dose as is safe and appropriate during the T cell infusions and for 3 weeks 
after each course. 
d) 
AIDS patients developing EBV lymphomas while being treated with AZT and other antiviral 
agents may continue to receive these agents at the same dose. 
e) 
All patients developing EBV lymphomas while receiving antiviral agents such as acyclovir or 
ganciclovir for prophylaxis or treatment of herpes simplex, zoster or CMV infections may be 
maintained on these agents at the same dose during treatment with EBV-specific T-cells. 
f) 
Blood support All blood products for transfusion, except the infusions of EBV-specific T-cells 
will be irradiated to inactivate lymphocytes capable of initiating lethal GvHD. Blood products are 
irradiated in the Blood Bank, using a cesium gamma emitter. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
The timing of evaluations below is approximate. The schedule of tests described should be 
adhered to whenever possible. However, in certain situations, particularly late after 
treatment, circumstances may preclude assessments at the times specified, at which point 
they may be held the discretion of the treating physician: 
 
 
Patients will be evaluated clinically by vital signs pre, post, and at 1 and 2 hours following 
initiation of each infusion of EBV-specific T-cells 
 
 
Patients will receive interim history, review of systems, and physical exam prior to starting a 
cycle of EBV-specific T-cells. Assessments will then be performed weekly, as clinically 
indicated, for the first 8 weeks post-initial infusion with EBV-specific T-cells, then monthly 
until 1 year post initial infusion 
 
 
Patients will also be assessed for the effects of the adoptively transferred EBV-specific T-
cells on circulating levels of EBV DNA.  For these studies, EDTA blood (10cc) will be drawn 
on day 1, then weekly for the first 8 weeks post initial infusion, and monthly until 1 year post 
initial infusion 
 
In order to assess the effects of infusions of EBV-specific T-cells on the level of circulating 
virus-specific cytotoxic T-cells in the circulation, limiting dilution analyses quantitating EBV-
specific CTLp will be performed using 10-20 cc blood samples drawn from the patient on 
days 1, 7, and 14 post initial infusion of EBV CTLs (ie: prior to the 2nd and 3rd T cell doses). 
EBV-specific CTLp will also be assessed on day 15, at weekly intervals for 6 weeks post-
initial infusion, and at 3, 6, 9, and 12 months post-initial infusion  
 
Research samples may be collected at approximately day 0, day 7, and day 14 testing for 
cytokines. Additional samples will be collected if there are clinical indications to monitor for 
cytokines. 
 
CBC and Flow Cytometry 7 panel will be obtained on the same days EBV CTLp are drawn 
 
 
Evaluations of T-cell proliferative responses to mitogens and non-EBV microbial antigens will 
be drawn at 5 weeks post initial infusion of EBV CTLs 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 22 of 41 
 
PET/CT and/or MRI scans will be performed on patients with radiologically identifiable 
disease prior to T cell therapy at 5 weeks post initiation of each 3 week course of cells and at 
6 and 12 months post initial infusion. Scans may be performed earlier if clinically indicated. 
 
 
In our experience, patients with Nasopharyngeal Carcinomas do not typically show response 
to treatment after one cycle. These patients may forgo scans at Week 5 and will have scans 
performed approximately 2 weeks post completion of a second cycle of cells. Evaluation for 
these patients will occur after a second cycle of cells, unless clinically indicated. 
 
 
Whenever possible and if clinically indicated, lymph nodes or parenchymal sites of 
lymphoma will be biopsied 2-3 weeks after the first and/or second 3 week course of EBV-
specific T-cells to assess the effects of the infusions on the tissues involved. Biopsied tissues 
will be examined for histopathologic evidence of EBV+ tumor cells. Immunohistochemical 
analyses will also be performed to characterize cells infiltrating the biopsied tissues. If 
sufficient biopsy tissue is available, single cell suspensions will be derived from portions of 
involved tissue and characterized as to immunophenotype, expression of EBV antigens, 
origin (donor or host) and clonality. Origin will be determined by analysis of separated B- and 
T lymphocytes for donor or host unique X, Y and/or autosomal polymorphisms by FISH 
and/or pcr amplified RFLP analyses. Cells will also be analyzed for residual populations of 
EBV+ tumor cells bearing the distinctive VDJ rearrangement of the Ig gene and the 
distinctive homogenous genomic terminus of EBV episomal DNA characteristic of the original 
tumor.  
 
 
Blood samples not to exceed 20 ml/sample and marrow samples not to exceed 10 ml/sample 
will also be drawn at approximately 6 month intervals for 1 year and thereafter as part of 
clinically indicated evaluation to assess the presence of minimal residual disease, using pcr 
amplified techniques for detection of EBV DNA and, when possible, lymphoma-associated 
VDJ rearrangements. 
 
 
Evaluations 
 
Pre 
Infusion 
 
Day 
0 
Day 
1 
Day 
7 
Day 
14 
Day 
15 
W k 
3 
W k 
4 
W k 
5*** 
W k 
6 
W k 
7 
W k 
8 
Mo 
3 
Mo 
4 
Mo 
5 
Mo 
6 
Mo 
7 
Mo 
8 
Mo 
9 
Mo 
10 
Mo 
11 
Mo 
12 
Clinical Evaluation  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GvHD evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
EBV specific CTLp 
(10-20cc blood)** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Cytokine Analysis  
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
EBV PCR (10 ccs)  
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T cell 
Immunophenotype 
short  panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Mitogens/Antigens 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/PET or MRI 
(if indicated)  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Lymph Node 
Biopsy (if possible)  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 23 of 41 
APPROXIMATE SCHEDULE OF EXAMINATIONS AND STUDIES* 
 
*Tests/examination w ill be performed as clinically necessary. If patient is without T-cell count, T-cell proliferation and research tests will be 
held 
** RESEARCH NON-BILLABLE (Sodium Heparin Tubes to Dr. O’Reilly’s lab: Z1645) 
***Patients w ill go on to receive tests/examinations post-week 5 once it is determined that they will not be infused w ith additional EBV CTLs 
****If patient is given additional cycles of EBV specific T-cells, calendar will restart from Day 0. Doses are given weekly (+/- 3 days) and can 
be held at the discretion of the attending in the case of toxicity  
 
11.0 TOXICITIES/SIDE EFFECTS 
11.1 Patient Toxicities/Side Effects 
On this study, we will be capturing and tracking Grade 3-5 toxicities which occur within 30 days 
following an infusion of EBV infusion CTLs and are possibly, probably, or related to treatment on 
study. We will also be capturing and tracking graft vs host disease occurring at any time point post-
infusion. Patients who might subsequently receive donor lymphocytes, boosts, or a secondary 
transplant will be evaluable up until that time point. Toxicities which are attributable to underlying 
malignancy and/or were present prior to initiation of therapy will not be tracked. Please see section 
17.2 for Serious Adverse Event reporting.  
Each of the following Toxicities and Side Effects is expected to be unlikely: 
1) 
Acute Toxicities: The EBV-specific T-cells to be used for adoptive immunotherapy are 
activated T-cells potentially capable of generating significant quantities of cytokine such as IL-2, IFN-
γ and TNF. These cytokines may acutely induce fever and could potentially cause 
hypotension and other manifestations of shock, including toxicity to the lung. However, 
experience with infusions of CMV-specific T-cells (55), in vitro expanded tumor infiltrating T-cells 
(54) and existing limited studies of adoptively transferred EBV-reactive T-cells, either as purified 
fractions or in donor leukocytes (34,46, 57, 58) suggest that these infusions will be well tolerated, 
with a low risk of systemic toxicity.  
2) 
Marrow or Organ Allograft Rejection: Patients receiving third party donor-derived EBV-
specific T-cell infusions for treatment of monoclonal EBV-lymphomas complicating the 
immunoablation used to prepare patients for an allogeneic hematopoietic transplant or the 
immunosuppression used to sustain an organ allograft may be at risk of an acute rejection episode 
following infusion of the T-cells. Such episodes could be precipitated if significant numbers of 
alloreactive T-cells are present in the T-cell inoculum. In allogeneic hematopoietic cell transplant 
recipients, this could lead to loss of the hematopoietic cell transplant, resulting in marrow aplasia, a 
potentially lethal complication. Therefore, if severe leukopenia or thrombocytopenia is observed that 
is potentially attributable to the infused T-cells, the patient will be treated with prednisone and/or 
anti-thymocyte globulin to eliminate the infused third party T-cells.  
In organ transplant recipients it is also possible that the EBV-specific T-cells, upon interaction with 
their targets, will generate cytokines capable of stimulating alloreactive host T-cells that have been 
suppressed by drugs used to prevent rejection. If a rejection crisis is precipitated, it will be treated as 
recommended by the patient's transplant physician. 
3) 
Graft Versus Host Disease: Acute Graft Versus Host Disease (GvHD) represents an immune 
assault induced by engrafted alloreactive donor T-lymphocytes, against host alloantigens 
Blood/BM samples 
< 10 ml/sample 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Treatment  
EBV specific 
T cells**** 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 24 of 41 
predominantly expressed on hematopoietic cells and their tissue-based progeny. It is manifested by 
skin rash, hepatitis, enteritis and suppression of host hematopoietic and lymphoid tissues resulting in 
blood count depressions or aplasia and prolonged immunodeficiency. 
The development of GvHD necessitates engraftment and proliferation of donor alloreactive T-cells. 
Patients who have received organ allografts and even the most severely immunodeficient AIDS 
patients are able to reject allogeneic lymphoid cells. Despite a large documented experience of 
transfusions of unirradiated cells, no instance of GvHD has been recorded in AIDS patients or 
recipients of kidney, lung, heart, or liver grafts (59). Thus, these patients are likely not at risk for this 
complication 
On the other hand, marrow transplant recipients and children with severe combined 
immunodeficiency are at risk of acute and chronic forms of GvHD if infused with unirradiated HLA-
matched or HLA-mismatched T-cells capable of responding to host alloantigens. Acute GvHD 
affects 60% of recipients of HLA-matched marrow grafts. Up to 85% of adults transplanted with HLA-
matched marrow from unrelated donors or partially matched related donors will develop moderate to 
severe (grade II-IV) acute GvHD despite drug prophylaxis (60). This complication is a principal 
contributor to mortality in 40-50% of cases. Furthermore, 50% of the survivors of acute GvHD will 
develop manifestations of chronic GvHD (61). 
The in vitro propagation of T-cells reactive against autologous EBV-transformed cells selects for the 
expansion of EBV-specific T-cells and the elimination of other T-cells, including alloantigen-
responsive T-cells (58). As a result, infusions of virus-specific T-cells generated over 4-6 weeks in 
vitro in our own and other published experience (46, 47, 49, 53) have thus far not been complicated 
by GvHD in HSCT transplant recipients. Nevertheless, there is a risk that small numbers of 
alloreactive T-cells could be transferred with the infusions of EBV-specific T-cells. To counter this 
risk, only HLA matched or HLA partially matched donors will be used as donors of EBV-specific T-
cells and only EBV-specific T-cells tested to be free of cells reactive against allogeneic cells will be 
administered to patients who could be durably engrafted following a T-cell infusion. 
4) 
Transmission of Infection: There is a potential that transfusions of white cells or T-
lymphocytes may also serve as vectors of serious infection. All precautions to maintain sterility will 
be taken. 
5) 
Transfusion Reactions: It is possible that during the course of repeated infusions of EBV-
specific T-cells derived from a normal donor, the host will develop an immune response against the 
donor cells, which could lead to an immediate allergic response, manifested by generalized urticaria 
of the skin, angioneurotic edema, or more serious manifestations such as bronchospasm or 
hypotension. Such reactions will be treated symptomatically. 
6) 
Treatment Failure: Treatment with EBV-specific T-cells may not alter the progression of EBV 
lymphoma or may induce only transient regressions of disease. Furthermore, because of host 
immune responses to donor cells, secondary or subsequent treatment by this adoptive 
immunotherapeutic approach may be precluded. 
7) 
Reproductive Risks: Patients should not become pregnant or father a baby while on this 
study because the drugs in this study can affect an unborn baby. Women should not breast feed 
while on this study. Women may need to use birth control while on the study, but should check with 
their study doctor regarding what type of birth control and how long to use it.  
 
11.1 Donor Toxicity/Side Effects 
Risks of blood donation are minimal and include: minor discomfort at site of blood draw, some 
bleeding and/or bruising, and lightheadedness.  
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 25 of 41 
Risks of Leukapheresis include: Lack of feeling or tingling of fingertips or around mouth, which 
normally last only a short time, and can, potentially, progress to cramps. This is normally treated with 
a calcium supplement. 
Other leukapheresis side effects include:  
 - Pain 
 - Bruising at the needle insertion sites 
 - Dizziness 
 - Nausea  
 - Fainting due to temporary lowering of the blood pressure (rare) 
 - Infection (rare)  
   
Platelet count may drop during the leukapheresis and will be measured after the collection. If platelet 
count falls enough to place the donor in danger of bleeding, count will be checked daily until it 
returns to normal. 
The leukapheresis requires that a needle be placed in a vein in each arm. About 15% of the time, we 
are unable to use the donor’s arm veins.  The donor may be asked to go through a minor surgical 
procedure to place a central line. The donor will be asked to sign another consent form if a central 
line needs to be put in.  
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
1) 
Acute toxicities induced by infusions of EBV-specific T-cells will be graded according to the 
NCI-CTC 4.0 criteria used to grade organ toxicities induced by chemotherapeutic agents (62). 
 
2) 
Allograft rejection episodes developing in organ transplant recipients will be diagnosed, 
assessed, and managed by the patient's transplant physician, utilizing standard criteria established 
for the identification and grading of rejection episodes in transplanted kidney, liver, heart or lung 
allografts (63-65). 
 
3) 
Acute Graft vs. Host Disease will be diagnosed and graded utilizing the IBMTR consensus 
criteria (66) and the histopathological criteria of Slavin and Woodruff (67). Chronic graft vs. host 
disease will be diagnosed and graded using the staging criteria developed by Sullivan et al (68). 
 
4) 
The responses of the clinically and/or radiologically evident EBV LPD or malignancies will be 
identified three weeks post-infusion cycle and may be performed earlier if clinically indicated. In our 
experience, patients with Nasopharyngeal Carcinomas do not typically show response to treatment 
after one cycle. Evaluation for these patients will occur after a second cycle of cells, unless clinically 
indicated. Outcome responses will be captured post-first cycle and post final-cycle of infusions of 
EBV specific T cells. Best response observed in the full course of treatment will also be recorded as 
a distinct entity. 
 Complete response: Complete resolution of all clinical and radiologic evidence of lymphoma, 
confirmed by biopsy of affected tissues when indicated, lasting for at least three weeks following 
completion of a course of cell infusions. 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 26 of 41 
 Partial response: A 50% or greater reduction in the size of all lymphomatous lesions as 
determined by CT or MRI based measurements of tumor volume, which is maintained for at least 
three weeks following completion of a course of cell infusions. A sustained PR is defined as a PR 
that is sustained for ≥ 6 months. 
 Stable disease: Less than 50% reduction of lymphomatous lesions without progression at any 
site maintained for at least 3 weeks following completion of a course of cell infusions. 
 Mixed response: A 50% or greater reduction in the size of one or more lymphomatous lesions as 
determined by CT or MRI based on measurements of tumor volume, which is maintained for at least 
three weeks following completion of a course of cell infusions, with no change or progression at 
another site. Or a decrease in viremia coupled with stable disease of lymphomatous lesions. 
 No response with disease progression: Progressive enlargement of one or more lymphomatous 
lesions by three weeks following a course of T-cell infusions. 
 
5) 
For recipients of HSCTs, and other severely immunocompromised patients in Groups 1 and 
2 (Section 9.0), who failed initial treatment with chemotherapy and/or Rituxan for their EBV 
malignancy and are, therefore, treated preemptively with EBV-specific T-cells because of high and 
increasing levels of EBV DNA in the blood, without clinical or radiological evidence of tumors, a 
therapeutic response will be defined as the following. Outcome responses will be captured post-first 
cycle and post final-cycle of infusions of EBV specific T cells. Best response observed in the full 
course of treatment will also be recorded as a distinct entity. 
A. 
Viral - Complete Response: Clearance of EBV without subsequent development of EBV 
LPD  
B. 
Viral – Partial Response: At least a ten-fold decrease in EBV DNA levels 
C. 
Viral - Stable Response: Persistence of circulating EBV DNA without development of EBV 
LPD  
D. 
Viral - No Response with Progression: Persistence of EBV DNA with subsequent 
development of EBV LPD  
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
In accordance with the Declaration of Helsinki, ICH Good Clinical Practice Guidelines, and the 
US FDA Regulations, a patient has the right to withdraw from the study at any time for any 
reason without prejudice to his/her future medical care by the physician or at the institution.  The 
Investigator also has the right to withdraw patients from the study (see below).  Should a patient 
(or a patient’s legally authorized representative) decide to withdraw, all efforts will be made to 
complete and report the observations as thoroughly as possible. 
A complete final evaluation should be made at the time of the patient’s withdrawal, the Study 
Status Outcome form in the case report form should be completed with an explanation of why 
the patient is withdrawing, and an attempt should be made to perform a follow-up evaluation.  
Patients may be removed from study, and not followed further, if one or more of the following 
events occur: 
 
Significant noncompliance on the part of the patient 
 
Refusal of the patient to continue treatment or observations 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 27 of 41 
 
Unacceptable toxicity (i.e.: grade 3-4 toxicity related to EBV CTL infusion). Removal 
for unacceptable toxicity does not necessarily preclude continued follow-up. 
 
Progressive disease that in the Investigator’s opinion requires therapeutic intervention 
that would interfere with the interpretation of results from the study 
 
Decision by the Investigator that termination is in the patient’s best medical interest 
 
Unrelated medical illness or complication 
 
Lost to follow-up 
 
14.0 
BIOSTATISTICS 
A phase 2 trial design will be applied to determine the efficacy of Epstein-Barr Virus Immune T-
lymphocyte lines for the treatment of EBV malignancies.  The evaluation of treatment will be 
assessed separately for 1) patients with EBV-LPD after allogeneic HSCT who are severely 
immunocompromised or patients with severe congenital or antineoplastic drug induced 
immunodeficiency and 2) patients with EBV-LPD after organ allograft recipients, AIDS patients, or 
patients who develop other EBV-associated malignancies without pre-existing immune deficiency. 
For patients with EBV-LPD, the primary endpoint is complete response or a sustained partial 
response for 6 months as defined in section 12.  
For patients in Group 1 who have an EBV-LPD, a two-stage design with a maximum of 28 patients 
will be accrued onto this study.  The therapy is considered active if the probability of a complete or 
sustained partial response for 6 months (CR/SPR) in the population exceeds 0.40. In the first stage, 
16 patients will be enrolled in the study. If 6 or fewer CR/SPRs are observed, then the trial will be 
stopped. If at least 7 responses are observed, then 12 additional patients will be accrued, for a total 
of 28 patients. At the conclusion of the trial, if 14 or fewer CR/SPRs are observed, we will conclude 
that the treatment combination is not sufficiently active. This design has power 0.90 for a population 
CR/SPR proportion of 0.64 using a one-sided 0.10 size test.  At the conclusion of the study, we will 
estimate the probability of a complete response or a sustained partial response for 6 months and the 
95% confidence interval for this response parameter. Kaplan-Meier estimates of overall and disease 
free survival over time will be computed.  
Patients in Group 2 (section 9.0 and 9.2) who develop an EBV LPD as a complication of an organ 
allograft or AIDS and patients with EBV-associated malignancies without pre-existing immune 
deficiency are expected to consistently reject the third party cells. As a result, the survival of cells 
post each infusion is expected to be shorter. Nevertheless, an initial expansion suggests that 50-
70% of these patients may achieve a durable CR or PR. Therefore, for this group, we will also adopt 
a two stage design, with a maximum of 28 patients to be accrued onto this study. The therapy is 
again considered active if the probability of a complete or sustainable partial response for 6 months 
(CR/SPR) exceeds 0.20. If at the conclusion of the study 9 or more of the 28 patients remain 
disease free for 6 months from the start of treatment, then the treatment will be considered active. 
This active region is based on a one-sided 0.10 size test. The study design has power 0.90 for a six-
month disease free probability equal to 0.40.  At the conclusion of the study, Kaplan-Meier estimates 
of overall and disease free survival over time will be computed.  
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 28 of 41 
The effects of infusing activated EBV-specific T-cells on the general immune function of the host will 
be assessed by recording CD4+ and CD8+, CD3+ T-cells, NK cells and B-cells as specified in the 
Schedule of Examinations and Studies Table on Page 22. Nonparametric curve smoothing methods 
will be employed to estimate the population trajectory of these immunologic recovery factors over 
time. In addition, a generalized estimating equation approach will be used to model the relationship 
between the immunologic reconstitution factors and complete response.   
It is anticipated that accrual for both groups will be completed within 3 years. 
In order to reduce patient risk, the study design includes early termination in the event of excessive 
graft versus host disease or early treatment related mortality during the accrual period.  The 
stopping rules for excessive failure and the corresponding power calculations are derived separately 
for Group 1 and Group 2 and are given in the tables below. In the event that the stopping boundary 
is crossed for one of the groups, the study will continue accrual in the other group. 
Group 1 
 
 
 
# of failures needed 
       Failure rate       
    Probability boundary 
Failure type 
 
to stop the study 
       in the population  
    is crossed 
 
One-year TRM  
2 within the first 10 patients 
3 within the first 23 patients 
4 within 28 patients  
   0.04 
         0.10 
   0.20 
         0.91 
Acute GvHD 
(grades 3-4) 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
Chronic GvHD 
(extensive) 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
 
 
 
 
 
Group 2 
 
 
 
# of failures needed 
       Failure rate       
    Probability boundary 
Failure type 
 
to stop the study 
       in the population  
    is crossed 
Graft failure 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
One-year TRM  
2 within the first 10 patients 
   0.04   
         0.10 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 29 of 41 
 
3 within the first 23 patients 
4 within 28 patients 
   0.20 
        0.91 
Acute GvHD 
(grades 3-4) 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
Chronic GvHD 
(extensive) 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
 
Patient accrual for the EBV-LPD patient cohorts is almost complete. The planned accrual for each 
cohort was 28 patients. To date, 20 patients in group 1 have been treated with 7 patients attaining a 
CR/SPR and 23 patients in group 2 have been treated with 5 patients attaining a CR/SPR.  In 
addition, the stopping boundaries for graft failure, treatment related mortality, acute GvHD, and 
chronic GvHD have not been exceeded. As a result, after the planned patient accrual is 
complete and the stopping boundaries have not been met, we propose to accrue an 
additional 28 patients in each cohort with amendment 6.  These additional patients will provide a 
more precise estimate of the CR/SPR rate in the two patient populations. With 56 patients, the 
probability of a CR/SPR can be estimated to within +/- 0.13 with 95% confidence. The stopping rules 
below will be used to monitor the additional 28 patients for graft failure, graft versus host disease 
and treatment related mortality. The stopping rules for excessive failure and the corresponding 
power calculations are derived separately for Group 1 and Group 2 and are given in the tables 
below. In the event that the stopping boundary is crossed for one of the groups, the study will 
continue accrual in the other group. 
 
 
 
 
 
 
 
Group 1 
 
 
 
# of failures needed 
             Failure rate              Probability boundary 
Failure type 
 
to stop the study 
             in the population       is crossed 
 
2 within the first 10 patients 
   0.04 
         0.10 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 30 of 41 
One-year TRM  
3 within the first 23 patients 
4 within 28 patients  
   0.20 
         0.91 
Acute GvHD 
(grades 3-4) 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
Chronic GvHD 
(extensive) 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
 
Group 2 
 
 
 
# of failures needed 
       Failure rate       
    Probability boundary 
Failure type 
 
to stop the study 
       in the population  
    is crossed 
Graft failure 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
One-year TRM  
 
2 within the first 10 patients 
3 within the first 23 patients 
4 within 28 patients 
   0.04   
         0.10 
   0.20 
        0.91 
Acute GvHD 
(grades 3-4) 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
Chronic GvHD 
(extensive) 
2 within the first 26 patients 
3 within 28 patients 
   0.02 
         0.10 
   0.15 
         0.92 
 
15.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 
. Registrations must be submitted via the PPR Electronic 
Registration System 
.  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018
PPD
PPD

 
 
 
Page 31 of 41 
15.2 
Randomization 
N/A 
16.0 
DATA MANAGEMENT ISSUES 
This is a single institution trial and all patients will be treated at Memorial Sloan-Kettering Cancer 
Center. 
A research Study Assistant (RSA) will be assigned to this study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol 
study team. The data manager will also monitor laboratory compliance throughout the study. 
Laboratory data will be tabulated and summarized based on MSKCC normal ranges. 
The data collected for this study will be entered into the MSKCC Clinical Research Data Base 
(CRDB). 
 
16.1 
Quality Assurance 
Registration reports will be generated by the RSA on a regular basis to monitor patient 
accruals and completeness of the registration data. Routine data quality reports will be 
generated to assess missing data and inconsistencies. Accrual rates and extent and 
accuracy of evaluations and follow-up will be monitored periodically throughout the study 
period and potential problems will be brought to the attention of the study team for discussion 
and action.   
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018
PPD

 
 
 
Page 32 of 41 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) Will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
    Consent process: Participation in this trial is voluntary.  All patients will be required to sign 
a statement of informed consent, which must conform to MSKCC IRB guidelines.  
 
