Clinical trial NCT02424968
Conditions: Acute Myeloid Leukemia B-Cell Non-Hodgkin Lymphoma Chronic Lymphocytic Leukemia Hodgkin Lymphoma Myelodysplastic Syndrome Myeloproliferative Neoplasm T-Cell Non-Hodgkin Lymphoma
Keywords: Healthy Stem Cell Donor
Sponsor: Robert Lowsky
Start date: 2015-06-01; Completion date: 2021-04-01
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase 2 trial studies how well cluster of differentiation 8 (CD8)+ memory T-cells work as a consolidative therapy following a donor non-myeloablative hematopoietic cell transplant in treating patients with leukemia or lymphoma. Giving total lymphoid irradiation and anti-thymocyte globulin before a donor hematopoietic cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them. Giving an infusion of the donor's white blood cells, such as CD8+ memory T-cells, may boost this effect and may be an effective treatment to kill any cancer cells that may be left in the body (consolidative therapy).

Detailed description:
Participants undergo total lymphoid irradiation (TLI) on Days -11 to -7 and Days -4 to -1 and receive anti-thymocyte globulin (ATG) per standard institutional practice on Days -11 to -7. Patients also receive oral cyclosporine daily starting on Day -3, and will continue for at least 6 months post-transplant. Patients undergo standard non-myeloablative allogeneic HSCT on Day 0. Patients also receive oral mycophenolate mofetil daily beginning on Day 0 and continuing until Day 28. Participants receive an intravenous infusion of allogeneic cluster of differentiation 8 (CD8)+ memory T-cells over 10 to 20 minutes sometime between day 30 and day 60.

PRIMARY OBJECTIVES:

I. To determine the rate of conversion to full-donor chimerism (FDC) following a post-transplant infusion (Day 30-60) of freshly-enriched allogeneic CD8+ memory T-cells in patients with acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or Hodgkin lymphoma (HL), who received standard non-myeloablative total lymphoid irradiation (TLI) anti-thymocyte globulin (ATG) transplant conditioning.

SECONDARY OBJECTIVES:

I. To determine the risk of disease progression, overall and event free survival, and non-relapse mortality.

II. To determine the incidence of acute and chronic graft-versus-host disease (GVHD) following the infusion of allogeneic CD8+ memory T-cells.

OUTLINE:

Patients undergo TLI on days -11 to -7 and -4 to -1 and receive ATG per standard institutional practice on days -11 to -7. Patients also receive cyclosporine orally (PO) daily starting on day -3 and will continue for at least 6 months post-transplant. Patients undergo non-myeloablative allogeneic hematopoietic stem cell transplant (HSCT) on day 0. Patients also receive mycophenolate mofetil PO daily beginning on day 0 and continue until day 28. