Administration of HIV-specific T Cells to HIV+ Patients Receiving High Dose Chemotherapy Followed by Autologous Stem Cell Rescue - Auto -RESIST BMT CTN 1903
Phase: PHASE2
Conditions: HIV Associated Lymphoma
Sponsor: Catherine Bollard

CONFIDENTIAL
Administration of HIV-specific T cells to HIV+ Patients Receiving High 
Dose Chemotherapy Followed by Autologous 
Stem Cell Rescue -Auto-RESIST
BMT CTN PROTOCOL 1903 (AMC-109)
VERSION 2.0
Study Chairpersons
Rich Ambinder, MD1 and Kieron Dunleavy, MD2
Protocol Officer
Steven Devine, MD3
Protocol Team
Joseph Alvarnas, MD4
Aliyah Baluch, MD5
Cath Bollard, MD6
Peter Dawson, PhD7
Christine Durand1
Uday Popat, MD12
Nancy DiFronzo, PhD8
Raphael Fraser, PhD9
Helen Heslop, MD11
Alex Lazaryan, MD5
Eric Leifer, PhD8
Rich Little, MD10
Bianca Noronha7
Dinma Ahaiwe7
Christine Borchert7
Nicole Ritzau, RN7
Michelle Rudek-Renaut1
Rena Xian, MD1
1Johns Hopkins University
2George Washington University
3National Marrow Donor Program
4City of Hope
5H. Lee Moffitt Cancer Center Institute
6Children’s National Hospital
7The Emmes Company
8National Heart, Lung, and Blood Institute 
9Center for International Blood and Marrow 
Transplant Research, Medical College of Wisconsin 
10National Cancer Institute
11Baylor College of Medicine
12MD Anderson Cancer Center
Sponsored by the National Institutes of Health
National Heart, Lung, and Blood Institute
National Cancer Institute
IND# 26807
________________________________
_________________________________
Approval Signature (Protocol Chair)
Approval Signature (Protocol Chair)
________________________________
Approval Signature (Protocol Officer)
Rich  Ambinder, MD
I am approving this document.
Rich Ambinder, MD
19/Apr/2022 12:38 PM EDT
Kieron  Dunleavy, MD
I am approving this document.
Kieron Dunleavy, MD
21/Apr/2022 12:10 PM
EDT
Steven  Devine, MD
Steven Devine, MD
19/Apr/2022 12:20 PM
EDT
I am approving this document.

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PROTOCOL SYNOPSIS - BMT CTN PROTOCOL #1903 
 
Administration of HIV-specific T cells to HIV+ Patients Receiving High Dose 
Chemotherapy Followed by Autologous Stem Cell Rescue - Auto-RESIST 
 
Study Chairpersons:  
Dr. Richard Ambinder and Dr. Kieron Dunleavy 
 
Protocol Officer: 
Dr. Steven Devine 
 
Primary Objective: 
The primary objective is to determine 1.) the proportion of 
participants who can be treated with HIV antigen-specific T-cells 
Targeting Conserved Epitopes (HST-NEETs) within 1 week of 
autologous hematopoietic stem cell transplantation (ASCT) in a 
cooperative multi-institutional setting and 2.) the efficacy of HST-
NEETs in reducing the HIV intact proviral reservoir at 6 months 
after ASCT. 
 
Secondary Objectives: 
Participants will be assessed for the following endpoints:  
 
1. Progression-free survival at 6 months and 1 year post-ASCT; 
2. The incidence and severity of acute infusion related toxicities; 
3. Impact of therapy on the HIV intact proviral reservoir at 1 year 
post-ASCT. 
 
Exploratory Objectives: 
Participants will be assessed for the following:  
1. CR and CR+PR rates at Day 100 post-ASCT; 
2. Overall survival at 6 months and 1 year post-ASCT; 
3. Time to hematopoietic recovery; 
4. Incidence of infections at 1 year post-ASCT; 
5. Non-relapse mortality at 6 months and 1 year post-ASCT; 
6. Toxicities through 1 year post-ASCT; 
7. Assessment of plasma DNA in blood (clonal Ig DNA) as a 
tumor marker at Day 100, 6 months and 1 year post-ASCT; 
8. Impact of therapy on the HIV intact proviral reservoir at Day 
100 post-ASCT; 
9. HIV RNA in plasma at Day 100, 6 months, and 1 year post-
ASCT; 
10. Impact of therapy on the total proviral HIV DNA at Day 100, 6 
months, and 1 year post-ASCT.  
11. HST-NEETs persistence and expansion in vivo. 
 
 

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Study Design: 
This is a Phase II multi-center trial single arm trial of autologous 
transplantation (ASCT) followed by administration of HST-NEETs 
for treatment of HIV associated lymphoma. 
 
Accrual Objective: 
The trial will enroll 12 participants. 
 
Accrual Period: 
The estimated accrual period is four years. 
 
Eligibility Criteria: 
Eligible participants are HIV positive and plan to be treated by high 
dose chemotherapy followed by an autologous stem cell transplant 
(ASCT). Participants are a minimum of 15 years of age with 
Karnofsky performance status greater than or equal to 70% that have 
primary refractory or recurrent diffuse large B-cell, immunoblastic, 
plasmablastic, high grade, Burkitt, primary effusion lymphoma, or 
classical Hodgkin lymphoma.  Participants must have received 2 or 
3 prior treatment regimens, including an induction chemotherapy 
and 1 or 2 salvage regimens.  Monoclonal antibody therapy and local 
radiation will not be counted as prior therapies.  Participants must 
have chemosensitive disease as demonstrated by complete or partial 
response to induction or most recent salvage chemotherapy.  
Participants cannot have had prior autologous, allogeneic HCT, or 
CART-cell therapy.  Participants must initiate conditioning therapy 
within 3 months of stem cell mobilization or bone marrow harvest.  
Blood cell mobilization or bone marrow harvest will be carried out 
per institutional guidelines.  Participants may not have HIV 
refractory to pharmacologic therapy.  Patients must not have an 
uncontrolled infection. Participants must not have received previous 
cellular therapy.  
 
Treatment Description: 
Participants will have 100-120 mL of peripheral blood drawn and 
sent to Children’s National Hospital for manufacturing of HST-
NEETs 6 weeks prior to ASCT.  Participants will receive 
Carmustine (BCNU) 300 mg/m2 Day -6, Etoposide (VP-16) 100 
mg/m2 BID Days -5 to -2, Cytarabine (Ara-C) 100 mg/m2 BID Days 
-5 to -2, and Melphalan 140 mg/m2 Day -1 followed by ASCT on 
Day 0 and will receive one dose of HST-NEETs (2 x107 cells) 
between Days +3 to +7.  
 
Study Duration: 
Participants will be followed on study for one year post-ASCT.  
 
Interim Analysis: 
No interim analyses for efficacy or futility are planned. 
 
 
Stopping Guidelines: 
Two key safety endpoints (Day 30 treatment related mortality and 
Grade 3 or higher infusion-related toxicities lasting greater than 24 
hours) will be monitored. Any treatment related mortality within 30 

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days of transplantation will trigger a safety review prior to treatment 
of subsequent study participants. Three or more infusion events for 
will trigger consultation with the Data and Safety Monitoring Board 
(DSMB). In the event of graft failure, the protocol will be 
temporarily halted and reviewed by the NHLBI DSMB. Graft failure 
will be defined as a failure to achieve three consecutive labs of 
greater than or equal to 500 neutrophils/μL by Day 100.  
 
Correlative Studies: 
Blood will be collected for monitoring the persistence/expansion of 
the infused T cells by ELIspot, multimer analysis, intracellular 
cytokine staining and TCR sequencing. We will also assess intact 
proviral DNA in peripheral blood mononuclear cells as a measure 
of the HIV reservoir, and clonal immunoglobulin DNA in plasma as 
an indicator of minimal residual disease/early relapse. 
 
STUDY SCHEMA 
 
6 Weeks Pre-ASCT 
x 
100-120mL Blood Drawn for HST-NEETs Manufacturing1  
x 
70 mL Blood Drawn for Intact Proviral DNA Assay (IPDA)2 
x 
 5 mL Blood Drawn for Single Copy HIV-1 RNA Assay3 
Disease Assessment 
Day -6 to -1 
BEAM Conditioning Regimen  
Day 0 
Autologous Stem Cell Transplant 
Day +3 to Day +7 
HST-NEETs (2x 107 cells/m2) Administered4 
Day 100 Post-ASCT 
x 
70 mL Blood Drawn for IPDA** 
x 
5 mL Blood Drawn for Single Copy HIV-1 RNA Assay3 
x 
Disease Assessment 
6 Months Post-ASCT 
x 
70 mL Blood Drawn for IPDA** 
x 
5 mL Blood Drawn for Single Copy HIV-1 RNA Assay3 
x 
Disease Assessment 
12 Months Post-ASCT 
x 
70 mL Blood Drawn for IPDA** 
x 
5 mL Blood Drawn for Single Copy HIV-1 RNA Assay3 
x 
Disease Assessment 
1Collection should be scheduled with Children’s National Hospital at least 2 weeks prior to acquisition. Sample    
should be shipped at ambient temperature to Children’s National Hospital. The standard manufacturing process 
takes 3 to 6 weeks.  
2 Sample should be shipped to Children’s National Hospital. 
3 Sample should be shipped to University of Pittsburgh School of Medicine.  
4HST-NEETs will be shipped to site.  Study staff will thaw and administer cells.  If the ideal window of 3-7 days 
post-transplant is missed, the cells may still be administered up to day 30 and the participant will continue study 
follow-up.   

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TABLE OF CONTENTS 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
ASCT in Patients with HIV Infection .......................................................................... 1-1 
1.2. 
T Cell Therapy in HIV-Infected Individuals ............................................................... 1-1 
1.2.1. 
Previous Experience Using HIV-Specific T-Cells ...................................................... 1-1 
1.2.2. 
Safety of HIV-Specific T-Cells (HXTCs) Targeting gag, pol and nef ....................... 1-2 
1.2.3. 
Manufacturing and Preliminary Data on Ex-vivo Expanded multi HIV antigen (gag, 
pol and nef) -specific T-cells Targeting Conserved Epitopes of Gag and Pol (HST-
NEETs) ........................................................................................................................ 1-4 
1.3. 
NHL and Hodgkin Lymphoma in Patients with HIV Infection ................................ 1-4 
1.4. 
ASCT for Patients with HIV Infection......................................................................... 1-5 
1.5. 
HIV Infection and Risk of Opportunistic Infection following ASCT ....................... 1-5 
1.6. 
Plasma DNA Tumor Markers ....................................................................................... 1-6 
1.7. 
Rationale for the Current Study and Design ............................................................... 1-6 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Hypothesis and Specific Objectives .............................................................................. 2-1 
2.2.1. 
Primary Hypothesis ..................................................................................................... 2-1 
2.3. 
Study Objectives............................................................................................................. 2-1 
2.3.1. 
Primary Objective ....................................................................................................... 2-1 
2.3.2. 
Secondary Objectives .................................................................................................. 2-1 
2.3.3. 
Exploratory Objectives................................................................................................ 2-2 
2.4. 
Participant Eligibility .................................................................................................... 2-2 
2.4.1. 
Participant Inclusion Criteria ...................................................................................... 2-2 
2.4.2. 
Participant Exclusion Criteria ..................................................................................... 2-3 
2.4.3. 
Eligibility for Conditioning Regimen and Transplant ................................................ 2-4 
2.5. 
Treatment Plan............................................................................................................... 2-4 
2.6. 
HST-NEETs – Eligibility, Dosage, and Administration ............................................. 2-6 
2.6.1. 
Eligibility to Receive HST-NEETs ............................................................................. 2-6 
2.6.2. 
HST-NEETs Dosage ................................................................................................... 2-6 
2.6.3. 
HST-NEETs Administration ....................................................................................... 2-6 
2.6.4. 
Duration ...................................................................................................................... 2-7 
2.7. 
Supportive Care ............................................................................................................. 2-7 
2.7.1. 
Growth Factors ............................................................................................................ 2-7 
2.7.2. 
Blood Products ............................................................................................................ 2-7 
2.7.3. 
Prophylaxis Against Infections ................................................................................... 2-8 
2.7.4. 
Post-HCT Lymphoma Therapy ................................................................................... 2-8 
2.7.5. 
Anti-Retroviral Therapy (ART) .................................................................................. 2-8 
2.8. 
Participant Risks ............................................................................................................ 2-9 
2.8.1. 
Therapy Toxicities ...................................................................................................... 2-9 
2.8.2. 
Carmustine (BCNU) ................................................................................................... 2-9 
2.8.3. 
VP-16 (Etoposide) ....................................................................................................... 2-9 
2.8.4. 
Cytarabine (Ara-C).................................................................................................... 2-10 

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2.8.5. 
Melphalan .................................................................................................................. 2-10 
2.8.6. 
ASCT ........................................................................................................................ 2-10 
2.8.7. 
HST-NEETs .............................................................................................................. 2-11 
2.9. 
Investigational Product Supply .................................................................................. 2-12 
2.10. Study Conduct .............................................................................................................. 2-12 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Definition of Disease Status ........................................................................................... 3-1 
3.2. 
Primary Endpoints......................................................................................................... 3-1 
3.2.1. 
Feasibility .................................................................................................................... 3-1 
3.2.2. 
Efficacy ....................................................................................................................... 3-1 
3.3. 
Secondary Endpoints ..................................................................................................... 3-1 
3.3.1. 
Progression-Free Survival ........................................................................................... 3-1 
3.3.2. 
Acute Infusion Related Toxicity ................................................................................. 3-2 
3.3.3. 
Intact Proviral Reservoir ............................................................................................. 3-2 
3.4. 
Exploratory Objectives .................................................................................................. 3-2 
3.4.1. 
CR and CR+PR Rate at Day 100 Post-ASCT ............................................................. 3-2 
3.4.2. 
Overall Survival .......................................................................................................... 3-2 
3.4.3. 
Time to Hematopoietic Recovery ............................................................................... 3-2 
3.4.4. 
Incidence of Infections ................................................................................................ 3-2 
3.4.5. 
Non-Relapse Mortality ................................................................................................ 3-2 
3.4.6. 
Toxicities ..................................................................................................................... 3-3 
3.4.7. 
Ig DNA in Blood ......................................................................................................... 3-3 
3.4.8. 
Intact Proviral Reservoir at Day 100 ........................................................................... 3-3 
3.4.9. 
HIV RNA in Blood ..................................................................................................... 3-3 
3.4.10. 
Total Proviral HIV DNA ............................................................................................. 3-3 
3.4.11. 
HST-NEETs Persistence and Expansion in Vivo ....................................................... 3-3 
4. 
Participant ENROLLMENT AND EVALUATION................................................... 4-1 
4.1. 
Enrollment Procedures .................................................................................................. 4-1 
4.1.1. 
Screening and Eligibility Procedures .......................................................................... 4-1 
4.2. 
Collection of Study Product Components.................................................................... 4-1 
4.2.1. 
Collection of peripheral Blood .................................................................................... 4-1 
4.3. 
Study Monitoring ........................................................................................................... 4-1 
4.3.1. 
Follow-Up Schedule ................................................................................................... 4-1 
4.4. 
Participant Assessments ................................................................................................ 4-2 
4.4.1. 
Evaluations Prior to Enrollment to Assess Eligibility................................................. 4-2 
4.4.2. 
Post-ASCT Evaluations .............................................................................................. 4-4 
4.4.3. 
Criteria for Forms Submission .................................................................................... 4-7 
4.4.4. 
Reporting Participant Deaths ...................................................................................... 4-7 
4.4.5. 
CIBMTR Data Reporting ............................................................................................ 4-7 
4.5. 
Adverse Event Reporting Requirements ..................................................................... 4-7 
4.5.1. 
Definitions ................................................................................................................... 4-7 
4.5.2. 
Classification of Adverse Events by Severity ............................................................. 4-8 
4.5.3. 
Classification of Adverse Events by Relationship to Investigational Product ............ 4-9 

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4.5.4. 
BMT CTN Adverse Event Reporting Guidelines ....................................................... 4-9 
4.5.5. 
Adverse Events of Special Interest ........................................................................... 4-10 
4.5.6. 
Procedure in Case of Pregnancy ............................................................................... 4-10 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 
5.1. 
Study Overview .............................................................................................................. 5-1 
5.1.1. 
Accrual ........................................................................................................................ 5-1 
5.1.2. 
Primary Endpoints ....................................................................................................... 5-1 
5.1.3. 
Primary Hypotheses .................................................................................................... 5-1 
5.2. 
Sample Size Calculations ............................................................................................... 5-1 
5.3. 
Interim Analysis and Stopping Guidelines .................................................................. 5-2 
5.3.1. 
Interim Analysis .......................................................................................................... 5-2 
5.3.2. 
Safety Monitoring ....................................................................................................... 5-2 
5.4. 
Demographic and Baseline Characteristics ................................................................. 5-3 
5.5. 
Analysis Plan .................................................................................................................. 5-3 
5.5.1. 
Analysis of the Primary Endpoints ............................................................................. 5-4 
5.5.2. 
Analysis of Secondary Endpoints ............................................................................... 5-4 
5.5.3. 
Analysis of Exploratory Endpoints ............................................................................. 5-4 
APPENDIX A:  HUMAN SUBJECTS .................................................................................... A-1 
APPENDIX B:  LUGANO CLASSIFICATION .................................................................... B-1 
APPENDIX C:  LABORATORY PROCEDURES ............................................................... C-1 
APPENDIX D:  SUGGESTED PROPHYLAXIS .................................................................. D-1 
APPENDIX E:  MANAGEMENT OF ADVERSE REACTIONS ....................................... E-1 
APPENDIX F:  REFERENCES .............................................................................................. F-1 
 