    Benefits:  It is not known whether this treatment will improve the overall survival 
of the patient. 
 
 
Risks: The potential risks of this therapy as described in Section 11 of this protocol may 
outweigh the potential benefits in an individual patient. The potential risks are related to 
adverse effects which could be induced by infusion of T cells derived from EBV sensitized 
T cell lines. Appropriate exclusion of patients are listed in the section of patient eligibility. 
 
    Costs: The patient’s health plan/ insurance company will need to pay for some or all of the 
costs of treating his/her disease in this study, including the production of EBV immune T 
cells. Patients will be charged for physician visits, routine laboratory and radiologic studies 
required for monitoring their condition.   
 
    Alternatives to the Planned Study: Alternative treatment options include continued 
treatment with Rituxan and standard antiviral drugs used for herpes virus infections and 
treatment with chemotherapeutic agents used for Lymphomas not associated with EBV 
infection in other investigational studies.  If relevant, other investigational options will also 
be outlined. Issues relating to best supportive care as a treatment option alone will be 
reviewed, given that most chemotherapy responses with standard drugs are infrequent and 
short lived. (see Patient Informed Consent). 
 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential.  Patient's names or any other personally identifying 
information will not be used in reports or publications resulting from this study.  The Food 
and Drug Administration or other authorized agencies (e.g., qualified   monitors from 
MSKCC or the NCI etc.), and appropriate personnel may review patient   records as 
required. 
 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB).  
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
17.2.1  
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 33 of 41 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at 
.  The report should contain the following 
information: 
Fields populated from CRDB: 
 
Subject’s name (generate the report with only initials if it will be sent outside of     
      MSKCC) 
 
Medical record number 
 
Disease/histology (if applicable) 
 
Protocol number and title 
Data needing to be entered: 
 
The date the adverse event occurred 
 
The adverse event 
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
17.2.2 Definition of SAEs 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
o Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
consent 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018
PPD

 
 
 
Page 34 of 41 
o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
o hospitalizations or prolongation of hospitalizations, due to complications of the 
patient’s previous therapy and/or underlying malignancy 
 
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above is 
not a serious adverse event. Additionally, events relating to the patient’s underlying 
malignancy or attributable to other therapy should not be reported serious adverse events.  
Attribution: 
 
Unrelated: The AE is clearly NOT related to the intervention 
 
Unlikely: The AE is doubtfully related to the intervention 
 
Possible: The AE may be related to the intervention 
 
Probable: The AE is likely related to the intervention 
 
Definite: The AE is clearly related to the intervention 
 
 
Expected and Unexpected Event: 
 
Expected: Any experience previously reported (in nature, severity, or incidence) in the 
current Investigator’s Brochure or general investigational plan 
 
Unexpected: Any experience not previously reported (in nature, severity, or incidence) in 
the current Investigator’s Brochure or general investigational plan 
 
17.2.3 Reporting Requirements 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient/guardian 
signed ICF has been obtained. Serious Adverse Events (SAEs) are any adverse events 
occurring while on treatment and within 30 days of the last dose  that result in any of the 
following outcomes (Note: Events beyond 30 days will be reported at the discretion of the PI): 
 
UNEXPECTED EVENT:  
 
 
Grades 1-2: Adverse Event Reporting NOT required. 
 
Grades 3-4: Possible, probable, and definite attribution to the drug and/or device will be 
reported. 
 
Grade 5: Regardless of Attribution will be reported.  
 
EXPECTED EVENT 
 
 
Grades 1-3: Adverse Event Reporting NOT required. 
 
Grade 4: Possible, probable, and definite attribution to the drug and/or device will be 
reported. 
 
Grade 5: Regardless of Attribution will be reported.  
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 35 of 41 
SAEs will be graded according to NCI CTCAE 4.0. 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following:  
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
Participants enrolled to the “historical donor” arm are, frequently, no longer under the care of 
MSKCC. This is because the primary patients, for whom their donations were initially 
intended, have completed treatment and are no longer at risk for EBV LPD. Donors who fall 
into this category will be mailed a copy of the consent form to review during the consent 
discussion, which will occur over the phone. If they agree to 3rd party use of their cells, the 
consent will be signed and sent back via MSKCC provided pre-paid/addressed envelope. 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 36 of 41 
 
 
 
 
19.0 
REFERENCES 
1.  Rickinson AB. EBV infection and EBV-associated tumors. In:Minson AC, Neil JC, McRae 
MA, eds. Viruses and Cancer. Cambridge: Cambridge University Press; 1994:81-100. 
 
2.  Straus SE, Cohen JI, Tosato G, Meier J. Epstein-Barr virus infections: biology, pathogenesis 
and management. Ann Intern Med 118:45-58, 1992. 
 
3. 
 Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000 Aug 17;343(7):481-92. PMID: 
10944566. 
 
4.  Tosato G, Steinberg AD, Yarchoan R, Heilman CA, Pike SE, De Seau V, Blaese RM. 
Abnormally elevated frequency of Epstein-Barr virus-infected B cells in the blood of patients with 
rheumatoid arthritis. J Clin Invest. 1984 Jun;73(6):1789-95. 
 
5. 
Rickinson AB, Moss DJ. Human cytotoxic T lymphocyte responses to Epstein-Barr virus 
infection. Annu Rev Immunol. 1997; 15: 405-431. 
 
6.  Lucas KG, Small TN, Heller G, Dupont B, O'Reilly RJ. The development of cellular immunity 
to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood. 1996 Mar 
15;87(6):2594-603. 
 
7.  Lacerda JF, Ladanyi M, Louie DC, Fernandez JM, Papadopoulos EB, O'Reilly RJ. Human 
Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes home preferentially to and induce 
selective regressions of autologous EBV-induced B cell lymphoproliferations in xenografted C.B-
17 scid/scid mice. J Exp Med. 1996 Mar 1;183(3):1215-28. 
 
8. 
 Murray RJ, Kurilla MG, Brooks JM, Thomas WA, Rowe M, Kieff E, Rickinson AB. 
Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus 
(EBV): implications for the immune control of EBV-positive malignancies. J Exp Med. 1992 Jul 
1;176(1):157-68. 
 
9. 
Murray RJ, Kurilla MG, Brooks JM, et al. Identification of target antigens for the human 
cytotoxic T cell response to Epstein-Barr virus(EBV): implications for the immune control of EBV-
positive malignancies. J Exp Med 1992; 176: 157-68. 
 
10.  MacArthur GJ, Wilson AD, Birchall MA, Morgan AJ. Primary CD4+ T-cell responses provide 
both helper and cytotoxic functions during Epstein-Barr virus infection and transformation of fetal 
cord blood B cells. J Virol. 2007 May;81(9):4766-75. Epub 2007 Feb 21. 
 
11.  Tan LC, Gudgeon N, Annels NE, Hansasuta P, O'Callaghan CA, Rowland-Jones S, 
McMichael AJ, Rickinson AB, Callan MF. A re-evaluation of the frequency of CD8+ T cells 
specific for EBV in healthy virus carriers. J Immunol. 1999 Feb 1;162(3):1827-35. 
 
12. Yang J, Lemas VM, Flinn IW, et al. Application of the ELISPOT assay to the characterization 
of CD8 (+) responses to Epstein-Barr virus antigens. Blood 2000; 95: 241-8. 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 37 of 41 
13.  O’Reilly RJ, Small TN, Papadopoulos EB, Lucas K, Lacerda J, Koulova L.  Adoptive 
immunotherapy for EBV-associated lymphoproliferative disorders complicating marrow allografts.  
Springer-Verlag.  Edited by G Klein,  Springer Seminars in Immunopathology, 20:455-491, 1998 
 
14.  Khan G, Coates PJ. The role of Epstein-Barr virus in the pathogenesis of Hodgkin's disease. 
J Pathol. 1994 Nov;174(3):141-9. 
 
15.  Burgos JS. Involvement of the Epstein-Barr virus in the nasopharyngeal carcinoma 
pathogenesis. Med Oncol. 2005;22 (2):113-21. 
 
16.  Suankratay C, Shuangshoti S, Mutirangura A, Prasanthai V, Lerdlum S, Shuangshoti S, 
Pintong J, Wilde H. Epstein-Barr virus infection-associated smooth-muscle tumors in patients with 
AIDS. Clin Infect Dis. 2005 May 15;40(10):1521-8. Epub 2005 Apr 12. 
 
17.  Swerdlow SH. Post-transplant lymphoproliferative disorders: A morphologic, phenotypic and 
genotypic spectrum of disease. Histopathol 20:373-385, 1992. 
 
18.  Hanto DW, Gajl-Peczalaska KJ, Frizzera G, et al. Epstein-Barr- virus induced polyclonal and 
monoclonal B-cell lymphoproliferative diseases occurring after renal transplantation. Ann Surgery 
198:356-369, 1983. 
19. Dharnidharka VR, Tejani AH, Ho PL, et al: Post-transplant lymphoproliferative disorder in the 
United States: young Caucasian males are at highest risk. AM J Transplant 2002 Nov;2(10):993-
8. 
20.  Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of 
lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in 
cardiac-transplant recipients. N Engl J Med 323:1723-1728, 1990. 
 
21.  Patton DF, Wilkowski CW, Hanson CA, et al. Epstein-Barr virus-determined clonality in post-
transplant lymphoproliferative disease. Transplantation 49:1080-1084, 1990. 
22.  Starzl TE, Nalesnik MA, Porter KA, et al. Reversibility of lymphomas and lymphoproliferative 
lesions developing under cyclosporine-steroid therapy. Lancet 1:583-587, 1984. 
23.  Leblond V, Dhedin N, Mamzel Bruneel MF, et al: Identification of prognostic factors in post-
transplantation lymphoproliferative disorders in 61 patients with posttransplantation 
lymphoproliferative disorders. J Clin Oncol 19:772-778, 2001 
24.  Straus SE, Cohen JI, Tosato G, Meier J. Epstein-Barr virus infections: biology, pathogenesis 
and management. Ann Intern Med 118:45-58, 1992. 
 
25. Kuehnle I, Huls MH, Liu Z, et al. CD20 monoclonal antibody (rituximab) for therapy of 
Epstein-Barr virus lymphoma after hematopoietic stem-cell transplantation. Blood. 2009;95:1502-
1505.  
 
26.  Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, Carabasi MH, Castro-
Malaspina H, Childs BH, Gillio AP, Small TN, Young JW, Kernan NA, O'Reilly R.J. Infusions of 
donor leukocytes as treatment of Epstein-Barr virus associated lymphoproliferative disorders 
complicating allogeneic marrow transplantation. NEJM 330:1185-1191, 1994. 
 
27.  Antin J, Bierer B, Smith B, Ferrara J, Guinan EC, Sieff C, Golan DE, Macklis RM, Tarbell NJ, 
Lynch E, Reichert TA, Blythman H, Bouloux C, Rappeport JM, Burakoff SJ, Weinstein HJ. 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 38 of 41 
Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: Effective 
prophylaxis for graft-versus-host disease in patients with hematologic malignancies. Blood 
78:2139-2149, 1991. 
 
28.  Martin PJ, Shulman HM, Schubach WH, Hansen JA, Fefer A, Miller G, Thomas ED. Fatal 
Epstein-Barr virus-associated proliferation of donor B-cells after treatment of acute graft-versus-
host disease with a murine anti-T-cell antibody. Ann Int Med 101:310-315, 1984. 
 
29.  O’Reilly RJ, Small TN, Papadopoulos EB, Lucas EB, Lasered J, Koulova L.  Adoptive 
immunotherapy for EBV lymphoproliferative disorders complicating marrow allografts.  Springer 
Seminars in Immunopathology, Springer Verlag.  Edited by G Klein.  20:455-491, 1998. 
 
30.  Curtis RE, Travis LB, Rowlings PA, Socié G, Kingma DW, Banks PM, Jaffe ES, Sale GE, 
Horowitz MM, Witherspoon RP, Shriner DA, Weisdorf DJ, Kolb HJ, Sullivan KM, Sobocinski KA, 
Gale RP, Hoover RN, Fraumeni JF Jr, Deeg HJ. Risk of lymphoproliferative disorders after bone 
marrow transplantation: a multi-institutional study. Blood. 1999 Oct 1;94(7):2208-16. 
 
31.  Verschuur A, Brousse N, Raynal B, Brison O, Rohrlich P, Rahimy C, Vilmer E. Donor B cell 
lymphoma of the brain after allogeneic bone marrow transplantation for acute myeloid leukemia. 
Bone Marrow Transplant. 1994 Sep;14(3):467-70. 
 