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CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. 
ASCT in Patients with HIV Infection 
 
The Blood and Marrow Clinical Trials Network (BMT CTN) has previously demonstrated that 
autologous stem cell transplant (ASCT) is a safe and potentially curative therapy for human 
immunodeficiency virus (HIV)-associated lymphomas in people living with HIV.1 For some 
patients, allogeneic transplantation is the preferred option and anecdotally has led to the 
eradication of the HIV-reservoir. More than ten years ago, Timothy Ray Brown (‘the Berlin 
Patient’) received an alloBMT for treatment of acute myeloid leukemia (AML) from a donor who 
ZDVKRPR]\JRXVIRUWKH&&5ǻYDULDQWDQGZDVFXUHG2 Recently, it was reported that a patient 
with Hodgkin lymphoma (‘the London Patient’) achieved long-term HIV-1 remission following 
alloBMT with a donor homozygous for  CCR5'32.3 The 32-base pair deleted variant of CCR5 
affects about 1% of Caucasians and results in a non-functional CCR5 receptor with resistance to 
infection with the most common strains of HIV (R5).4 &&5ǻǻGRQRUVDUHUHODWLYHO\UDUH
Moreover, for many patients with HIV and refractory/relapsed lymphoma, an ASCT would be the 
UHFRPPHQGHGWUHDWPHQWRYHUDQDOORJHQHLFWUDQVSODQWDQGWKXVXVLQJD&&5ǻǻGRQRU
would not be an option. Recent data suggest it may be possible to impact the long term HIV 
reservoir using autologous HIV-specific T cells in the immediate post-ASCT setting. This is the 
focus of the present study. 
As noted above, most HIV-infected indiYLGXDOVGRQRWKDYH&&5ǻǻGRQRU options. Instead 
donors who are not HIV-resistant are used. A recent report indicated that in these patients, 
reconstitution of the T cell compartment after allo-HSCT was slow and heterogeneous and that 
HIV-specific T cells had limited functionality and that an initial short phase of high T cell 
activation may constitute a window of vulnerability for the reseeding of viral reservoirs5—a 
finding that suggests there may be a role for adoptive T cell therapy in alloBMT for HIV patients 
as well. 
 
1.2. 
T Cell Therapy in HIV-Infected Individuals 
 
1.2.1. Previous Experience Using HIV-Specific T-Cells 
 
The feasibility and safety of infusing HIV-infected subjects with ex vivo-expanded autologous 
HIV-specific T-cells was demonstrated in several studies.6,7,8,9 The earliest study of ex vivo 
expanded HIV-specific T cells in actively viremic patients found that infusion with up to 1010 non-
specifically activated, expanded autologous CD8+ T cells was safe and tolerable with no cytotoxic 
T-lymphocyte (CTL) related adverse events in 5 patients with AIDS, but enhancement of HIV 
specific cytotoxicity post infusion was transient and no impact on virologic outcome was found.10 
In another pilot study of actively viremic participants with Chronic HIV Infection (CHI), 
autologous administration of CD8+ CTLs primed to express cytotoxicity against HIV-1 epitopes 
gp120, gag p17, p24m and nef produced no toxicity or clinical deterioration over six months of 
follow-up.6 Three of six participants showed improvements in plasma HIV RNA levels or CD4 

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count at six months despite low enrollment CD4 counts (100-400 /mm3). Two additional studies 
of one patient each who received an infusion of CTL clones against Gag and Nef, respectively, did 
not find any impact on viremia due to the short lived nature of the Gag clone and development of 
HIV escape variants to the Nef clone, but did find that the infusion was safe and well tolerated. 8,11 
Another small study in 3 patients on anti-retroviral therapy (ART) but with low level viremia 
established the safety and tolerability of escalating doses of gag-specific CTL clones of up to 3.3 
x 109 /m2.12 Transferred HIV-specific CTLs migrated to lymph nodes where they co-localized 
with HIV RNA+ cells in the parafollicular regions. The presence of CTL clones in the peripheral 
blood correlated with a significant but transient reduction in the number of HIV infected peripheral 
CD4+ T cells. These studies established the feasibility and safety of adoptive transfer of HIV-
specific CTL clones but showed only modest efficacy in reducing HIV-load. Notably, these studies 
included actively viremic patients, and infused cells were generally monoclonal, had been 
expanded extensively in vitro and, hence, were likely highly differentiated. In a more recent study, 
HIV-specific CD8+ T cell clones derived from the central memory population of chronically HIV-
infected patients on suppressive ART were expanded in vitro, and following autologous re-
infusion could be detected for up to 84 days in blood and rectal tissue and retained or re-expressed 
memory markers (CD28+, CD62L+) and function (secretion of IL-2 and proliferation on cognate 
Ag exposure).13 Virologic outcomes were not assessed in this study, however. In contrast to the 
latter study, we propose in this study to generate polyclonal CD4+ and CD8+ T cells specific for 
multiple HIV epitopes in multiple antigens. Among these studies and others with HIV-specific T 
cells, the only adverse events reported were mild with transient fever, arthralgias, myalgias, chills, 
and rigors following the infusions. Some of these events were associated with the administration 
of exogenous IL-2 given in conjunction with T cell infusion.14,15  
 
It should be noted that there is also experience using gene modified autologous T cells in people 
living with HIV. For example, patients have been infused with CD4 T cells in which the CCR5 
gene was rendered permanently dysfunction by a zinc-finger nuclease and the procedure was 
shown to be safe.16 However, no sustained impact on CD4 T cells was achieved. Engineered 
antigen-specific T cells have also been employed in the context of multiple myeloma.17 And CD19 
CAR T cells have been used in the context of autologous transplantation in poor-risk relapsed and 
refractory B cell non-Hodgkin lymphoma.18  
 
1.2.2. Safety of HIV-Specific T-Cells (HXTCs) Targeting gag, pol and nef 
 
A study conducted in a collaboration between Children’s National Health Systems and University 
of North Carolina (IND 15984) hypothesized that targeting gag, pol and nef simultaneously in a 
single CD4+ and CD8+ T cell product (HXTCs) would be safely tolerated in patients that have 
been on stable ART regimen with undetectable viral load based on the rationale that earlier studies 
demonstrated the safety of infusing CTLs in higher risk groups, including viremic and HIV patients 
with advanced immunosuppression. This was a Phase 1 proof of concept study (NCT02208167) 
of the administration of HXTCs to HIV-infected participants with undetectable plasma viremia 
(less than 50 copies/mL) on stable combination ART. Autologous T cells were stimulated ex vivo 
with autologous dendritic cells pulsed with a consensus Gag, Pol and Nef peptide mix to reflect 
the high sequence diversity of the HIV-1 virus. T cell expansion was performed in the presence of 
indinavir and raltegravir to inhibit HIV replication in cultures. After several rounds of stimulation 
(24–26 days), ex vivo expanded HXTCs showed a mean expansion of 146-fold  

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(range: 37–287).  Participants meeting eligibility criteria received two HXTC infusions 2 weeks 
apart. Each HXTC dose was 2x107 cells/m². Additionally, all participants underwent two 
leukapheresis procedures to measure the frequency of resting cell infection by the Quantitative 
Viral Outgrowth Assay (QVOA), at baseline and 12 weeks after the second HXTC infusion. All 
participants remained on ART throughout the study, classified by the stage of HIV infection stage 
during which treatment was initiated. Treatment during acute HIV infection was defined as starting 
ART within 30 days of the first positive HIV test identifying acute HIV infection.  
 
Six participants enrolled and completed the study protocol consisting of two HXTC infusions  
(2 × 10e7/m2/dose) 2 weeks apart, without dose-limiting toxicity. Overall, the cell infusions were 
safe and well tolerated. Two participants (HXTC-02 and HXTC-07) had transient, self-limiting 
fevers and myalgias of DAIDs toxicity grade 1 severity 1 day post-infusion (HXTC-02) and 
2 months post-infusion (HXTC-07). One participant (HXTC-07) also experienced a transient 
increase in viremia above the 40 copies/mL limit of detection 1 month following infusion, with a 
peak detectable viral load of 80 copies/mL that resolved without intervention within 60 days. No 
other treatment-related adverse events occurred. Other adverse events recorded were not 
attributable to the HXTC infusion. This included a transient increase in blood pressure with the 
leukapheresis procedure in four of six participants, an expected and well-described effect of the 
procedure, all at or below grade 3. We also determined whether the antiviral activity of CD8 T cells 
isolated from PBMCs of participants was altered following HXTC infusion using a viral inhibition 
assay (VIA). Baseline antiviral activity varied among participants and ranged from modest 
reduction of p24 production, to 50% of that seen in the absence of CD8 T cell addition, to no 
reduction. 
 
To measure the antiviral activity in an assay with potentially more clinical relevance for 
participants on ART, during which time HIV antigen exposure is likely rare and at very low levels, 
we performed latency clearance assays (LCAs). In two of the six participants, the frequency of 
latent virus infection was too low at baseline to perform this assay with the cells available. The 
participant with the most improved CD8 performance in the VIA (HXTC-02) also showed an 
improved activity of CD8 T cells in the LCA following HXTC infusion, from modest (50%) 
reduction in virus recovery with co-culture with pre-infusion CD8 T cells to complete ablation of 
virus recovery with co-culture with post-infusion CD8 T (p = 0.01 by Fisher’s exact test). 
Although a trend toward reduction was seen for the other three participants, it was not statistically 
significant due to the low number of positive wells in the control condition (three or fewer positive 
wells in control condition). The total number of wells plated was restricted due to limited cell 
availability and the large number of cells required for the assay, a known limitation of the assay, 
preventing definitive conclusions from being drawn. The week 13 post-infusion time point 
evaluated was chosen based on cell availability from the leukapheresis procedure; earlier post-
infusion time points were not assessed.14 
 
Thus harvest, expansion, and reinfusion of HXTCs from ART-treated, aviremic HIV-infected 
participants appears safe and well-tolerated. AEs were minimal and typically associated with the 
leukapheresis and the infusion of cryopreserved T-cells.  HXTC infusion did not induce clinically 
perceptible signs of immune activation perhaps due to the low HIV antigen burden expressed 
during ART. Evaluations of the virological and immunological impact of HXTC infusion in this 
study are ongoing. Hence, this study demonstrated the safety of the HIV-specific T cell product 

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alone. Further, the data suggest that HXTCs confer a measurable augmentation of HIV-specific 
immune response and provide the rationale for a study to enhance the HIV-specific T cell response 
when administered to HIV+ individuals during the period of lymphopenia following high dose 
chemotherapy and ASCT. In a series of experiments in mouse models, Dr. Brad Jones has data 
that suggest that after cytotoxic chemotherapy, infused T cells in murine models are much more 
likely to persist and expand (personal communication). The importance of the timing of T 
lymphocyte infusion relative to lymphodepleting therapies has been emphasized previously in 
other contexts.19 
 
1.2.3. Manufacturing and Preliminary Data on Ex-vivo Expanded multi HIV antigen (gag, pol 
and nef) -specific T-cells Targeting Conserved Epitopes of Gag and Pol (HST-NEETs) 
For this study, HST-NEETs will be manufactured in a process similar the one used for the HXTC 
products. Only differences are: 1) No use of the artificial K562 cells; and, 2) the unique peptide 
sequences used for gag and pol targeting conserved epitopes. The nef pepmixes are the same as 
used for the HXTC product manufacture and include a pool of 150 15meric peptides derived from 
nef polyprotein designed to cover the high sequence diversity of the HIV-1 virus. For gag and pol 
pepmixes, the peptide cocktails are enriched for conserved/protective epitopes using a bivalent 
mosaic of peptides to cover the most common escape variants. The gag and pol pepmixes comprise 
402 15meric peptides spanning the tHIVconsvX immunogen.20 tHIVconsvX is a bivalent mosaic 
of peptides (two versions of each peptide to cover common escape variants) which spans only 
conserved regions of HIV and is further selected for epitopes that are associated with protection in 
natural HIV infection. HIV-infected individuals have previously been vaccinated with this 
tHIVconsvX in a prime/boost strategy using a ChAd.HIVconsv prime and a MVA.HIVconsv boost 
(BCN01 vaccine trial - NCT01712425). 
1.3. 
NHL and Hodgkin Lymphoma in Patients with HIV Infection 
 
Non-Hodgkin lymphoma (NHL) is an AIDS-defining diagnosis for patients infected with the 
Human Immunodeficiency Virus (HIV). While the incidence of NHL has decreased amongst HIV-
infected patients since the advent of anti-retroviral therapy (ART), lymphoma remains a significant 
cause of death in this patient population.21,22,23 Most patients with AIDS-related lymphoma have 
B-cell malignancies that include common entities such as diffuse large B-cell lymphoma, Burkitt 
lymphoma and Hodgkin lymphoma as well as less common clinical entities such as primary 
effusion lymphoma, plasmablastic lymphoma and primary central nervous system lymphoma.24  
 
The prognosis for patients with AIDS-related lymphoma significantly improved in the era of ART 
therapy. Recent experience reported from the AIDS Malignancy Consortium (AMC) reports a 1-
year event free survival of 83% in diffuse large B cell lymphoma (DLBCL) treated with DA-
EPOCH-R.25  The outcome for HIV-infected patients with DLBCL is now similar to the outcome 
for patients without HIV infection.23,25  
 
While Hodgkin lymphoma is not an AIDS-defining diagnosis, the incidence of this disease is 
increased among patients with HIV infection.23  Hodgkin lymphoma occurs more frequently in 
HIV infected patients than the general population with a standardized risk ratio of 14.7 (95% CI, 
11.6-18.2) and is the third most common non-AIDS-defining malignancy in patients with HIV 

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infection.26  The survival for this group of patients also improved in the ART era.  In patients with 
advanced disease (N=34), the 2-year PFS was 87% in a recently completed AMC trial of 
brentuximab-AVD.  This is equivalent to HIV negative patients who develop Hodgkin lymphoma. 
 
1.4. 
ASCT for Patients with HIV Infection 
 
The prognosis for patients with refractory and relapsed NHL is poor with overall survival rates of 
less than 20% for patients treated with non-transplant salvage therapies.  Based upon a randomized 
trial and numerous phase II trials, high-dose therapy with ASCT has been established as the 
standard of care for patients with chemotherapy-sensitive relapsed non-Hodgkin lymphoma.27,28,29  
 
A trial published by the AMC enrolled 27 patients with either AIDS-related NHL or Hodgkin 
lymphoma in the setting of HIV infection.30  Twenty patients, including 15 with NHL and 5 
patients with Hodgkin lymphoma, subsequently underwent autologous HCT using a preparative 
regimen that consisted of dose-reduced busulfan and cyclophosphamide.  One patient died of 
regimen-related toxicity.  At a median follow-up time of 23 weeks, 10 patients were alive and free 
of disease. 
 
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0803/AMC 071 trial was 
a multicenter phase 2 study of ASCT for patients with HIV-related lymphoma (HRL) that further 
demonstrated ASCT to be a safe and effective therapy for patients with HRL who meet standard 
transplant criteria.1 Forty-three patients enrolled on this multi-institutional Phase II study, and forty 
underwent autologous transplantation after undergoing conditioning with the BEAM preparative 
regimen. Three patients had disease progression before conditioning and did not proceed to 
transplantation.  At a median follow up of 24.8 months, the 1-year and 2-year overall survival rates 
were 87.3% and 82%, respectively. This compared favorably to the 1-year overall survival of 
87.7% in a CIBMTR control cohort. The estimated risk of 1-year transplant related mortality 
(TRM) was 5.2%. The hazard ratio for TRM in the HIV-infected patient group compared to the 
CIBMTR control group was 1.05 (95% CI, 0.25-4.47; P = .9428).   
 
1.5. 
HIV Infection and Risk of Opportunistic Infection following ASCT 
 
Prior to the advent of ART, opportunistic infection was a key limitation to the use of ASCT for 
patients with HIV-related lymphoma.  In the evolving transplant experience in the era of ART, 
opportunistic infection has not proven to be a significant limitation to the use of high-dose therapy.  
In the City of Hope group, Gabarre et al and AIDS Malignancy Consortium trial, CMV reactivation 
was noted in 3, 2 and 4 patients, respectively.31,32 
 
A key finding in the transplant experience to date is that, with availability of ART, uncontrolled 
HIV infection is not a significant transplant-related complication.  Even amongst those groups in 
which ART therapy was withheld on a planned basis during the peri-transplant period, most 
patients were able to achieve suppression of HIV to undetectable levels by the end of the first post-
transplant year.31 Gabarre et al. noted marked viral suppression in evaluable patients by 2 years 
post-transplant while 82.6% of patients enrolled on CTN 0803/AMC 071 had undetectable viral 
loads by Day+365.33  
 

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CD4 reconstitution following transplant appears comparable between groups.  The City of Hope 
group, the AIDS Malignancy Consortium trial and Gabarre, et al all have noted a decrement in the 
CD4 count occurs through the 3rd transplant month, followed by a progressive rise in median CD4 
counts through the first and second post-transplant years.34 Alvarnez et al. demonstrated that the 
median CD4 counts returned to pretransplant levels by +Day 60 and remained at pretransplant 
levels through Day+365.1   
 
1.6. 
Plasma DNA Tumor Markers 
Over the past several years, several studies have demonstrated the potential for non-invasive 
“liquid biopsies” in the diagnosis and monitoring of cancer.34 Plasma cell-free DNA (cfDNA) is 
double stranded, fragmented and highly labile.35 NHL and HL patients have relatively high levels 
of tumor-derived DNA in cfDNA, referred to as ctDNA36,37 compared to very low levels (<0.5% 
variant allele frequency, VAF) in solid-organ malignancies.38 Mutations, including copy number 
abnormalities (aneuploidy), found in ctDNA in HL mirror those found in tumor biopsies.38,39,40 
Another sensitive tumor-derived marker found in ctDNA in lymphoma patients is clonal 
immunoglobulin (cIg).41 There is similar sensitivity of cIg in HIV-associated lymphomas, 
including HL. 42,43 This approach has promise to identify high risk patients with residual disease 
or to identify recurrence of disease after relapse. 
 
1.7. 
Rationale for the Current Study and Design 
The experience with high dose therapy in patients with HIV and lymphoma is very encouraging 
with regard to tumor outcomes and safety. The investigators believe that ASCT may also provide 
a platform for interventions that might impact HIV disease and provide insights into cure 
strategies. The use of HST-NEETs is one such strategy. As noted above, the autologous transplant 
setting provides an opportunity in which hematopoietic space can be created by the preparative 
regimen and the persistence and efficacy of HIV-specific T cells can be best tested. With this in 
mind, we seek to assess the effect of these T cells on the long term retroviral reservoir. In the past, 
the standard approach to assessing this reservoir was the viral outgrowth assay. The assay requires 
a very large blood draw and is labor intensive, requiring in vitro culture for 2-3 weeks. In addition, 
evidence has emerged that the assay misses a large part of the reservoir. A new assay, the intact 
proviral DNA assay (IPDA), is more sensitive and does not require a large volume blood draw or 
in vitro cultures.44 Furthermore, it does not miss cells that may harbor intact HIV proviral DNA, 
but which fail to reactivate in the viral outgrowth assay. We will use the IDPA to assess the HIV-
reservoir in this study, measured in copies of intact proviruses per million CD4 cells. The overall 
rationale for the study is that HIV-specific T cells infused before engraftment may be most likely 
to expand and persist. We note that some studies have monitored total proviral DNA45.   The IPDA 
assay as implemented here will also yield measurement of total proviral DNA.  The HST-NEETs 
may be especially efficient at targeting HIV antigens. By infusing T cells at the time when 
hematopoietic space has been created and measuring the impact on the HIV reservoir, we should 
gain insight into whether the general strategy of adoptive immunotherapy targeting HIV is worth 
pursuing. 
 

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CHAPTER 2 
 
2. 
STUDY DESIGN  
 
2.1. 
Study Overview  
 
Eligible participants will have 100-120 mL of peripheral blood collected and shipped to Children’s 
National Hospital at ambient temperature. The peripheral blood will be used to manufacture the 
HST-NEET product. The autologous peripheral blood stem cell graft suitable for rescue following 
conditioning will be obtained either before or after the collection of blood to generate HST-NEETs.  
Pre-transplant conditioning will consist of BEAM; BCNU 300 mg/m2 on Day -6, Etoposide 100 
mg/m2 BID and Ara-C 100 mg/m2 BID on Days -5, -4, -3 and -2 and Melphalan 140 mg/m2 on 
Day -1. ASCT on Day 0. If the mobilized graft contains greater than 5.0 x 106 CD34+ cells per kg, 
any additional cells should be cryopreserved as a “back-up” graft in the event of graft failure 
related to the HST-NEETs. Participants will receive one dose (2 x 107 cells/m2) of HST-NEETs 
between Days +3 to +7 based on the clinical condition of the participant (as outlined in Section 
2.6).  If this window is missed, the HST-NEETs may be administered up to Day +30 post-ASCT. 
Participants will be followed for at least one year after ASCT. 
 
2.2. 
Hypothesis and Specific Objectives 
 
2.2.1. Primary Hypothesis 
 
Following high dose chemotherapy and ASCT for participants with HIV-associated lymphoma, 
infusion of T cells targeting multiple HIV antigens (HST-NEETs) within 1 week will be feasible 
and these cells will persist and deplete the intact HIV proviral reservoir. 
2.3. 
Study Objectives  
 
2.3.1. Primary Objective 
 
The primary objective is to determine both the proportion of participants receiving ASCT who 
were able to be treated with HST-NEETs within 1 week of ASCT in a cooperative multi-
institutional setting and the efficacy of infused HST-NEETs in reducing the HIV intact proviral 
reservoir at 6 months after ASCT. 
 
2.3.2. Secondary Objectives 
 
The secondary objectives are to assess:  
1. Progression-free survival at 6 months and 1 year post-ASCT; 
2. The incidence and severity of acute infusion-related toxicities; 
3. The impact of therapy on the HIV intact proviral reservoir at 1 year post-ASCT. 
 

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2.3.3. Exploratory Objectives 
 
The exploratory objectives are to assess: 
1. CR and CR+PR rates at Day 100 post-ASCT; 
2. Overall survival at 6 months and 1 year post-ASCT; 
3. Time to hematopoietic recovery; 
4. Incidence of infections through 1 year post-ASCT; 
5. Non-relapse mortality at 6 months and 1 year post-ASCT; 
6. Toxicities through 1 year post-ASCT; 
7. Assessment of plasma DNA in blood (clonal Ig DNA) as a tumor marker at Day 100, 6 
months and 1 year post-ASCT; 
8. Impact of therapy on the HIV intact proviral reservoir at Day 100 post-ASCT; 
9. HIV RNA in plasma at Day 100, 6 months, and 1 year post-ASCT; 
10. Impact of therapy on the total proviral HIV DNA at Day 100, 6 months, and 1 year post-
ASCT; 
11. HST-NEETs persistence and expansion in vivo. 
 
2.4. 
Participant Eligibility 
 
Participants must meet specified eligibility criteria for entry into the study.   
 
2.4.1. Participant Inclusion Criteria 
 
Participants fulfilling the following criteria will be eligible for entry into this study: 
1. Age 15 years old or older at time of enrollment. 
2. Receiving antiretroviral therapies (ART) with HIV viral load < 200 copies or below the 
limit of detection by standard commercial assay. An HIV-1 RNA measuUHPHQWWKDWLV
200 copies measured by an  FDA-approved commercial assay but <500 copies may be 
allowed if this is followed by an HIV-1 RNA measurement below the limit of detection or 
if an exception is approved. 
3. Diagnosis of refractory or recurrent diffuse large B-cell lymphoma, composite lymphoma 
with greater than 50% diffuse large B-cell lymphoma, mediastinal B-cell lymphoma, 
immunoblastic, plasmablastic, Burkitt or high grade B cell lymphoma or classical Hodgkin 
lymphoma.  Participants with aggressive B-cell lymphoma that is transformed from 
follicular lymphoma are eligible for the study, pending fulfillment of other criteria. 
4. Two or three prior regimens of chemotherapy over the entire course of their disease 
treatment (induction chemotherapy and salvage chemotherapies).  Monoclonal antibody 
therapy and involved field radiation therapy will not be counted as prior therapies.   
5. All participants must have chemosensitive disease as demonstrated by at least a partial 
response (as defined by the criteria in Chapter 3) to induction or salvage therapy. 
6. Absolute Lymphocyte Count (ALC) greater than or equal to 1000/μL. 

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7. Participants with adequate organ function as measured by: 
a) Cardiac: Participants must have a left ventricular ejection fraction at rest greater 
than or equal to 40% demonstrated by MUGA or echocardiogram. 
b) Hepatic:   
i. Bilirubin less than or equal to 2.0 mg/dL (except for isolated 
hyperbilirubinemia attributed to Gilbert syndrome or antiretroviral therapy 
as specified in Appendix D) and ALT and AST less than or equal to 3x the 
upper limit of normal.    
ii. Concomitant Hepatitis: Participants with chronic hepatitis B or C may be 
enrolled on the trial providing the above criteria are met. In addition, they 
must not have evidence of active viral replication by PCR, and no clinical or 
pathologic evidence of irreversible chronic liver disease.   
c) Renal: Creatinine clearance (calculated creatinine clearance is permitted based on 
institutional practice) greater than 40 mL/min. 
d) Pulmonary DLCO (corrected for hemoglobin), FEV1, FVC greater than or equal to 
45% of predicted.  
8. Plan to treat participant with high dose chemotherapy and autologous hematopoietic stem 
cell transplantation (ASCT). 
9. Voluntary written consent or assent obtained prior to enrollment on study with the 
understanding that consent or assent may be withdrawn by the participant at any time 
without prejudice to future medical care. 
 
2.4.2. Participant Exclusion Criteria 
 
Participants with the following will be ineligible for registration onto this study: 
1. Karnofsky performance score less than 70%. 
2. Participant is known to have an HIV subtype other than B.  
3. Participant has documented raltegravir or protease inhibitor resistance. 
4. Myocardial infarction within 6 months prior to enrollment or New York Heart Association 
(NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular 
arrhythmias, or electrocardiographic evidence of acute ischemia. 
5. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with 
progression or no clinical improvement).  
6. Participant has active CNS involvement. 
7. Participants with prior malignancies except resected non-melanoma skin cancer or treated 
cervical carcinoma in situ. Cancer treated with curative intent greater than or equal to 5 
years previously will be allowed. Cancer treated with curative intent less than 5 years 

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previously may be eligible must be reviewed and approved by the Protocol Officer or 
Chairs.  
8. Female participants that are pregnant as per institutional definition or breastfeeding.   
9. Fertile men or women unwilling to use contraceptive techniques from the time of initiation 
of mobilization until six-months post-transplant. 
10. Prior autologous or allogeneic HCT, or prior therapy with chimeric antigen receptor (CAR) 
T-cells. 
11. Participants with evidence of MDS/AML or abnormal cytogenetic analysis indicative of 
MDS on the pre-transplant bone marrow examination.  Pathology report documentation 
need not be submitted. 
12. Steroids greater than 0.5 mg/kg/day prednisone equivalents. 
13. Bone marrow involvement by lymphoma at time of workup. Prior history of bone marrow 
involvement is allowed if cleared prior to ASCT. 
 
2.4.3. Eligibility for Conditioning Regimen and Transplant 
 
Participants must meet the criteria specified above prior to enrollment. Additionally, the 
participant must meet the following (eligibility) criteria for conditioning and ASCT: 
1. Procurement of an autologous peripheral stem cell graft judged adequate by institutional 
standards (recommended target is greater than or equal to 2.0 x 106 CD 34+ cells/kg) or if 
PBSC mobilization fails, cells can be obtained by bone marrow harvest per institutional 
practices (in cases where bone marrow will be used for transplantation, the required CD34+ 
dose does not apply and institutional requirements for total nucleated cell dose should 
apply). If the mobilized graft contains greater than 5.0 x 106 CD34+ cells per kg, any 
additional cells should be cryopreserved as a “back-up” graft in the event of graft failure 
related to the HST-NEETs. 
2. Within 10 days prior to conditioning regimen, participants should be assessed for adequate 
organ function, as measured by: 
a) Hepatic:  Bilirubin less than or equal to 2.0 mg/dL (except for isolated 
hyperbilirubinemia attributed to Gilbert syndrome or antiretroviral therapy as 
specified in Appendix D) and ALT and AST less than or equal to 3x the upper limit 
of normal.    
b) Renal: Creatinine clearance (calculated creatinine clearance is permitted based on 
institutional practice) greater than 40 mL/min. 
2.5. 
Treatment Plan  
 
Once enrolled, the Cellular Therapy Laboratory (CTL) at Children’s National Hospital (CNH) 
should be contacted by the site at CTL@childrensnational.org at least 2 weeks priors to collection 
to confirm a date for shipping. The site will collect 100-120 mL of peripheral blood to be shipped 
at ambient temperature to the manufacturing center and used to generate the HST-NEET product. 
This collection will need to occur at least 6 weeks prior to ASCT due to the time required to 

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manufacture the HST-NEETs. Should the initial production of the HST-NEETs product be 
unsuccessful, the BMT CTN Data Coordinating Center (DCC) staff and clinical site study team 
will be notified and a second blood draw and manufacturing attempt may occur pending feasibility. 
Details on shipping will be provided in the Appendix C. However, treatment with high dose 
chemotherapy and autologous peripheral blood stem cell transplantation should NOT be delayed 
for the sole purpose that the patient participate on this trial.  
 
The immediate pre-ASCT evaluation will be carried out according to the operating procedures of 
the participating institutions and should be in keeping with the data reporting requirements of this 
study. All participants enrolled on this protocol will be hospitalized in accordance with the 
procedures for recipients of ASCT as defined by the treating institutions. Table 2.5 below describes 
the conditioning regimen (BEAM) for this study. Transplant day is referred to as Day 0. Treatment 
plan activities prior to or after Day 0 are denoted as Day minus or Day plus, respectively.  
 
TABLE 2.5: BEAM + HCT REGIMEN* 
 
Day 
 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+3-+7 
BCNU 
300 
mg/m2 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Melphalan 
140 mg/m2 
HCT 
HST-
NEETs 
2x107 
cells 
(single 
dose) 
*Conditioning Regimen Administration Schedule: The conditioning regimen 
administration schedule may be modified ± 1 day according to institutional practice.  Day 
0 will be the day of HCT. 
 
1. Carmustine (BCNU):  300 mg/m2 on Day –6, to be administered intravenously per 
institutional guidelines. 
2. Cytarabine (Ara-C):  100 mg/m2 BID on Days –5 through –2, for a total of 8 doses, to be 
administered intravenously per institutional guidelines. 
3. Etoposide (VP-16): 100 mg/m2 BID on Days –5 through –2, for a total of 8 doses, to be 
administered intravenously per institutional guidelines. 
4. Melphalan: 140 mg/m2 on Day -1, to be administered intravenously per institutional 
guidelines. 
5. Autologous graft: Hematopoietic progenitor cells will be cryopreserved according to the 
institutional standards and administered post thaw on Day 0.  If the mobilized graft contains 
greater than 5.0 x 106 CD34+ cells per kg, any additional cells will be cryopreserved as a  
“back-up” graft in the event of graft failure related to the HST-NEETs. 

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6. HST-NEETs: One dose (2 x 107 cells/m2) should be given between Days+3 to +7, or at 
the earliest time participant is deemed able to receive the cells based on clinical assessment 
of the participant as described in Section 2.6.1. 
   
2.6. 
HST-NEETs – Eligibility, Dosage, and Administration  
 
2.6.1. Eligibility to Receive HST-NEETs 
 
HST-NEETs should be administered between Day +3 and Day +7 post-ASCT. Prior to 
administration, the site investigator should evaluate the participant’s condition to receive the 
infusion. The following criteria must be met at the time of infusion: 
x No active or uncontrolled infections 
x Participant must be hemodynamically stable 
If HST-NEET infusion is not feasible between Day +3 and Day +7, the participant may be  
re-assessed and the infusion occur through Day +30 post-ASCT. 
2.6.2. HST-NEETs Dosage 
 
Participants will receive 2x107/m2 cells as a single intravenous (IV) infusion.  The cells will be 
cryopreserved ideally at 1x107 T cells per mL but up to 5x107 cells/mL. 
 