32.  Lucas KG, Small TN, Heller G, Dupont B, O'Reilly RJ. The development of cellular immunity 
to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood. 1996 Mar 
15;87(6):2594-603. 
 
33.  Ziegler JL, Beckstead JA, Volberding PA, Abrams DI, Levine AM, Lukes RJ, Gill PS, Burkes 
RL, Meyer PR, Metroka CE, Mouradian J, Moore A, Riggs SA, Butler JJ, Cabanillas F, Hersh E, 
Newell GR, Lauberstein LJ, Knowles D, Odajnyk C, Raphel B, Koziner B, Urmacher C and 
Clarkson BD. Non-Hodgkin's lymphoma in 90 homosexual men. NEJM 311:565-570, 1984. 
 
34.  Roithmann S, Toledano M, Tourani JM, Raphel M, Gentilini M, Gastaut JA, Armengaud M, 
Morlat P, Tilly H, Dupont B, Taillan B, Theodore C, Donadio D and Andrieu JM. HIV-associated 
non-Hodgkin's lymphomas: Clinical characteristics and outcome. The experience of the French 
Registry of HIV-associated Tumors. Ann Oncol 2:289-295, 1991. 
 
35.  Gisselbrecht C, Oksenhendler E, Tirelli U, Lepage E, Gabarre J, Farcet JP, Gastaldi R, 
Coiffer B, Thyss A, Raphael M and Monfardini S. Human immunodeficiency virus-related 
lymphoma treatment with intensive combination chemotherapy. Amer J Med 95:188-196, 1993. 
 
36.  Knowles DM, Chamulak GA, Subar M, Burke JS, Dugan M, Wernz J, Slywotzky C, Pelicci G, 
Dalla-Favera R and Raphael B. Lymphoid neoplasia associated with the acquired 
immunodeficiency syndrome (AIDS). Ann Int Med 108:744-753, 1988. 
 
37.  Knowles DM, Chamulak GA, Subar M, Burke JS, Dugan M, Wernz J, Slywotzky C, Pelicci G, 
Dalla-Favera R and Raphael B. Lymphoid neoplasia associated with the acquired 
immunodeficiency syndrome (AIDS). Ann Int Med 108:744-753, 1988. 
 
38.  Baumgartner JE, Rachlin JR, Beckstead JH, Meeker TC, Levy RM, Wara WM and 
Rosenblum ML. Primary central nervous system lymphomas: Natural history and response to 
radiation therapy in 55 patients with acquired immunodeficiency syndrome. J Neurosurg 73:206-
211, 1990. 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 39 of 41 
39.  Goldstein JD, Dickson DW, Moser FG, Hirschfeld AD, Freeman K, Llena IF, Kaplan B and 
Davis L. Primary central nervous system lymphoma in acquired immune deficiency syndrome. A 
clinical and pathological study with results of treatment with radiation. Cancer 67:2756-2765, 
1991. 
 
40.  Fischer A, Blanche S, LeBidois J, Gamier JL, Niaudet P, Morinet F, LeDeist F, Fischer AM, 
Griscelli C, Hirn M. Anti-B-cell monoclonal antibodies in the treatment of severe B-cell 
lymphoproliferative syndrome following bone marrow and organ transplantation. NEJM 324:1451-
1456, 1991. 
 
41.  Choquet S, Leblond V, Herbrecht R, Socié G, Stoppa AM, Vandenberghe P, Fischer A, 
Morschhauser F, Salles G, Feremans W, Vilmer E, Peraldi MN, Lang P, Lebranchu Y, 
Oksenhendler E, Garnier JL, Lamy T, Jaccard A, Ferrant A, Offner F, Hermine O, Moreau A, Fafi-
Kremer S, Morand P, Chatenoud L, Berriot-Varoqueaux N, Bergougnoux L, Milpied N. Efficacy 
and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a 
prospective multicenter phase 2 study. Blood. 2006 Apr 15;107(8):3053-7. Epub 2005 Oct 27. 
 
42.  Milpied N, Vasseur B, Parquet N, Garnier JL, Antoine C, Quartier P, Carret AS, Bouscary D, 
Faye A, Bourbigot B, Reguerre Y, Stoppa AM, Bourquard P, Hurault de Ligny B, Dubief F, 
Mathieu-Boue A, Leblond V. Humanized anti-CD20 monoclonal antibody (Rituximab) in post 
transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients. Ann Oncol. 
2000;11 Suppl 1:113-6. 
43. Moss DJ, Rickinson AB, &  Pope JH. Long-term T-cell-mediated immunity to Epstein-Barr 
virus in man. I. Complete regression of virus-induced transformation in cultures of seropositive 
donor leukocytes. Int. J Cancer 22, 662-668. 
44.  Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, 
Mavilio F, Traversari C, Bordignon C. HSV-TK gene transfer into donor lymphocytes for control of 
allogeneic graft-versus-leukemia. Science. 1997 Jun 13;276(5319):1719-24. 
 
45. Lucas KG, Burton RL, Zimmerman SE, et al. Semiquantitative Epstein-Barr virus (EBV) 
polymerase chain reaction for the determination of patients at risk for EBV-induced 
lymphoproliferative disease after stem cell transplantation. Blood. 2000; 95; 807-814.  
 
46. Rooney CM, Smith CA, Ng CYC, et al. Infusion of cytotoxic T cells for the prevention and 
treatment of Epstein-Barr cirus-induced lymphoma in allogeneic transplant recipients. Blood. 
1998; 92: 1549-1555. 
 
47.  O'Reilly RJ, Small TN, Papadopoulos E, Lucas K, Lacerda J, Koulova L. Biology and 
adoptive cell therapy of Epstein-Barr virus-associated lymphoproliferative disorders in recipients 
of marrow allografts. Immunol Rev. 1997 Jun;157:195-216. 
 
48. Gottschalk S, Heslop HE, Rooney CM. Adoptive immunotherapy for EBV-associated 
malignancies. Leuk Lymphoma 2005; 46: 1-10.  
 
49. Comoli P, Basso S, Labirio M, et al. T cell therapy of Epstein-Barr virus and adenovirus 
infections after hematopoietic stem cell transplant. Blood Cells Mol Dis 2008; 40: 68-70. 
 
50. Bollard CM, Gottschalk S, Leen AM, et al. Complete responses of relapsed lymphoma 
following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood 
2007; 110: 2838-45. 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 40 of 41 
51. Lee SP. Nasopharyngeal carcinoma and the EBV-specific T cell response: prospects for 
immunotherapy. Semin Cancer Biol 2002; 12:463-71. 
 