2.6.3. HST-NEETs Administration 
 
HST-NEETs will be manufactured from peripheral blood, stored and maintained in the Children’s 
National Hospital (CNH) Cellular Therapy Laboratory (CTL) until shipment to the enrolling 
institution. The cryopreserved product will be shipped to the study site from Children’s National 
Hospital in a Liquid Nitrogen Dry Shipper via overnight shipping to arrive by Day -7.  Prior to 
releasing the HST-NEETs to the site, the manufactured product will undergo viability testing, 
endotoxin testing, sterility testing (aerobic, anerobic and fungal), mycoplasma testing, 
phenotyping, alloreactivity testing and HLA typing. In the case of HLA typing, the HLA typing 
of the final drug product will be compared to the HLA typing of the participant to ensure the correct 
identity of the drug product.  On day of infusion the study site will then thaw the cryovial(s) 
containing the product, transfer to a sterile syringe, and administer to the participant. The 
cryovial(s) will be cultured locally to assess product sterility at time of administration.  Specific 
instructions will be provided to all study sites regarding the procedure for thawing and 
administration of the product. In summary, the following should occur: 
 
x The HST-NEETs product will be reviewed prior to administration by two licensed health 
care providers per institutional standards.  This review should confirm that the identity of 
the cryovial/syringe matches the prescription for infusion, as well as a visual inspection of 
the cryovial/syringe. 
x The participant will receive Diphenhydramine (Benadryl®) and Acetaminophen 
(Tylenol®) as pre-medications or equivalent per institutional guidelines prior to HST-

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NEET infusion. Steroids should be avoided given their detrimental effect on the survival 
of the infused virus specific T cells 
x Cell Administration: HST-NEETs will be given by intravenous infusion over 1-10 minutes 
through a peripheral or central line. 
x The infusion will be given under supervision by a transplant physician. The participant will 
be monitored according to below:   
o Participants should remain on continuous pulse oximetry for at least 30 minutes 
post-infusion. 
o Vital signs should be monitored pre-infusion, at the end of infusion and at 30 and 
60 minutes post infusion.  
o Acute toxicities should be reported up to 24 hours after infusion. For outpatients, 
this may be accomplished by self-report or report from a caregiver. 
x Participants will receive supportive care for acute toxicity directly attributable to HST-
NEETs as appropriate (See Appendix E). Steroids, though contraindicated, can be 
administered if there are life-threatening anaphylactic reactions (See Appendix E).  ͒ 
2.6.4. Duration 
 
Participants will be followed for 1 year post ASCT. A time period of 28 days from infusion of 
HST-NEETs will constitute the time for clinical safety monitoring specific to HST-NEETs. 
 
2.7. 
Supportive Care 
 
All supportive care will be given in keeping with local institutional guidelines. 
 
2.7.1 Corticosteroids 
As steroids will have a detrimental effect on the survival of the infused virus specific T cells they 
should be avoided if possible, for the first 6 weeks following infusion. If the subject has a clinical 
indication for steroid use such as CRS or engraftment syndrome steroids may be administered at 
1-2mg/kg/day and then weaned/discontinued as soon as possible.  
 
2.7.1. Growth Factors 
 
All participants will receive G-CSF 5-10 mcg/kg/day or per institutional guidelines, beginning no 
sooner than 24 hours following the infusion of HST-NEETs or no later than Day +7 post-transplant 
in participants not receiving HST-NEETs and continuing until an ANC greater than or equal to 
500/mm3 is obtained for 2 consecutive days.   
 
2.7.2. Blood Products 
 
Transfusion thresholds for blood product support will be consistent with standard institutional 
guidelines. All blood products will be irradiated. 
 

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2.7.3. Prophylaxis Against Infections  
 
All participants will receive prophylaxis against bacterial, fungal and viral infections during the 
post-ASCT period according to institutional guidelines. Additional guidelines for HIV participants 
in this study are summarized in Appendix D.  
 
2.7.4. Post-HCT Lymphoma Therapy 
 
Consolidative localized radiation therapy (maximum 3 sites) is allowed to areas of previous bulk 
disease (greater than 5 cm).  Localized radiation should be completed by Day 100 post-ASCT.  No 
other anti-lymphoma therapy is allowed in the post-transplant setting or the participant will be 
considered to have progressed.   
 
2.7.5. Anti-Retroviral Therapy (ART) 
 
Anti-retroviral (ART) therapy is only effective when administered in combination and with 
consistency.  Single agent therapy or repeated interruptions in therapy lead to resistance.  The ART 
guidelines below are designed to minimize the possibility of drug interactions with high dose 
chemotherapy and to administer ART only when it is anticipated that the ART regimen can be 
consistently complied with (i.e., preparative regimen toxicities such as nausea and mucositis will 
not interfere with dosing schedules). A few ARTs require special mention as discussed below. 
 
Zidovudine (AZT): 
AZT is myelosuppressive and should not be used in the ART regimen administered after ASCT. 
 
Efavirenz: 
Efavirenz has a long half-life and resistance develops especially rapidly when it is administered in 
the absence of other ARTs. When an efavirenz containing regimen is stopped, levels of other ARTs 
will fall much more rapidly than those of efavirenz resulting in the functional equivalent of single 
agent therapy and risking resistance. In order to avoid this risk, ideally at least 4 weeks prior to 
autologous transplant the participant should be switched to a different triple drug regimen without 
efavirenz.  Approximately 2 to 3 months post ASCT the participant can revert to previous regimen 
if wished. 
 
Protease inhibitor based regimen, or a regimen boosted with either ritonavir or cobicistat: 
Protease inhibitor based regimen, or a regimen boosted with either ritonavir or cobicistat contain 
ARTs that have a strong potential to inhibit CYP3A4.  These regimens would inhibit a route of 
elimination and may cause the substrate drug (e.g., VP-16) to increase to a potentially supra-
therapeutic or toxic level, resulting in the need to decrease the dose of the substrate. Since the pre-
treatment conditioning regimen should not be dose-adjusted, in order to avoid this risk, ideally at 
least 2 weeks prior to autologous transplant the participant should be switched to a different triple 
drug regimen.  Approximately 2 to 3 months post ASCT the participant can revert to previous 
regimen if wished. 
 

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Patients on established antiretroviral regimens: 
1) If patient is on AZT containing regimen, efavirenz containing regimen, a protease inhibitor 
based regimen, or a regimen boosted with either ritonavir or cobicistat, change ART to an 
alternative medicine (such as an integrase inhibitor) prior to starting conditioning.  
2) In the rare cases of chemotherapy induced mucositis where no oral medications can be 
taken, then ART should be discontinued.  In this case, weekly HIV RNA levels should be 
checked to monitor for HIV breakthrough. 
3) Resume an ART regimen as soon as participant can tolerate the total ART regimen as 
mucositis has improved sufficiently to resume PO.   
 
2.8. 
Participant Risks 
 
2.8.1. Therapy Toxicities 
 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. Please refer to www.fda.gov for full adverse event information regarding 
the commercially available conditioning regimen agents listed below.   
 
2.8.2. Carmustine (BCNU) 
 
Carmustine is an alkylating agent.   
Carmustine side effects include: 
x Cardiovascular: tachycardia, chest pain 
x Cutaneous: alopecia, rash, skin burning/swelling/erythema 
x Gastrointestinal: nausea, vomiting, diarrhea, anorexia, constipation, abdominal pain, GI 
bleeding 
x Hematologic: leukopenia, thrombocytopenia, anemia, bleeding 
x Hepatic: hepatotoxicity 
x Neurologic: seizure, encephalopathy, headache, aphagia, depression, stroke, fluid leakage 
from brain/spinal cord, intracranial hemorrhage 
x Renal: renal toxicity 
x Respiratory: pneumonitis, interstitial lung disease, pulmonary fibrosis 
x Miscellaneous: lethargy, infection, infusion reaction, allergic reaction including 
anaphylaxis, secondary malignancy 
2.8.3. VP-16 (Etoposide) 
 
VP-16 is a semi-synthetic podophyllotoxin derivative.   Etoposide side effects include:  
x Cardiovascular: hypotension 
x Cutaneous: alopecia, rash, itching, Stevens-Johnson Syndrome  
x Gastrointestinal: nausea, vomiting, diarrhea, anorexia, abdominal pain, mucositis, 
difficulty swallowing 

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x General: lethargy 
x Hematologic: leukopenia, thrombocytopenia, anemia 
x Hepatic: Hepatotoxicity 
x Neurologic: seizure, peripheral neuropathy 
x Miscellaneous: infection, cortical blindness, optic neuritis, infusion reaction, allergic 
reaction including anaphylaxis, secondary malignancy 
2.8.4. Cytarabine (Ara-C) 
 
Cytarabine, commonly known as Ara-C, is a synthetic nucleoside.  Cytarabine side effects include:  
x Cardiac and vascular: thrombophlebitis, pericarditis, chest pain 
x Cutaneous: photosensitivity, rash, itching, alopecia 
x Gastrointestinal: nausea, vomiting, diarrhea, anorexia, ulcers, mucositis, rectal swelling, 
abdominal pain  
x Hematologic: anemia, thrombocytopenia, leukopenia 
x Hepatic: hepatotoxicity 
x Neurologic: peripheral neuropathy (motor and sensory), dizziness, headache, Posterior 
Reversible Encephalopathy Syndrome (PRES), somnolence/drowsiness, personality 
changes, coma 
x Pulmonary: interstitial pneumonitis 
x Miscellaneous: back pain, conjunctivitis, infection, myalgia/myopathy, allergic reaction 
including anaphylaxis 
2.8.5. Melphalan 
 
Melphalan, an alkylating agent, is a phenylalanine derivative of nitrogen mustard.  Melphalan side 
effects include: 
x Cardiac and vascular: edema, heart failure, vasculitis 
x Gastrointestinal: mucositis, nausea, vomiting, diarrhea  
x General: fatigue 
x Hematologic: anemia, thrombocytopenia, neutropenia 
x Hepatic: abnormal liver function tests, hepatitis 
x Pulmonary: shortness of breath, pulmonary fibrosis 
x Renal: renal impairment  
x Miscellaneous: allergic reaction including anaphylaxis, secondary malignancy 
2.8.6. ASCT  
 
ASCT recipients incur risks from high-dose conditioning and post-ASCT therapy, which must be 
weighed against the risk of the disease for which the ASCT is prescribed.  Major risks following 
transplantation include: 1) Infection which can be bacterial, viral, parasitic, or fungal.  Often, these 
infections are life-threatening, particularly when caused by viral or fungal agents, and are 
associated with high mortality in the transplant population.  The recent published experience shows 

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no increased risk of CMV viremia in HIV+ patients, and no increase in mortality related to that 
virus; 2) Damage of all or any of the major organs may occur as a result of reactions to drugs  
(e.g., chemotherapy, antibiotics, anti-fungal medications), and as a result of destructive processes 
(e.g., infection), and may have a fatal outcome; brain damage can result in severe loss of cognitive 
or neurologic function; 3) Relapse or progression of lymphoma may occur, especially in 
participants with advanced disease status at time of treatment; 4) Unknown toxicities may occur 
in any individual participant due to multiple events and cumulative effects which may involve any 
and all organs, including the brain; and, 5) Death. 
 
2.8.7. HST-NEETs 
 
The experience with T cell recipients as reported in the literature suggests that serious reactions to 
virus –specific T cell therapy are rare. Possible side effects of virus specific T cell therapy in 
participants with virus-associated malignancies and HIV include fever and flu-like symptoms. In 
the case of participants with EBV+ lymphoma, these symptoms, along with swelling of tumor 
sites, have occurred primarily in participants who have bulky disease due to lymphoma following 
infusion of T cells or in participants receiving genetically-enhanced T-cells. Six participants 
enrolled and completed a study protocol consisting of two HIV-specific T cells (HXTC) infusions 
(2 × 10e7/m2/dose) 2 weeks apart, without dose-limiting toxicity (NCT02208167).14 Overall, the 
cell infusions were safe and well tolerated. Two participants (HXTC-02 and HXTC-07) had 
transient, self-limiting fevers and myalgia of DAIDs toxicity grade 1 severity 1 day post-infusion 
(HXTC-02) and 2 months post-infusion (HXTC-07). One participant (HXTC-07) also experienced 
a transient increase in viremia above the 40 copies/mL limit of detection 1 month following 
infusion, with a peak detectable viral load of 80 copies/mL that resolved without intervention 
within 60 days. No other treatment-related adverse events occurred. Other adverse events recorded 
were not attributable to the HXTC infusion. This included a transient increase in blood pressure 
with the leukapheresis procedure in four of six participants, an expected and well-described effect 
of the procedure, all at or below grade 3. We also determined whether the antiviral activity of CD8 
T cells isolated from PBMCs of participants was altered following HXTC infusion using a viral 
inhibition assay (VIA). Baseline antiviral activity varied among participants and ranged from 
modest reduction of p24 production, to 50% of that seen in the absence of CD8 T cell addition, to 
no reduction. 
 
The HST-NEETs product in this study does not include genetically-enhanced T-cells. As the HST-
NEETs product is an autologous product, there should not be a risk of graft-versus-host disease 
(GVHD). The HST-NEETs product will undergo release testing for microbial contaminants. 
However, it is possible that undetected infectious agents could be administered with the HST-
NEETs and cause fever, chills, hypotension, sepsis, or death. Since this is an autologous product, 
it is unlikely that novel infectious agents will be transferred to participants. None of these adverse 
events (AEs) have been observed in studies of T cell therapy to date including our experience with 
the HXTC product (IND15984) which uses the exact same manufacturing SOP with the only 
difference being the gag and pol pepmixes used to pulse the antigen presenting cells ex vivo.  
The planned HST-NEETs infusion is an immunotherapeutic product using HIV-infected 
participants’ biological materials. Thus, this product will be handled as if infectious agents are 
present.  

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2.9.
Investigational Product Supply
HST-NEETs product will be generated from 100-120 mL of recipient peripheral blood. These 
whole blood samples will be shipped in ambient temperature to the Cellular Therapy Laboratory 
at Children’s National Hospital with shipping details provided in Appendix C.  The HST-NEETs
cell product is cryopreserved and shipped to the transplant centers for administration. 
An overview of the Manufacturing Logistics is provided below.
Carmustine, etoposide, cytarabine and melphalan are commercially available agents and will not 
be provided by the study. Please administer commercially available medications per institutional 
standards, as described in Section 2.5, and store per package insert instructions
2.10.
Study Conduct
This study will be conducted in accordance with the protocol, the BMT CTN MOP, and the 
following:
x
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki
x
Applicable ICH Good Clinical Practice (GCP) Guidelines
x
Applicable laws and regulations
The National Marrow Donor Program (NMDP) single Institutional Review Board (IRB) of Record 
will oversee this study and conduct the study-specific reviews as required by federal regulations 
and per the NMDP IRB Standard Operating Procedures (SOPs).
Enrollment
•After the participant is 
deemed eligible and is 
enrolled on the study, 
the center will contact 
the GMP Facility 
(Cellular Therapy 
Laboratory (CTL) at 
Children's National 
Hospital (CNH)) at 
least 2 weeks prior to 
collection of blood for 
HST-NEETs 
Generation.
•Day -42 (42 days prior 
to transplant) or 
earlier if possible, 100-
120mL blood will be 
collected and shipped 
at ambient 
temperature to the 
GMP Facility.
Manufacturing
•Day -41 to 
approximately Day -
13 The CTL will 
generate the HST-
NEET product and 
undertake QC 
testing and inform 
the center when QA 
has released the 
product. This is 
anticipated to be at 
Day +1.
•If manufacture is 
not successful, the 
referring center will 
be notified by Day -
13 and will decide if 
they wish to 
attempt again or 
proceed to 
transplant without 
HST-NEET cells.
Infusion
•Day +3 to +7 post-
transplant, the cells 
will be infused.
•If it is not feasible to 
infuse during this 
time frame, infusion 
is allowed up to Day 
+30 post transplant.

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Site personnel will enter data in the electronic case report form (eCRF) in Advantage eClinical® 
as described in the BMT CTN 1903 Forms Guide. Source documentation should be made available 
for monitoring visits, audits and regulatory inspections as described in the BMT CTN MOP.  
Participating Principal Investigators (PIs) bear ultimate responsibility for training of site staff as 
well as the scientific, technical, and administrative aspects of conduct of the protocol, even when 
certain tasks have been delegated to coinvestigators, sub-investigators, or staff.  The PIs have a 
responsibility to protect the rights and welfare of participants and comply with all requirements 
regarding the clinical obligations and all other pertinent requirements in 21 CFR part 312. In 
addition to following applicable federal, state, and local regulations, investigators are expected to 
follow ethical principles and standards and receive training in GCP every three years and human 
subjects training within the past 3 years and thereafter as per institutional requirements. 

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CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS 
 
3.1. 
Definition of Disease Status 
 
Tests used for evaluation of disease status include physical examination, laboratory testing, bone 
marrow biopsy and aspirate, PET scans, and CT scans of neck, chest, abdomen and pelvis as 
indicated.   
 
Imaging will be assessed at baseline prior to transplant and prospectively. The Lugano 
Classification46 will be used to assess response after baseline in comparison to the baseline 
imaging. As outlined in Appendix B, lymphoma response is defined as any participant who does 
not progress on this study, including participants with active disease who achieve Complete 
Metabolic Response (CMR)/Complete Radiologic Response (CR), Partial Metabolic Response 
(PMR)/ Partial Remission (PR), or No Metabolic Response(NMR)/Stable Disease (SD) by 
PET/CT. Because the natural history of these high risk relapsed and refractory participants is 
progression (and often mortality), any response or even stable disease is an improvement over 
expected outcomes. 
 
CT responses will be based on anatomical measurements of target/evaluable/new lesions. 
 
The possible response outcomes are complete radiologic response (CR), partial remission (PR), 
stable disease (SD) or progressive disease (PD) as defined in Appendix B. 
 
3.2. 
Primary Endpoints 
 
3.2.1. Feasibility 
 
Feasibility is defined as a participant receiving HST-NEETs within 1 week post-ASCT. All 
eligible and enrolled participants will be considered part of the feasibility assessment.  
3.2.2. Efficacy 
 
Efficacy will be measured by the reduction in intact proviral reservoir.  This will be evaluated 
using the change in intact proviral DNA assay (IPDA) at enrollment through 6 months post-ASCT 
among participants with samples at both timepoints.  
3.3. 
Secondary Endpoints  
 
3.3.1. Progression-Free Survival 
 
Participants are considered a failure for this endpoint if they die or if they relapse/progress or 
receive anti-lymphoma therapy, other than post-transplant consolidative localized radiation 
(maximum 3 sites) to sites of prior bulk disease pre-transplant (greater than 3cm).  The time to this 
event is the time from transplant until death, relapse/progression, receipt of anti-lymphoma 

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therapy, or last follow up, whichever comes first. This will be assessed at 6 months and 1 year 
post-ASCT. 
 
3.3.2. Acute Infusion Related Toxicity 
 
Acute infusion related toxicities are defined as toxicities related to the infusion of HST-NEETs that 
occur within 24 hours of the infusion. Toxicities will be graded per CTCAE criteria v5.0. 
 
3.3.3. Intact Proviral Reservoir 
 
Impact on intact proviral reservoir will be assessed using the IPDA at 4-8 weeks prior to transplant 
and 12 months following ASCT. 
 
3.4. 
 Exploratory Objectives 
 
3.4.1. CR and CR+PR Rate at Day 100 Post-ASCT 
 
CR or PR will be assessed according to the LYRIC criteria at Day 100 post-ASCT (see Appendix 
B). 
 
3.4.2. Overall Survival  
 
Overall survival is defined as death from any cause within 6 months and within 1 year post-ASCT. 
Surviving participants will be censored at the date of last follow-up. 
 
3.4.3. Time to Hematopoietic Recovery 
 
Time to neutrophil recovery will be the first of three consecutive labs of greater than or equal to 
QHXWURSKLOVȝ/IROORZLQJWKHH[SHFWHGQDGLU7LPHWRSODWHOHWHQJUDIWment will be the date 
platelet count is greater than or equal to ȝ/IRUWKHILUVWRIthree consecutive labs with no 
platelet transfusions 7 days prior. 
 
3.4.4. Incidence of Infections  
 
The incidence of viral, fungal and bacterial infections will be tabulated. All Grade 2 and Grade 3 
infections will be reported according to the BMT CTN Technical MOP from Day 0 up to 1 year 
post-transplant. Infections of interest will be captured and described. The incidence rate of 
infections is defined by the number of infections divided by the total person-time accumulated 
over the duration of the study. 
 
3.4.5. Non-Relapse Mortality 
 
Non-Relapse Mortality (NRM) is defined as death occurring in a participant without relapse 
progression and will be measured at 6 months and at 1 year.  
 

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3.4.6. Toxicities 
 
Toxicities related to the BEAM conditioning regimen and HST-NEETs infusion beyond the 24 
hour acute toxicity monitoring period will be defined by using the version 5.0 CTCAE criteria. All 
grades of toxicity related to HST-NEETs will be collected.  Only grade 3 or higher conditioning 
regimen related toxicities will be collected. 
 
3.4.7. Ig DNA in Blood 
 
Blood specimens will be collected prior to the initiation of conditioning, and at Days 100, 6 months 
and 1 year post-ASCT. The presence of clonal Ig DNA in plasma will be assessed at each of these 
time points. 
 
3.4.8. Intact Proviral Reservoir at Day 100 
Impact on intact proviral reservoir assessed using the IPDA Day 100 post-ASCT as compared to 
baseline at 4-8 weeks prior to transplant. 
 
3.4.9. HIV RNA in Blood 
 
HIV RNA in plasma will be measured by a sensitive investigational single copy assay (SCA, 
detection limit 0.38 copy/ml). Blood specimens will be collected, and plasma HIV RNA measured, 
at study visits corresponding to those associated with IPDA testing: 4-8 weeks prior to transplant, 
and at Days 100, 6 months and 1 year post-ASCT.  
 
3.4.10. Total Proviral HIV DNA 
 
This assay will be measured at study visits corresponding to those associated with IPDA testing: 
4-8 weeks prior to transplant, and at Days 100, 6 months and 1 year post-ASCT.  This assay will 
provide information about the proviral reservoir in patients where the IPDA fails due to sequence 
variation. 
 
3.4.11. HST-NEETs Persistence and Expansion in Vivo 
 
Persistence of HST-NEETs will be measured by frequency of HIV-1 antigen-specific (gag, pol, 
nef) CD8+ T-cells by ELIspot at baseline and post-infusion at timepoints at Days 100, 6 months, 
and 1 year post transplant.  Change in T cell responses from baseline to post-infusion, measured 
by frequency of cells secreting IFN-ȖE\PXOWLPHUDQDO\VLVDQGRULQWUDFHOOXODUF\WRNLQHVWDLQLQJ
and/or ELIspot and/or TCR sequencing will be done depending on PBMC cell numbers available 
and reagent availability.  
 

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CHAPTER 4 
 
 
4. 
PARTICIPANT ENROLLMENT AND EVALUATION 
 
4.1. 
Enrollment Procedures 
 
4.1.1. Screening and Eligibility Procedures 
Prior to collection of peripheral blood needed to manufacture HST-NEETs, the transplant center 
will confirm participant eligibility as per section 2.4.  Once confirmed, participants will be 
registered using the BMT CTN Electronic Data Capture System (Advantage eClinical®).  An 
authorized user at the transplant center completes initial screening by entering participant 
demographics and Segment 0 Enrollment Form in Advantage eClinical®.  The eligibility screening 
includes questions that will verify eligibility. If the participant is eligible, a participant study 
number will be generated. The participant will be consented to the conditioning regimen and ASCT 
per institutional standards. 
 
4.2. 
Collection of Study Product Components  
 
4.2.1. Collection of peripheral Blood  
 
Once enrolled, the Cellular Therapy Laboratory at Children’s National Hospital will be notified 
by the site at CTL@childrensnational.org at least 2 weeks priors to collection to confirm a date for 
shipping. HST-NEETs product will be generated from 100-120 mL of recipient peripheral blood.  
This collection will need to occur at least 6 weeks prior to ASCT due to the time required to 
manufacture the HST-NEETs. Additionally, it should occur before the participant starts G-CSF or 
at least 1 week after their last dose of G-CSF.  The participant’s Absolute Lymphocyte Count 
should be 1000/μL prior to blood draw.  Should the initial production of HST-NEETs product be 
unsuccessful, the BMT CTN DCC and clinical study team will be contacted and have the 
opportunity to re-initiate the HST-NEETs cell line. These whole blood samples will be shipped in 
ambient temperature to the Cellular Therapy Laboratory at Children’s National Hospital as 
described in the Appendix C.  
 
4.3. 
Study Monitoring 
 
4.3.1. Follow-Up Schedule 
 
The follow-up schedule for scheduled study visits is outlined in Table 4.3.1.  A detailed description 
of each of the forms and the procedures required for forms completion and submission can be 
found in the BMT CTN 1903 eCRF Completion Guide.  This guide is available on the homepage 
of the Internet data entry system. 
 
Follow-up Visits: Follow-up visits will begin as soon as participants are enrolled onto the study.  
The follow-up period is 1 year post ASCT. 
 

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TABLE 4.3.1:  FOLLOW-UP SCHEDULE  
 
Study Visit 
Target Day  
(Day 0 is ASCT) 
Baseline 
6 weeks prior to transplant 
Pre-Conditioning 
Within 1 week prior to conditioning* 
Transplant 
Day 0 
HST-NEETs Infusion 
Day +3 to +7   
Week 2 
Day 14 + 3 days 
Week 3  
Day 21 + 3 days 
Week 4  
Day 28 + 3 days 
Week 5  
Day 35 + 3 days 
Week 8 ** 
Day 56 + 3 days** 
Day 100  
Day 100 + 14 days 
Month 6  
Day 180 + 28 days 
Month 12  
Day 365 + 28 days 
*Can occur locally, does not require a transplant center visit. 
**This study visit is only required for participants receiving HST-NEETs outside of the +3 to 
+7 day window. 
 
4.4. 
Participant Assessments 
 
Table 4.4 summarizes participant clinical assessments over the course of the study. 
 
4.4.1. Evaluations Prior to Enrollment to Assess Eligibility 
 
The following observation need to be performed within 3 months of enrollment: 
1. Hepatitis panel (HBsAb, HBsAg, HBcAb, HCV Ab).  If the Hep B core Ab are positive, 
HepB DNA PCR; if HepC serology is positive, then DNA PCR or NAT Testing. 
2. Baseline EKG 
3. Baseline metabolic panel: Creatinine clearance (calculated creatinine clearance is 
permitted per institutional guidelines). 
4. Baseline Pulmonary Function Tests: DLCO, FEV1 and FVC. 
5. Bone marrow biopsy for pathology is not required, but if performed per institutional 
standards, results should be submitted.  
6. Serum HIV RNA, CD4 Count. 
7. Baseline ECHO: Ejection fraction 

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8. Diagnostic lymphoma pathology specimens (paraffin blocks or 10 unstained slides cut at 
5 um thickness and placed on charged glass slides) sent to the Ambinder Laboratory 
within 3 weeks of ASCT, if specimens are available (See Appendix C).   
 
The following observations need to be performed within 1 month of enrollment: 
1. History, physical examination, height and weight, body surface area, neurologic 
examination, measurement of all palpable peripheral lymph nodes and measurement of 
other sites of disease present on physical. 
a. Lumbar puncture(s) for determination of presence of CNS disease for non-Hodgkin’s 
lymphoma participants only, is not required, but if performed per institutional standards, 
results should be submitted. 
b. Duration of AIDS diagnosis, history of prior opportunistic illnesses. 
c. Presence or absence of “B” symptoms (unexplained fevers, night sweats, involuntary 
weight loss greater than 10% normal body weight). 
d. Medication list to include all antiviral, antibiotics and opportunistic prophylaxis.  
2. Pregnancy test for females of childbearing potential, per institutional standards. 
3. Karnofsky performance status. 
4. CBC with differential, platelet count, creatinine, bilirubin, LDH, ALT, AST. 
5. PET-CT or CT: PET-CT or CT scans of neck, chest, abdomen and pelvis.  Neck CT only 
required if previous site of disease. 
The following samples should be collected after enrollment and within 6 weeks of initiation 
of conditioning at the transplant center: 
1. Blood draw for the following study-specific procedures: (see Appendix C) 
a. HST-NEETs Manufacturing. 
b. IPDA (including total HIV proviral DNA). 
c. Single-Copy HIV RNA Assay. 
d. IDM (unless performed by the site within 30 days; see Appendix C) 
e. HLA (unless results available from any prior testing; see Appendix C) 
2. CBC with differential, platelet count, creatinine, bilirubin, LDH, ALT, AST. This should 
be collected at the same time as the IPDA.  
The following samples should be collected no more than 1 week prior to initiation of 
conditioning: 
1. Chemistry panel with creatinine, bilirubin, ALT, AST. 
2. Plasma DNA (Ig DNA) collected within one week prior to initiation of conditioning. (See 
Appendix C). Must be performed at transplant center.  
 

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4.4.2. Post-ASCT Evaluations 
1. CBC at least twice a week from Day 0 until ANC greater than 500/mm3 for 3 days after 
nadir reached.  Thereafter CBC at least once per week until Day 28 (or 4 weeks), then at 
Day 100, 180 and 365 post-ASCT. CBCs collected at Day 100, 180 and 365 should be 
drawn at the same time as blood draws for the IPDA. 
2. Toxicity assessments at Day 0, 28, 35, 56 (if HST-NEETs cells were received outside the 
Day 3 to 7 window), 100, 180 and 365 post-ASCT. 
3. Disease restaging: 
a. If institutional standard is to perform PET-CT, patient should receive PET-CT at Day 
100 post-ASCT.  If equivocal results, repeat PET-CT at Day 180. 
b. If institutional standard is to perform CT scan, patient should receive CT scan at Day 
100, 180 and 365 post-ASCT.  
4. Study-specific blood draw: (see Appendix C) 
a. IPDA (including total HIV proviral DNA) at Day 100, 180 and 365 post-ASCT. 
b. Single-Copy HIV RNA Assay at Day 100, 180 and 365 post-ASCT 
c. Plasma DNA (Ig DNA) assessments at Day 100, 180 and 365 post-ASCT.  
5. HIV viral copy number, at Day 100, 180 and 365 post-ASCT by standard clinical assay.    

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Table 4.4: Study Evaluations 
 
 
ASCT 
Post-ASCT 
Study Assessments Testing 
Pre-
Enrollment 
6 weeks 
before 
conditioning 
Pre- 
Conditioning 
Day 0 
Day  
3 to 
7 
Day 
14 
Day 
21 
Day 
28 
Day 
35 
Day 
561 
Day 
100 
Day 
180 
Day 
365 
History and Physical Exam2 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Score 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
CBC3and Chemistries4 
X 
X 
X 
X 
X4 
X4 
X4 
X4 
 
 
X 
X 
X 
Hepatitis Panel (HBsAb HBsAg, 
HBcAb, HCV Ab) 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT or PET-CT 
X6 
 
X6 
 
 
 
 
 
 
 
X 
X 
X 
DLCO, FEV1, FVC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine Clearance7 
X  
 
X 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy for pathology8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV RNA, CD4 Count 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Serology Testing 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Ejection Fraction 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic Lymphoma pathology11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma DNA Tumor Monitoring 
(Ig) 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Blood Collection for HST-NEETs 
Manufacturing12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
IPDA3,13 & HST-NEETs persistence 
and expansion 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Single-Copy HIV-1 RNA Assay14 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
HST-NEETs Administration 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Toxicity Assessment15 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
HIV Titer by standard assay 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 

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Footnotes for Table 4.4: 
 
1 This study visit is only required for participants receiving HST-NEETs outside of the Day +3 to Day +7 window. 
2To include: 
a. Lumbar puncture(s) for determination of presence of CNS disease for non-Hodgkin's lymphoma participants only. 
b. Duration of AIDS diagnosis, history of prior opportunistic illnesses. 
c. Presence or absence of “B”- symptoms (unexplained fevers, night sweats, involuntary weight loss greater than 10% normal body weight). 
d. Medication list to include all antiviral, antibiotics and opportunistic prophylaxis. 
This includes Height and Weight, body surface area, neurologic examination, careful measurement of all palpable peripheral lymph nodes and measurement of 
other sites of disease present on physical. 
3It is critical that a clinical CBC be collected at the same time as IPDA research sample, as indicated in the table above. 
4CBC with differential, Platelet Count, Creatinine, Bilirubin, Alkaline Phosphatase, AST, ALT, LDH. To be performed at least twice weekly from Day 0 until 
ANC greater than 500/mm3 for 3 days after nadir reached. Thereafter, once weekly until Day 28 (or 4 weeks), then at Day 100, 180 and 365 post-ASCT. 
5If the Hep B Core AB is positive then HepB DNA PCR; if Hep C serology is positive, HCV PCR, or NAT Testing, per institutional standards. 
6If enrollment has occurred more than 2 months before conditioning starts, a CT scan should be performed to confirm if there has been progression in the interim. 
CT scans of neck, chest, abdomen and pelvis. Neck CT only required if previous site of disease. 
7Calculated creatinine clearance is permitted per institutional guidelines. 
8 Bone marrow biopsies for pathology will be collected, optional per institutional standards. 
9Serology testing will include CMV IgG, HSV-1 and HSV-2 IgG, RPR or VDRL, toxoplasma IgG, VZV IgG, and HTLV-1 antibody, performed per institutional 
standards. 
10Pregnancy test is required for females of child-bearing potential and may be performed per institutional practices. 
11Diagnostic lymphoma pathology local report should be available prior to enrollment. Optional pathology specimens (paraffin block(s) or 10 unstained slides cut 
at 5 um thickness and placed on charged glass slide) collected pre-enrollment should be sent to the Ambinder Laboratory within 3 weeks of transplant. 
12100-120 mL whole blood shipped to CNH at ambient temperature. 
13Assessment of the Total Proviral HIV DNA will be included in the IPDA sample. A separate blood draw is not required. 
14 Blood for this plasma assay must be centrifuged and plasma frozen within 3 hours of blood draw. 
15 Toxicities related to the BEAM conditioning will be collected at Day 0.

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4.4.3. Criteria for Forms Submission  
 
Criteria for timeliness of submission for all study forms are detailed in the BMT CTN 1903 eCRF 
Completion Guide.  Forms that are not entered into Advantage eClinical® within the specified time 
will be considered delinquent.  A missing form will continue to be requested either until the form 
is entered into the Advantage eClinical® and integrated into the Data Coordinating Center’s (DCC) 
master database or until an exception is granted, as detailed in the Advantage eClinical® User’s 
Guide. 
 
4.4.4. Reporting Participant Deaths 
 
Participant death Information must be entered into Advantage eClinical® within 24 hours of 
knowledge of the participant’s death.  If the cause of death is unknown at that time, the cause does 
not need to be recorded at that time.  However, once the cause of death is determined, the form 
must be updated in Advantage eClinical®. 
 