52.  Haque T, Wilkie GM, Taylor C, et al. Treatment of Epstein-Barr-virus-positive post 
transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. 
Lancet 2002; 360: 436-42. 
 
53.  Haque T, Wilkie GM, Jones MM, Higgins CD, Urquhart G, Wingate P, Burns D, McAulay K, 
Turner M, Bellamy C, Amlot PL, Kelly D, MacGilchrist A, Gandhi MK, Swerdlow AJ, Crawford DH. 
Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative 
disease: results of a phase 2 multicenter clinical trial. Blood. 2007 Aug 15;110(4):1123-31. Epub 
2007 Apr 27. 
 
54.  Wilkie GM, Taylor C, Jones MM, Burns DM, Turner M, Kilpatrick D, Amlot PL, Crawford DH, 
Haque T. Establishment and characterization of a bank of cytotoxic T lymphocytes for 
immunotherapy of epstein-barr virus-associated diseases. J Immunother. 2004 Jul-
Aug;27(4):309-16. 
 
55.  Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD Restoration of viral 
immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257:238-
241, 1992. 
 
56.  Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating   lymphocytes and 
interleukin-2 in the immunotherapy of patients with metastatic 
melanoma: Special report. N Engl J Med 319:1676-1680, 1988. 
 
57.  Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, Carabasi 
MH, Castro-Malaspina H, Childs BH, Gillio AP, Small TN, Young JW, Kernan NA, 
O'Reilly R.J. Infusions of donor leukocytes as treatment of Epstein-Barr virus associated 
lymphoproliferative disorders complicating allogeneic marrow transplantation. NEJM 
330:1185-1191, 1994. 
 
58.  Rooney CM, Smith CA, Ng CYC, Loftin S, Li C, Krance RA Brenner MK, Heslop HE. Use of 
gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related 
lymphoproliferation. Lancet 345:9-13, 1995. 
 
59.  Greenbaum BH. Transfusion-associated graft-versus-host disease: Historical perspectives, 
incidence, and current use of irradiated blood products. J Clin Oncol 9:1889-1902, 1991. 
 
60.  Kernan NA, Bartsch G, Ash RC, et al. Retrospective analysis of 462 unrelated marrow 
transplants facilitated by the National Marrow Donor Program (NMDP) for treatment of acquired 
and congenital disorders of the lymphohematopoietic system and congenital metabolic disorders. 
N Engl J Med 328:592-602, 1993. 
 
61.  McGlave P, Bartsch G, Anasetti C, Ash R, Beatty P, Gajewski J, Kernan NA. Unrelated 
donor marrow transplantation therapy for chronic myelogenous leukemia: Initial experience of the 
National Marrow Donor Program. Blood 81(2):543-550, 1993. 
 
62.  Appendix A: Grading of Toxicity. In: Robert E. Wittes (Ed): Manual of Oncologic 
Therapeutics. Philadelphia, PA, 1990. 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018

 
 
 
Page 41 of 41 
63.  Billingham ME, Cary NRB, Hammond ME, et al. A working formulation for the standardization 
of nomenclature in the diagnosis of heart and lung rejection: Heart rejection study group. J Heart 
Transplant 9:587-593, 1990. 
 
64.  Adams D, Newberger J. Patterns of graft rejection following liver transplantation. J Hepatol 
10:113, 1990. 
 
65.  Morris PJ. The clinical and laboratory diagnosis of graft rejection. In: Brent L, Sells RA (Eds): 
Organ transplantation: current clinical and immunological concepts. London: Balliere Tindall, 
1989. 
 
66.  Rowlings, P. A., D. Przepiorka, et al. (1997). "IBMTR Severity Index for grading acute graft-
versus-host disease: retrospective comparison with Glucksberg grade." Br J Haematol 97(4): 855-
864 
 
67.  Slavin RE, Woodruff JM. The pathology of bone marrow transplantation. Path Ann 91:291, 
1974. 
 
68.  Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB, Schubert 
MM, Atkinson K, Thomas ED. Chronic graft-versus-host disease in 52 patients: Adverse natural 
course and successful treatment with combination immunosuppression. Blood 57:267, 1981. 
 
69. Comoli P, Pedrazzoli P, Maccario R, Basso S, Carminati O, Labirio M, Schiavo R, Secondino 
S, Frasson C, Perotti C, Moroni M, Locatelli F, Siena S. Cell therapy of stage IV nasopharyngeal 
carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. Laboratorio di 
Ricerca Area Trapianti e Oncoematologia Pediatrica, IRCCS Policlinico S. Matteo, V.le Golgi 19, 
27100 Pavia, Italy 
70. Barker JN, Doubrovina E, Sauter C, Jaroscak JJ, Perales MA, Doubrovin M, Prockop SE, 
Koehne G, O'Reilly RJ. Successful treatment of Epstein-Barr virus (EBV)-associated post-
transplant lymphoma after cord blood transplant using third-party EBV-specific cytotoxic T-
lymphocytes. Blood. 2010 Sep 8. [Epub ahead of print] 
 
71. Vaysberg M, Balatoni CE, Nepomuceno RR, Krams SM, Martinez OM. Rapamycin inhibits 
proliferation of Epstein-Barr virus-positive B-cell lymphomas through modulation of cell-cycle 
protein expression. Transplantation. 2007 Apr 27;83(8):1114-21. 
 
72. Doubrovina E, Oflaz-Sozmen B, Kernan NA, et al. Adoptive transfer of EBV-specific T-cells 
for treatment of primary and Rituxan resistant EBV lymphomas following allogeneic stem cell 
transplants (HSCT): clinical, viral and immunologic corelates. Biol Blood Marrow Transplant 
2010;16(2): S220-S21. 
 
73. O’Reilly RJ, Hasan A, Doubrovina E, Koehne G, Prockop S. Novel strategies for adoptive 
therapy following HLA disparate transplants. Best Prac & Res Clin Hem. In Press, 2011 
 
74. Gottschalk S, Ng CY, Perez M, Smith CA, Sample C, Brenner MK, Heslop HE, Rooney CM. 
An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease 
unresponsive to therapy with virus-specific CTLs. Blood. 2001 Feb 15;97(4):835-43.  
 
 
20.0 
APPENDICES 
N/A 
Memorial Sloan Kettering Cancer Center
IRB Number: 11-130 A(23)
Approval date: 15-Mar-2018