4.4.5. CIBMTR Data Reporting 
 
The participant must be registered with the CIBMTR and have a valid CRID number. Centers 
participating in BMT CTN trials must register pre and post-transplant outcomes on all consecutive 
hematopoietic stem cell transplants done at their institution during their time of participation to the 
Center for International Blood and Marrow Transplant Research (CIBMTR).  Registration is done 
using procedures and forms of the Stem Cell Transplant Outcomes Database (SCTOD).  
Enrollment of BMT CTN 1903 must be indicated on the SCTOD pre-transplant registration form.  
Additionally, CIBMTR pre- and post- transplant Report Forms must also be submitted for all 
participants enrolled on this trial.  CIBMTR forms will be submitted directly to the CIBMTR at 
the times specified on the Form Submission Schedule.   
4.5. 
Adverse Event Reporting Requirements 
4.5.1. 
Definitions 
Adverse Event: An Adverse Event (AE) is defined as any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease that is temporally associated with 
the use of a medical treatment or procedure regardless of whether it is considered related to the 
medical treatment or procedure. 
 
Expectedness: An adverse event can be Expected or Unexpected 
x Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, 
the package insert or is included in the informed consent document as a potential risk. 
x Unexpected adverse events are those that vary in nature, intensity or frequency from 
information in the current adverse event list, the Investigator’s Brochure, the package 
insert, or when it is not included in the informed consent document as a potential risk. 
 

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Serious Adverse Event: A serious adverse event (SAE), as defined by per 21 CFR 312.32, is any 
adverse event that results in one of the following outcomes, regardless of causality and 
expectedness:  
x Results in death 
x Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
x Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered SAEs if the illness or 
disease existed before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
x Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
x Is a congenital anomaly or birth defect; or 
x Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Medical and scientific judgment should be exercised in deciding whether expected reporting is 
also appropriate in situations other than those listed above. For example, important medical events 
may not be immediately life threatening or result in death or hospitalization but may jeopardize 
the participant or may require intervention to prevent one of the outcomes listed in the definition 
above (e.g., suspected transmission of an infectious agent by a medicinal product is considered a 
Serious Adverse Event). Any event is considered a Serious Adverse Event if it is associated with 
clinical signs or symptoms judged by the investigator to have a significant clinical impact. 
 
4.5.2. Classification of Adverse Events by Severity 
The severity refers to the intensity of the reported event. The Investigator must categorize the 
severity of each SAE according to the National Cancer Institute (NCI) CTCAE Version 5.0. 
CTCAE guidelines can be referenced at the following website:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_5x7.pdf. For any term that is not specifically listed in the CTCAE scale, intensity 
will be assigned a grade of one through five using the following CTCAE guidelines: 
x Grade 1: Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated 
x Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 

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x Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
x Grade 4: Life-threatening consequences; urgent intervention indicated 
x Grade 5: Death related to AE 
4.5.3. Classification of Adverse Events by Relationship to Investigational Product 
The relationship of each reported event to the study therapy will be assessed by the Investigator; 
after careful consideration of all relevant factors such as (but not limited to) the underlying study 
indication, coexisting disease, concomitant medication, relevant history, pattern of the SAE, 
temporal relationship to any study therapy interventions and dechallenge or rechallenge according 
to the following guidelines: 
x Possibly, Probably, or Definitely Related: there is a reasonable possibility that the study 
therapy caused the event. A relationship of possibly, probably or definitely related to the 
investigational product is considered related for the purposes of regulatory authority 
reporting. 
x Unlikely, or Not Related: There is no reasonable possibility that the investigational 
product caused the event. An unlikely or not related relationship to the investigational 
product is considered not related for the purposes of regulatory authority reporting.  
 
4.5.4. 
BMT CTN Adverse Event Reporting Guidelines 
Adverse event reporting will be consistent with BMT CTN procedures (BMT CTN Administrative 
Manual of Procedures, Chapter 6). It is BMT CTN policy that AEs must be reported irrespective 
of the attribution of the event by the investigator to the study intervention. Determination of 
expectedness for events will be at the discretion of the investigator. 
The BMT CTN 1903 protocol has two distinct time periods of study intervention: Segment 0 and 
Segment A. Segment 0 includes a study intervention of blood collection for HST-NEET 
generation, a period of rest from study intervention, and then the beginning of the protocol defined 
conditioning regimen. Segment A begins at transplant Day 0 and includes infusion of the HST-
NEET product several days later. Surrounding study interventions (around the time of Segment 0 
interventions, and from the start of Segment A through the study follow up period of one year), all 
unexpected SAEs will be reported. 
 
Unexpected, serious adverse events (SAEs) will be reported through an expedited AE reporting 
system via Advantage eClinical®. Unexpected, life-threatening and fatal SAEs must be 
reported within 24 hours of knowledge of the event. All other unexpected SAEs must be 
reported within 3 business days of knowledge of the event. Events entered in Advantage 
eClinical® will be reported using NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0.  
 
Expected AEs will be reported using NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 at regular intervals as defined on the Form Submission Schedule, including 

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calendar-driven case report forms (e.g., Toxicity and GVHD) or event-driven case report forms 
(e.g., Relapse/Progression, Infection, and Death). Any expected life-threatening SAE not 
collected on another study form must be reported through the expedited AE reporting 
system via Advantage eClinical®. 
 
The Data and Safety Monitoring Board (DSMB) will receive reports of all unexpected SAEs, 
pregnancies, and HST-NEET infusion related reactions that meet SAE criteria upon review by the 
BMT CTN Medical Monitor. Summary reports for all reported SAEs will be reviewed by the 
DSMB on a semi-annual basis. 
 
4.5.5. Adverse Events of Special Interest 
 
Adverse events of special interest (AESIs) are required to be reported by the investigator within 
24 hours of notification of the event. 
 
Adverse events of special interest for this study are as follows: 
x Infusion related reaction including allergic reactions and anaphylaxis occurring during or 
post HST-NEETs infusion (infusion reactions occurring within 24 hours of the infusion). 
4.5.6. Procedure in Case of Pregnancy 
If a female participant becomes pregnant during the study dosing period or within 90 days from 
the HST-NEETs infusion, the investigator should report within 24 hours through an expedited AE 
reporting system via Advantage eClinical®. The expected date of delivery or expected date of the 
end of the pregnancy, last menstruation, estimated conception date, pregnancy result, neonatal data 
and other related information will be requested.   
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome. Additional information regarding the outcome 
of a pregnancy (which is categorized as an SAE) is mentioned below. 
Ɣ “Spontaneous abortion” includes miscarriage, abortion and missed abortion 
Ɣ Death of an infant within 1 month after birth should be reported as an SAE regardless of its 
relationship with the study drug 
Ɣ If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as “possible” by the 
investigator 
Ɣ In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at the 
birth 
Ɣ Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination 
Information will be collected at the time of delivery/birth and 6 months and 12 months after birth. 
If the participant completes the final study follow-up prior to 12 months after birth, a final status 
should be reported following the final study visit.  

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CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. 
 Study Overview 
 
This is a Phase II single arm multicenter trial designed to evaluate the feasibility and efficacy of 
ASCT followed by administration of HST-NEETs for treatment of HIV associated lymphoma. The 
study has two primary objectives: (1) estimate the HST-NEETs infusion proportion within 1 week 
of ASCT and (2) test for a reduction in the intact proviral reservoir using the intact proviral DNA 
assay (IPDA)at 6 months post-HSCT. The target enrollment is 12 participants. 
 
5.1.1. Accrual 
 
The study will accrue 12 participants.  It is estimated that four years of accrual will be necessary 
to enroll the targeted sample size. 
 
5.1.2. Primary Endpoints 
 
There are two primary endpoints for this study. The first primary endpoint is  the infusion of HST-
NEETs within 1 week of ASCT. The second primary endpoint is the reduction in intact proviruses 
(measured with IPDA in intact proviruses per million CD4 cells) at 6 months post-HSCT.  
 
5.1.3. Primary Hypotheses 
 
HST-NEET infusion proportion 
The study is not formally powered to test the HST-NEET infusion proportion. Instead, it is 
designed to estimate this rate.  
 
Intact provirus reduction in participants who were transfused 
The null hypothesis is that there is zero difference between the mean baseline and post-intervention 
logarithm of IPDA vs. the alternative that the mean baseline and post-intervention logarithm of 
IPDA difference is not zero. 
 
5.2. 
 Sample Size Calculations 
 
Since this is a feasibility pilot study, the sample size of 12 participants is based on the anticipated 
enrollment over a 4 year accrual period. Based on enrolling 12 participants, we provide the possible 
confidence intervals for the HST-NEET infusion proportion (Table 5.2.1A) and the statistical 
power (Table 5.2.1B) for the IPDA outcome.  
 
HST-NEET infusion proportion: 
Table 5.2.1A presents the exact 90% confidence intervals corresponding to zero to 12 infusions of 
HST-NEETs. 
 

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Table 5.2.1A. Exact 90% confidence intervals for the possible HST-NEET infusion 
proportions in the 12 participants 
Number of 
HST-NEET 
Infusions  
 
Infusion  
Proportion 
(%) 
Exact 
(Clopper-Pearson) 
90% 
Confidence Interval 
Number of 
HST-NEET 
Infusions  
Infusion  
Proportion 
(%) 
Exact 
(Clopper-Pearson) 
90% 
Confidence 
Interval 
0 
0.00 
(0.00, 22.09) 
7 
58.33 
(31.52, 81.90) 
1 
8.33 
(0.43, 33.87) 
8 
66.67 
(39.09, 87.71) 
2 
16.67 
(3.05, 43.81) 
9 
75.00 
(47.27, 92.81) 
3 
25.00 
(7.19, 52.73) 
10 
83.33 
(56.19, 96.95) 
4 
33.33 
(12.29, 60.91) 
11 
91.67 
(66.13, 99.57) 
5 
41.67 
(18.10, 68.48) 
12 
100 
(78.91, 100) 
6 
50.00 
(24.53, 75.47) 
 
 
 
 
Intact Provirus reduction in participants who were transfused: 
Pilot estimates for the baseline distribution of the natural logarithm of IPDA indicate a standard 
deviation of 1.46.  We assume the correlation between baseline and post-intervention log(IPDA) 
measurements is 0.5.  Using a paired t-test with a two-sided significance level of 10%, we estimate 
that 12 infused participants will have 84.8% statistical power to detect a mean difference of -1.2040 
between the baseline and post-intervention log(IPDA).  The mean baseline and post-intervention 
log(IPDA) difference of -1.2040 corresponds to a reduction of 70% (100%[1 - exp(-1.2040)]) in 
IPDA on the original scale.  Participants who were not infused will not be included in this analysis. 
  
Table 5.2.1B Power Analysis to Detect the Reduction of Intact Proviruses on the Original 
Scale 
 
 
No. of Infused Participants 
 
Mean Percent Reduction of IPDA 
6 
8 
10 
12 
Statistical Power (%) 
75% 
63.9 
77.9 
86.9 
92.4 
70% 
53.8 
67.5 
77.6 
84.8 
60% 
37.8 
48.3 
57.5 
65.3 
40% 
19.2 
23.2 
27.1 
30.9 
20% 
11.8 
12.6 
13.4 
14.2 
 
5.3. 
Interim Analysis and Stopping Guidelines 
 
5.3.1. Interim Analysis 
 
There will be no interim analyses for efficacy or futility.   
 
5.3.2. Safety Monitoring 
 
Monitoring of safety will be conducted by reviewing treatment-related mortality (TRM) within 30 
days of transplantation and infusion-related toxicities. Any treatment-related mortality event 
observed within 30 days of transplantation will undergo a thorough safety review by the NHLBI 
DSMB prior to treatment of subsequent participants. Policies and composition of the DSMB are 
described in the BMT CTN's Manual of Procedures. As there is underlying risk of TRM associated 
with autotransplantion, Table 5.3.1 shows the probability of observing 1 or more, 2 or more, and 

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3 or more events as a function of the underlying TRM rate to help guide decision making during 
the safety review.  The probability of observing three or more events is 0.02 and 0.75 if the TRM 
rate is 5% and 30%, respectively. If the TRM rate is 5%, the probability of observing one or more 
events, two or more events and three or more events is 0.46, 0.12 and 0.02, respectively.  
 
Table 5.3.1. Probabilities of Observing Events Based On Underlying Day 30 TRM Rates 
 
Day 30 TRM Rate 
5% 
10% 
20% 
25% 
30% 
Probability of 1 or more events 
0.46 
0.72 
0.93 
0.97 
0.99 
Probability of 2 or more events 
0.12 
0.34 
0.73 
0.84 
0.91 
Probability of 3 or more events 
0.02 
0.11 
0.44 
0.61 
0.75 
 
The frequency of Grade 3 or higher infusion-related toxicities with a duration of 24 hours or more 
will also be monitored. If three or more of these events are observed, the NHLBI will be notified 
and the DSMB will be consulted regarding continuation of the study. This stopping guideline 
serves as a trigger for consultation with the DSMB for additional review and is not a formal 
stopping rule that would mandate closure of study enrollment.  
 
In the event of graft failure, the protocol will be temporarily halted and reviewed by the NHLBI 
DSMB. Graft failure will be defined as a failure to achieve three consecutive labs of greater than 
or equal to 500 neutrophils/μL by Day 100. 
 
5.4. 
Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all participants using 
descriptive statistics.  Characteristics to be examined are age, gender, race/ethnicity, performance 
status, disease stage, genotype, HIV viral load, CD4+ counts, and number of prior chemotherapy 
regimens as treatment of primary malignancy and number of prior HIV regimens.  
 
5.5. 
Analysis Plan 
Analysis populations include:  
x Feasibility Population 
o All participants who have blood drawn for HST-NEETs manufacturing. 
x Transplant Population 
o All participants enrolled on the study who proceed to transplant.  
x Infusion Population 
o All participants who are enrolled on the study that received both a transplant and HST-
NEETs. 
 

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5.5.1. Analysis of the Primary Endpoints 
 
HST-NEET infusion proportion: 
We will report the proportion of HST-NEET infusion. Additionally, a 90% Clopper-Pearson 
confidence interval approach for that rate will be computed.47  This analysis will include all 12 
participants. 
 
Intact provirus reduction in participants who were  transfused: 
The difference in logarithm of IPDA measured pre-transplant and at 6 months post-transplant will 
be compared using a paired t-test. The difference in means will be computed with 90% confidence 
interval based on the t-distribution along with the corresponding p-value. This analysis will be 
done for all infused participants.  
 
5.5.2. Analysis of Secondary Endpoints 
 
Progression-Free Survival (PFS)  
The event is relapse/progression or death or receive anti-lymphoma therapy, other than post-
transplant consolidative localized radiation (maximum 3 sites) to sites of prior bulk disease pre-
transplant (greater than 3cm).  The time to this event is the time from transplant until death, 
relapse/progression, receipt of anti-lymphoma therapy, or last follow up, whichever comes first.  
Progression-free survival (PFS) will be estimated using the Kaplan-Meier product limit estimator 
and Kaplan-Meier plots with 95% confidence intervals using Greenwood’s formula and the log-
log transformation.  The PFS probability and 95% confidence interval will be calculated at 6 
months and one year post-transplant. 
 
Acute Infusion Related Toxicities 
Toxicities that occur over the course of time will be tabulated using the version 5.0 CTCAE 
criteria.  The clinical safety monitoring period for HST-NEETs will be 28 days following infusion. 
The proportion of participants developing toxicity will be described by type of toxicity, grade, and 
time period.  The 95% Clopper-Pearson confidence interval will be used. This analysis will be 
done on the infusion or transplant population. 
 
Intact Proviral Reservoir at One Year 
Impact on intact proviral reservoir will be assessed using the IPDA at 12 months following 
autologous HCT. The difference in log(IPDA) measured pre-transplant and at 12 months post-
transplant will be compared using a paired t-test. The difference in means will be computed with 
95% confidence interval based on the t-distribution along the corresponding p-value.  This analysis 
will be done on the infusion population. 
 
5.5.3. Analysis of Exploratory Endpoints 
 
CR and CR+PR Rate at Day 100 after ASCT 
The frequencies and proportions of participants who have a CR (or PR) will be described with 
95% Clopper-Pearson confidence intervals at Day 100 after ASCT. This analysis will be done on 
the transplant population. 
 

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Overall Survival 
The event is death by any cause. The time to this event is from transplant.  Participants are censored 
at the time of last follow-up.  We will estimate the Kaplan Meier curve at 6-month and 1-year 
overall survival (OS) probability based on the Kaplan-Meier product limit estimator with 
corresponding 95% confidence intervals using Greenwood’s formula and the log-log 
transformation. 
 
Time to Hematopoietic Recovery   
Hematologic function will be defined by ANC greater than 500, Hemoglobin greater than 10g/dL 
without transfusion support, and platelets greater than 100,000 and measured at Day 100 and 1 
year.  Use of growth factors will be noted. Time to neutrophil recovery and platelet engraftment 
from transplant will be estimated using cumulative incidence function with corresponding 95% 
confidence interval with death prior to engraftment as the competing risk. 
 
Incidence of Infections 
The incidence rate of infections is defined by the number of infections divided by the total person-
time accumulated over the duration of the study. All Grade 2 and higher infections will be reported 
according to the BMT CTN Technical MOP from Day 0 up to 1 year post-transplant.  The 
incidence rate of infections will be computed with corresponding 95% exact confidence interval 
based on the Poisson distribution.    
Non-Relapse Mortality 
Non-Relapse Mortality (NRM) is defined as death occurring in a participant without relapse or 
progression.  Progression is a competing risk event. A cumulative incidence curve will be 
computed along with a 95% confidence interval at 6 months and at 1 year post-transplant. 
 
Toxicity: 
Toxicities related to the BEAM conditioning regimen and HST-NEETs infusion beyond the 24 
hour acute toxicity monitoring period will be defined by using the version 5.0 CTCAE criteria. 
The data will be collected up to day +28. All grade of toxicity related to HST-NEETs will be 
collected. Only grade 3 or higher conditioning regimen related toxicities will be collected. The 
frequencies and proportions of participants with toxicities will be described with 95% Clopper-
Pearson confidence intervals. 
 
Ig DNA in Blood 
Blood specimens will be collected within 1 week prior to the initiation of conditioning, and at Day 
100, 6 months, and 1 year post-transplant.  The presence of clonal Ig DNA in plasma will be 
assessed at each time point and will be summarized using descriptive statistics with plots of the 
outcome vs Days. We will model the Ig DNA in blood using a mixed model with Days as a 
covariate.   
 
Intact Proviral Reservoir at Day 100 
Impact on intact proviral reservoir will be assessed using the IPDA at Day 100 following 
autologous HCT. The difference in log(IPDA) measured pre-transplant and at Day 100 post-
transplant will be compared using a paired t-test. The difference in means will be computed with 
95% confidence interval based on the t-distribution along the corresponding p-value.  This analysis 
will be done on the infusion population. 

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HIV RNA in Blood 
The difference in log(HIV RNA) measured pre-transplant and at 6 months post-transplant will be 
compared using a paired t-test. The difference in means will be computed with 95% confidence 
interval based on the t-distribution along with the corresponding p-value. This analysis will be 
done for all participants whose HIV RNA could be ascertained. Additionally, HIV RNA will be 
summarized using descriptive statistics with plots of the outcome vs Days. We will model the HIV 
RNA in blood using a mixed model with Days as a covariate.   
 
Total Proviral HIV DNA (TPDNA) 
Impact on total proviral HIV DNA will be assessed using the TPDNA at 6 months following 
autologous HCT. The difference in log(TPDNA) measured pre-transplant and at 6 months post-
transplant will be compared using a paired t-test. The difference in means will be computed with 
95% confidence interval based on the t-distribution along the corresponding p-value.  This analysis 
will be done on the infusion population. 
 
Persistence and expansion of HST-NEETs in vivo 
Persistence and expansion of HST-NEETs will be measured by frequency of HIV-1 antigen-
specific (gag, pol, nef) CD8+ T-cells by ELIspot at baseline and post-infusion at timepoints at Day 
100, 6 months, and 1 year post transplant.  Change in T cell responses from baseline to post-
infusion, measured by frequency of cells secreting IFN-ȖE\PXOWLPHUDQDO\VLVDQGRULQWUDFHOOXODU
cytokine staining and/or ELIspot and/or TCR sequencing will be done depending on PBMC cell 
numbers available and reagent availability.  
 
These will be summarized at each time point using descriptive statistics with plots of the outcome 
vs Days. We will model these outcomes using a mixed model with Days as a covariate. 
 
 

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APPENDIX A:  HUMAN SUBJECTS 
 

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APPENDIX A 
 
HUMAN SUBJECTS 
 
 
1. 
Subject Consent 
 
Candidates for the study will be identified as described in Chapter 4 of the protocol. The Principal 
Investigator or his/her designee at each transplant center will contact the candidates, provide them 
with information about the purpose of the study and obtain voluntary consent if the candidates 
agree to participate. The BMT CTN will provide a template of the consent form to each center. 
Each center will add their NMDP IRB-approved boiler-plate language to the consent and submit 
it for review by the NMDP Institutional Review Board (IRB). The DCC will verify the adequacy 
of the consent forms prior to submission to the IRB. The NMDP IRB will provide evidence of IRB 
approval. 
 
2. 
Confidentiality 
 
Confidentiality will be maintained by individual names being masked and assigned a participant 
identifier code.  The code relaying the participant’s identity with the ID code will be kept 
separately at the center.  The ID code will be transmitted to the BMT CTN Data Coordinating 
Center upon enrollment. 
 
3. 
Participation of Women and Minorities and Other Populations 
 
Women and ethnic minorities and other populations will be included in this study.  Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities expected 
from data reported to the CIBMTR and from published data on incidence of DLCL in these groups.  
Centers will be notified if their rates differ significantly from those expected and asked to develop 
appropriate recruitment reports. 
 
4. 
GCP 
 
This study will be conducted in accordance with standards of Good Clinical Practice (as defined 
by the International Council for Harmonization) and all applicable national and local regulations. 
 
 

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APPENDIX B:  LUGANO CLASSIFICATION 
 

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The following tables are derived from Lymphoma Response to Immunomodulatory Therapy Criteria46  
 
 
 
 
PET-CT Based Response 
CT-Based Response 
Complete 
Response 
(CR) 
 
Complete metabolic response (CMR) 
Complete radiologic response (CR) (all of 
the following) 
 
 
 
 
 
Lymph nodes and 
extra lymphatic 
sites 
Score 1, 2, or 3a with or without a residual mass 
on 5PS† 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake or 
with activation within spleen or marrow (e.g., 
with chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal 
mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater 
than surrounding normal tissue even if the tissue 
has high physiologic uptake 
 
 
 
 
 
Target nodes/nodal masses must 
regress to less than or equal to  1.5 cm 
in LDi 
No extra lymphatic sites of disease 
Non-measured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Partial 
Response 
(PR) 
 
Partial metabolic response (PMR) 
Partial remission (PR) (all 
of the following) 
 
 
Lymph nodes 
and extra 
lymphatic sites 
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
At interim, these findings suggest 
responding disease 
At end of treatment, these findings 
indicate residual disease 
Greater than or equal to  50% 
decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure on 
CT, assign 5 mm X 5 mm as the default 
value 
When no longer visible, 0 X 0 mm For a 
node > 5 mm X 5 mm, but 

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PET-CT Based Response 
CT-Based Response 
 
 
smaller than normal, use actual 
measurement for calculation 
Non-measured 
lesions 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by greater than 
50% in length beyond normal 
New lesions 
None 
None 
 
 
 
 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the 
context of a nodal response, consideration should 
be given to further evaluation with MRI or 
biopsy or an interval scan 
 
 
 
 
Not Applicable 
No Response 
or Stable 
Disease 
 
No metabolic response (NMR) 
 
Stable disease (SD) 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of 
treatment 
Less than  50% decrease from baseline in 
SPD of up to 6 dominant, measurable nodes 
and extranodal sites; no criteria for 
progressive disease are met 
Non-measured 
lesions 
Not applicable 
No increase consistent with 
progression 
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not Applicable 

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PET-CT Based Response 
CT-Based Response 
Progressive 
disease (PD) 
*** Excludes patients who meet criteria for Indeterminate Response (IR) *** 
Progressive metabolic disease (PMD) 
Progressive disease (PD) 
requires at least 1 of the following 
Individual 
target 
nodes/nodal 
masses 
 
 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
 
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment 
An individual node/lesion must be 
abnormal with: 
LDi greater than  1.5 cm and 
Increase by greater than or equal to  50% 
from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions less than or equal to2 cm 
1.0 cm for lesions greater than 2 cm 
In the setting of splenomegaly, the splenic 
length must increase by >50% of the extent of 
its prior increase beyond baseline (e.g., a 15 
cm spleen must increase to greater than16 
cm). 
If no prior splenomegaly, must 
increase by at least 2 cm from 
baseline 
New or recurrent splenomegaly 
Extranodal 
lesions 

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PET-CT Based Response 
CT-Based Response 
Non-measured 
lesions 
None 
New or clear progression of preexisting 
non-measured lesions 
 
 
 
 
New lesions 
 
 
New FDG-avid foci consistent with 
lymphoma rather than another etiology (e.g., 
infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy or 
interval scan may be considered 
Regrowth of previously resolved 
lesions 
A new node greater than 1.5 cm in any axis 
A new extranodal site greater than 1.0 cm in 
any axis; if less than 1.0 cm in any axis, its 
presence must be unequivocal and must be 
attributable to lymphoma Assessable disease 
of any size unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron 
emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to 
the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
a.  A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider 
a score of 3 as inadequate response (to avoid under treatment). Measured dominant lesions: Up to six of the largest 
dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes 
should preferably be from disparate regions of the body and should include, where applicable, mediastinal and 
retroperitoneal areas. Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, and lungs), GI 
involvement, cutaneous lesions, or those noted on palpation. 
Non-measured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should 
be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as 
well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and 
other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal sites (e.g., GI 
tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, 
but should be no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of 
chemotherapy or myeloid growth factors). 
† PET 5PS: 1, no uptake above background; 2, uptake less than or equal to mediastinum; 3, uptake greater than 
mediastinum but less than or equal to liver; 4, uptake moderately greater than liver; 5, uptake markedly higher 
than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 
 

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APPENDIX C:  LABORATORY PROCEDURES 

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APPENDIX C 
 
LABORATORY PROCEDURES 
 
1. HST-NEETS PRODUCT MANUFACTURING, HLA TYPING, AND INFECTIOUS DISEASE MARKER (IDM) 
TESTING 
100-120 mL of peripheral blood is collected in multiple 10 mL-fill sodium heparin tubes for HST-NEETs product manufacturing 
within 6-8 weeks of transplant.  Collect an additional 20-24 mL of peripheral blood for testing.  For Infectious Disease testing 
collect  2 purple EDTA and 2 red Vacutainer tubes (4mL per tube). See specific IDM tests listed in the table below.  Collect 4-8 
mL in a yellow top ACD tube for HLA testing. HLA testing is performed before and after manufacturing to verify product identity. 
The blood tubes are shipped by priority overnight FedEx to the Cellular Therapy Laboratory at Children’s National Hospital. 
 
2. INTACT PROVIRAL DNA ASSAY (IPDA) AND HST-NEETS PERSISTENCE AND EXPANSION 
There is a critical need for accurate, HIV reservoir assays to evaluate potential HIV cure approaches. In this correlative study, we 
will be employing the recently developed intact proviral DNA assay (IPDA). This assay takes advantage of advancements in 
droplet digital PCR, where a single HIV genome can be amplified by PCR within an oil droplet. Two amplicons are used, which 
can with high sensitivity distinguish between defective and intact proviral HIV genomes. Note we will also extract total HIV DNA 
data from the IPDA assay, even if sequence diversity causes the IPDA to fail. Published Env primers/probe and the backup Env 
primers/probe that are reported in a Biorxiv manuscript will also be reported for all donors. With both of these together, the assays 
should cover most of the inter-individual diversity. It also gives us an opportunity to flag and further investigate cases where 
within-donor HIV diversity causes the IPDA to underestimate the reservoir48. 
 
Persistence of HST-NEETs will be measured by frequency of HIV-1 antigen-specific (gag, pol, nef) CD8+ T-cells by ELIspot at 
baseline and post-infusion at timepoints at Days 100, 180 and 365 post-transplant.  Change in T cell responses from baseline to 
post-infusion, measured by frequency of cells secreting IFN-ȖE\PXOWLPHUDQDO\VLVDQGRULQWUDFHOOXODUF\WRNLQHVWDLQLQJDQGRU
ELIspot and/or TCR sequencing will be done depending on PBMC cell numbers available and reagent availability. 
 
70 mL of peripheral blood is collected in multiple 10 mL-fill sodium heparin tubes at approximately 4-8 weeks prior to transplant 
and at Days 100, 180 and 365 post-transplant.   The blood tubes are shipped by priority overnight FedEx to the Cellular Therapy 
Laboratory at Children’s National Hospital. 
 

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3. CHARACTERIZATION OF THE UTILITY OF PLASMA DNA MARKERS FOR AIDS LYMPHOMA 
Tumor DNA detected in plasma is emerging as a potentially useful tumor marker. Clonal Ig DNA tumor marker, as recognized by 
Ig rearrangements or characteristic somatic hypermutation in participants with HIV associated lymphomas will be evaluated in 
this correlative laboratory study.  In previous studies, clonal Ig DNA is characteristic of a particular participant’s B cell tumor and 
is detected in approximately half of AIDS diffuse large B cell lymphoma prior to treatment. In those studies, participants in whom 
clonal Ig DNA persists in plasma inevitably relapse. Plasma DNA (clonal Ig) will be measured prior to conditioning, prior to stem 
cell infusion, and at Day +100, 6 months and 1 year post-transplant will be summarized using descriptive statistics.   
 
25 mL of peripheral blood is collected in three 10-mL fill STRECK Cell Free BCT tubes within 1 week prior to initiation of 
ablative therapy, and on Days 100, 180 and 365 post-transplant. The blood tubes are shipped at ambient temperature on the day of 
collection by priority overnight FedEx to the Ambinder Laboratory at Johns Hopkins University.  
 
4. CIRCULATING PLASMA HIV RNA MEASUREMENTS  
In the current study, we will monitor the presence of circulating HIV RNA before and after transplant and following the 
administration of HST-NEETs. HIV viral load will be measured with a sensitive investigational single copy PCR assay (SCA) 
with a viral RNA detection limit of 0.38 copy/ml.  In patients with no detectable viral load by standard clinical assays, this assay 
regularly detects low copy number viral RNA. This RNA is believed to be released from latency compartments established in 
hematopoietic cells.   
 
5 mL of peripheral blood is collected in a single EDTA Vacutainer tube approximately 4-8 weeks prior to transplant and at Days 
100, 180 and 365 post-transplant. The samples will be promptly processed locally within 3 hours of collection and plasma aliquots 
frozen at -70° C. The frozen plasma aliquots will be periodically batch-shipped by priority overnight FedEx to the Mellors  
Laboratory at the University of Pittsburg School of Medicine. 

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Research Sample Collection Schedule for 
Participant Blood Samples for Required Product Manufacturing and Protocol-Defined Research Testing 
 
RESEARCH 
TOPIC 
RESEARCH 
SAMPLE 
TYPE OF  
SAMPLE 
SAMPLE COLLECTION, 
PROCESSING AND 
STORAGE REQUIREMENTS 
SAMPLE 
COLLECTION TIME 
POINTS 
SHIPPING 
SPECIFICATIONS 
HST-NEETs 
Product 
Manufacturing, 
HLA typing, 
Infectious 
Disease Marker 
(IDM) Testing1 
Peripheral Blood for 
HST-NEETs 
Manufacturing, HLA 
typing, and IDM 
Testing 
HST-NEETS: 100-120 mL 
peripheral blood collected in 
multiple 10 mL sodium heparin,  
IDM: 16mL peripheral blood 
collected in 2 purple EDTA and 2 
red Vacutainer tubes (4mL per 
tube) 
HLA: 7-10mL peripheral blood 
collected in 1 yellow ACD tube 
Gently mix blood tubes with the 
anticoagulant by inverting the 
tube 8-10 times. Store at room 
temperature while preparing to 
ship to manufacturing laboratory 
Approximately 6-8 
weeks prior to transplant 
Cellular Therapy Laboratory at 
Children’s National Hospital 
 
1 IDM testing includes: Chagas Disease (if applicable), Hepatitis B Surface Antigen, Hepatitis B Core, Hepatitis C Core, HIV 1 and 2, TAQ Screen MPX (HBV, HCV, 
HIV-1 group M RNA, HIV-1 Group O), NAT HCV, NAT HIV, NAT HBV, NAT West Nile Virus, Serological Test for Syphilis, CMV IgG/IgM, Anti-HTLV I/II 
 

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Required Research Samples 
RESEARCH 
TOPIC 
RESEARCH 
SAMPLE 
TYPE OF  
SAMPLE 
SAMPLE COLLECTION, 
PROCESSING AND STORAGE 
REQUIREMENTS 
SAMPLE 
COLLECTION TIME 
POINTS 
SHIPPING SPECIFICATIONS 
Intact Proviral 
DNA Assay 
(IPDA) and HST-
NEETs Persistence 
and Expansion 
Peripheral Blood for 
IPDA Measurements 
and HST-NEETs 
Evaluation 
70 mL peripheral 
blood collected in 
seven 10 mL 
sodium heparin 
Vacutainer tubes 
Gently mix blood tubes with the 
anticoagulant by inverting the tube 8-10 
times. Store at room temperature while 
preparing to ship to manufacturing 
laboratory 
Pre-transplant 
Approximately 4-8 weeks 
prior to transplant 
Post-transplant 
Days 100, 180, 365 
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the 
Cellular Therapy Laboratory at 
Children’s National Hospital by priority overnight 
FED EX delivery for processing and research 
testing. Guidelines for specimen handling and 
shipment to the Cellular Therapy Laboratory is 
detailed in the BMT CTN 1903 Laboratory Sample 
Guide. 
Plasma DNA 
Tumor Monitoring 
Clonal Ig B-cell DNA 
 
25 mL peripheral 
blood sample 
collected in three 
10 mL Streck Cell-
Free DNA BCT®  
tubes. 
Gently mix blood with cell stabilizer by 
inverting the tube 8-10 times. Store at 
room temperature while preparing to ship 
to project laboratory. 
Pre-transplant 
Within 1 weeks prior to 
initiation of ablative 
therapy. 
Post-transplant 
Days 100, 180, 365 
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the 
Ambinder Laboratory at Johns Hopkins University 
by priority overnight FED EX delivery for 
processing and research testing. Guidelines for 
specimen handling and shipment to the Ambinder 
Laboratory is detailed in the BMT CTN 1903 
Laboratory Sample Guide. 
Lymphoma 
Pathology  
Diagnostic Tissue 
(If Available) 
Paraffin block(s) 
or 10 unstained 
slides cut at 5 um 
thickness and 
placed on charged 
glass slides 
Store at room temperature while preparing 
to ship to project laboratory. 
Specimens on enrolled 
participants will be 
submitted to project lab 
within 3 weeks of 
transplant. 
Tissue samples will be shipped at ambient 
temperature to the Guidelines for specimen handling
and shipment to the Ambinder Laboratory at Johns 
Hopkins University is detailed in the BMT CTN 
1903 Laboratory Sample Guide. 
Plasma HIV 
Measurement 
Single-Copy HIV RNA 
Assay 
5 mL peripheral 
blood collected in 
an EDTA 
containing 
Vacutainer tube 
Gently mix blood tubes with the 
anticoagulant by inverting the tube 8-10 
times. Blood samples will need to be 
centrifuged, and plasma separated, 
aliquoted into cryovials and frozen at -70° 
C within 3 hours of blood collection. 
Detailed sample processing information 
will be found in the BMT CTN 1903 
Laboratory Sample Guide. 
Pre-transplant 
Approximately 4-8 weeks 
prior to transplant 
Post-transplant 
Days 100, 180, 365 
Frozen plasma sample aliquots will be periodically 
batched-shipped to the Mellors Laboratory at the 
University of Pittsburgh School of Medicine 
by priority overnight FedEx® delivery. Guidelines 
for specimen handling and shipment to the Mellors 
Laboratory is detailed in the BMT CTN 1903 
Laboratory Sample Guide. 
  

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APPENDIX D:  SUGGESTED PROPHYLAXIS 
 
HIV MANAGEMENT 
 
ANTIRETROVIRALS AND BILIRUBIN 
  
The following antiretroviral medications lead to elevated bilirubin 
in the absence of other evidence of liver dysfunction. 
 
 

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APPENDIX D 
 
SUGGESTED PROPHYLAXIS 
 
Infectious prophylaxis for HIV patients undergoing HCT will include prophylaxis for: 
 
1. Bacteria:  In keeping with the BMT CTN MOP and local institutional standards. 
2. Pneumocystis Jiroveci Pneumonia: Prophylaxis will be administered until CD4 counts are 
greater than 200 and for a minimum of 6 months. Several effective regimens are available. 
Patient tolerance (nausea, allergic reaction, G6PD or other considerations) may 
contraindicate a particular regimen. Choices in order of preference are 1) TMP/SMX 1 DS 
daily, 2) TMP/SMX 1 SS daily, 3) Atovaquone 1500 mg daily,  4) Dapsone 100 mg daily  
5) Aerosolized pentamidine monthly. 
3. Toxoplasmosis:  Patients on TMP/SMX do not require additional prophylaxis. If 
toxoplasma IgG is positive and TMP/SMX cannot be used, then patients should be 
prophylaxed for at least 3 months after HCT and until CD4 greater than 100.  This 
prophylaxis may be either: 1) atovaquone 1500 mg po daily or 2) dapsone 50 mg po daily 
and pyrimethamine 50 mg/week and leucovorin 25 mg/week  
4. Fungi:  Anti-fungal prophylaxis will be per local institutional practice. It is noted that in 
histoplasma endemic areas (Midwest and Puerto Rico) antifungal prophylaxis is standard 
for CD4 less than 150 and would be appropriate for at least 3 months after HCT and until 
CD4 greater than 150. 
5. HSV/VZV:  One of the following regimens should be used for 1 year after HCT i.e. 
Acyclovir 400 - 800 mg bid, valaciclovir 500 mg bid, or famciclovir 500 mg po bid.  
6. Hepatitis: 
a. Patients with positive hepatitis B surface antigen should be evaluated for viral DNA 
replication (viral load) by a quantitative PCR method before enrolling the patient on 
the study.  
b. Newer generation of anti-hepatitis B agents, like Tenofovir, should be started in 
those with detectable Hepatitis B viral load according to institutional preferences. 
The goal of the treatment should be achieving undetectable (less than 500 copies/ml) 
viral load status before stem cell mobilization chemotherapy.  
c. Patients should be maintained on anti-Hepatitis B treatment throughout the 
transplant and at least 12 months after the transplant. 
d. Patients with hepatitis-C infection may be enrolled on the trial providing the above 
Hepatic criteria are met. Anti-hepatitis C treatment with directly acting antivirals 
(DAAs) is recommended in order to be eligible for the study. 
e. Liver biopsy must be performed in patients with Hepatitis-B or C infections if the 
severity assessment of liver disease based on Child-Turcotte-Pugh (CTP) 
classification indicates all of the following criteria; Serum bilirubin greater than 2, 
serum albumin less than 3.5, and INR greater than 1.7 
f. Patients with no pathologic evidence of irreversible chronic liver disease such as 
bridging necrosis and/or significant fibrosis can be eligible for the study.  

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Pharmacokinetic Drug-Drug Interactions with Antiretroviral (ART) Medications 
 
Preferred ART for Patients Undergoing Autologous Hematopoietic Cell Transplant 
x Tier 1: Integrase strand transfer inhibitor (INSTI) based therapy requires no interruption of 
therapy (example: bictegravir in the combination Biktarvy, dolutegravir (alone or 
combination product), or raltegravir (alone)). Elvitegravir is contraindicated due to the 
combination with cobicistat. If combinations of non-boosted elvitegravir are approved, 
then this INSTI could be considered. 
x Tier 2: NNRTI based therapy 
x Tier 3: Boosted-PI based therapy 
 
Summary of ART and Drug-Drug Interactions 
1. INSTI: bictegravir, dolutegravir, raltegravir, elvitegravir 
a. Dosing 
i. Avoid giving concomitantly with magnesium containing antacids 
b. Toxicity 
i. Raltegravir can exacerbate depression in patients with a previous history of 
depression.  
ii. Common side effects of diarrhea, headache and nausea has been seen.  With 
raltegravir also there have been issues with hypersensitivity issues with rash 
and Stevens-Johnson syndrome.  
c. Metabolism 
i. Excreted into feces and urine 
d. Drug Interactions 
i. No interactions with CYP450 co-enzymes 
2. Nucleoside Reverse Transcriptase Inhibitors (NRTI): abacavir, didanosine, emtricitabine, 
lamivudine, stavudine, tenofovir alafenamide fumarate, tenofovir disproxil fumarate, 
zidovudine  
a. Dosing 
i. Zidovudine (AZT) should not be used in pts receiving hematopoietic cell 
transplantation 
b. Toxicity 
ii. As a class, adverse effects include lactic acidosis, peripheral neuropathy and 
hepatic steatosis 
c. Metabolism 
iii. Not extensively metabolized, eliminated renally (except abacavir) 
d. Drug Interactions 
iv. No interactions with CYP450 co-enzymes 
3. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI): delavirdine, doravirine, 
efavirenz, etravirine, nevirapine, rilpivirine 
a. Dosing 

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i. Efavirenz is the preferred agent in this class but it not recommended for use in 
this trial due to prolonged half life 
b. Toxicity 
ii. All NNRTIs can cause rash, hepatotoxicity and gastrointestinal intolerance 
c. Metabolism 
iii. NNRTs are metabolized hepatically via cytochrome P450 co-enzymes 
d. Drug Interactions 
iv. Nearly all NNRTIs induce CYP3A4 (except for rilpivirine) 
4. Protease Inhibitors (PI): atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, 
ritonavir, saquinavir, tipranavir 
a. Dosing 
v. All protease inhibitors (except nelfinavir) are typically given in combination 
with ritonavir to reach optimal pharmacokinetic targets 
b. Toxicity 
vi. All PIs can cause gastrointestinal intolerance, hyperglycemia, lipohypertrophy, 
osteonecrosis, hepatotoxicity and hyperlipidemia 
c. Metabolism 
i. PIs are metabolized hepatically via cytochrome P450 co-enzymes especially 
CYP3A4 
d. Drug Interactions 
ii. When given in combination with ritonavir, all PIs are potent CYP3A inhibitors 
5. Other 
a. Fusion inhibitor: enfuvirtide 
b. CCR5 inhibitor: maraviroc 
c. Pharmacokinetic enhancer (CYP450 inhibitor): cobicistat (current co-formulations 
include: Atazanavir-Cobicistat, Darunavir-Cobicistat, Elvitegravir-Cobicistat-
Tenofovir 
DF-Emtricitabine, 
Elvitegravir-Cobicistat-Tenofovir 
alafenamide-
Emtricitabine, Darunavir-Cobicistat-Tenofovir alafenamide-Emtricitabine) 
d. Attachment inhibitor: ibalizumab-uiyk 
 

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APPENDIX E:  MANAGEMENT OF ADVERSE REACTIONS 

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Appendix E 
 
Management of Adverse Reactions to HST-NEETs T Cell Infusions 
 
HST-NEETs infusions are typically well tolerated but adverse reactions may occur early (within 
24 hours of infusion) or late (greater than 24 hours after infusion). Early reactions are usually 
related to the cryopreserved components.   
 
A. Monitoring Post HST-NEETs Infusion  
Medical staff will assess for any adverse effects for 1 hour post-infusion. Vital signs 
should be monitored immediately at end of infusion then at 30 and 60 minutes. Patients 
should remain on continuous pulse oximetry for at least 30 minutes after infusion. 
 
1. Common, mild complications from HST-NEETs infusion include:  
x Mild increase in blood pressure not requiring intervention 
x Mild headache 
x Mild flushing 
x Slight slowing of the heart rate 
x Bad taste in mouth 
 
2. Severe early reactions from HST-NEETs infusion are rare but may include: 
x Acute pulmonary edema and dyspnea 
x Persistent nausea and vomiting 
x Sustained or significant increase in blood pressure  
x Fever 
x Anaphylactic shock  
x Bradycardia or cardiac arrest 
 
B. Management of Early Reactions 
Most common, mild early reactions do not require intervention. 
  
1. Management of anaphylaxis: Emergency medications should be ordered in advance 
and available at the patient’s bedside at the time of infusion.  Hydrocortisone (or other 
steroids) should not be administered without approval of physician administering 
HST-NEETs. 
x Hydrocortisone 5-10 mg/kg IV (maximum 500 mg) or methylprednisolone 1-2 
mg/kg IV (maximum 125 mg) 
x Epinephrine 0.01 mg/kg IM (preferred) or SubQ (maximum 0.5 mg; 0.01 mL/kg 
of 1 mg/mL solution, maximum of 0.5 mL) 
2. In the event of a severe reaction, the patient should be immediately transferred to the 
intensive care unit for intensive monitoring and intervention, which usually includes 
blood pressure support, steroids, and management of anaphylaxis.   

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C. Monitoring and Management of Late Reactions 
Late reactions to HST-NEETs infusion may occur but also may be similar to symptoms 
that occur during neutrophil engraftment.  
 
1. Late reactions to T-cell infusion may be related to a T-cell engraftment syndrome or 
cytokine release syndrome (CRS), and rarely to contamination of the product. 
 
2. Symptoms and signs of late complications from infusion of T-cell products may 
include: 
 
Systemic 
 
fever 
malaise, fatigue 
myalgias and arthralgias 
skin rash mimicking acute GvHD 
general feeling of unwellness 
disseminated intravascular coagulation (DIC) +/- bleeding 
macrophage activation syndrome/hemophagocytotic lymphohistiocytosis (HLH) 
anorexia, nausea, vomiting, diarrhea 
Cardiorespiratory 
 
tachycardia 
blood pressure changes (either hyper- or hypotension) 
acute pulmonary edema, dyspnea, hypoxia 
pulmonary infiltrates 
capillary leak syndrome 
cardiac dysfunction 
stress cardiomyopathy (Takotsubo cardiomyopathy) 
adult respiratory distress syndrome (ARDS) 
Hepatic and Renal 
weight gain 
renal impairment 
azotemia 
hyperuricemia 
hepatic impairment – transaminitis, hyperbilirubinemia 
Neurological 
headache 
mental status changes 
confusion 
delirium 
hallucinations 
altered gait 
seizures 
encephalopathy 
mild encephalopathy with reversible splenial lesion syndrome (MERS) 

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3. Management of Late Reactions 
 
(1) The development of a severe late reaction necessitates immediate notification 
of the PI and Study Chair AND urgent medical assessment (if an 
outpatient will necessitate transfer to the hospital). It is important to evaluate 
the patient and initiate therapy as quickly as possible since rapid deterioration 
is possible. 
 
(2) Biomarkers: Circulating cytokine levels can serve as biomarkers to diagnose 
and potentially quantify syndrome severity. 
(a) IL-6 signaling is major component of severe cytokine release syndrome 
(b) If possible, cytokine levels should be evaluated at inhouse or external (e.g. 
Viracor) laboratories prior to starting any anticytokine directed therapy. CRP 
serves as a reliable surrogate for IL-6 bioactivity and levels should be sent pre 
and post therapy to monitor response 
(c) Ferritin may also be used in conjunction with CRP monitoring 
 
(3) The immediate assessment and treatment may also include: 
(a) Intensive monitoring (BP, cardiovascular monitoring, pulse oximetry or ABG) 
(b) CXR or CT of chest 
(c) Steroids – single dose. See #(4) below 
(d) Microbiological studies (especially blood cultures and virus studies) and 
initiation of broad-spectrum antibiotics +/- antivirals should be considered. 
(e) Blood pressure/Cardiovascular support – early institution of inotropic 
medications. Limit fluid resuscitation to the minimum volume needed to 
support blood pressure, no more than 20 mL/kg, (up to 1,000 mL), if possible. 
(f) Fluid management/Renal support – Aggressive diuresis. Institute early 
involvement of the renal service for fluid management especially if evidence 
of capillary leak syndrome. Consider infusion of 25% albumin if serum 
albumin is less than 3 g/dL.  
(g) Respiratory support – supplemental oxygen therapy should be initiated for all 
hypoxemic patients. Patients also may require intubation and mechanical 
ventilation. 
(h) Management of tumor lysis syndrome if there is laboratory evidence it is 
occurring. 
 
(4) Treatment of the cytokine release syndrome or other T-cell associated adverse 
reactions must be discussed with the PI and Study Chair. If the situation is 
emergent, the first dose of steroids can be given prior to consultation with the PI. 
 
In general, the cytokine release syndrome is managed similarly to engraftment 
syndrome EXCEPT: 
x As the patient received an investigational T-cell agent, steroids may not be 
considered first line therapy and anti-IL-6 directed therapy MAY be given 
without first starting steroids.  

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x When managing CRS, anti-IL-6 directed therapy should be initiated before 
anti-TNFa directed therapy. 
x Caution is required when using tocilizumab in the setting of hepatic 
impairment. 
 
(5) If treatment with a biological agent is necessary, the order of priority will usually 
be: 
x Tocilizumab 
x Infliximab(anti-TNFa) 
x Etanercept (soluble TNFa receptor inhibitor) 
 
Drug 
Dosing 
Duration 
Tocilizumab 
Less than 30 kg: 8 mg/kg IV 
Greater than or equal to 30 kg: 4 mg/kg 
(maximum 800 mg) IV 
One dose, with repeat dosing if no 
improvement observed within 24-48 
hours. 
Infliximab 
10 mg/kg IV 
One dose, may give second 3-4 days 
later 
Etanercept 
0.4 mg/kg (maximum 25 mg) SubQ  
One dose, may give second 3-4 days 
later 
 
 
 
 

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APPENDIX F:  REFERENCES 
 

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APPENDIX F 
 
REFERENCES 
 
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3 Gupta RK, Abdul-Jawad S, McCoy LE, et al. HIV- UHPLVVLRQ IROORZLQJ &&5ǻǻ
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National Academy of Sciences, 1999. 96(26): p. 15109-15114. 
 
13 Kaufmann, D.E., et al., Limited durability of viral control following treated acute HIV 
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24 Ribera JM, Navarro JT.  Human immunodeficiency virus related non-Hodgkin’s lymphoma.  
 

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Haematologica.  2008;93:1129. 
 
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37 Jin MC, Schroers-Martin JG, Kurtz DM, et al. Noninvasive Genotyping and Monitoring of 
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II cancer clinical trials. Journal of biopharmaceutical statistics, 16(6), pp.765-775 
 
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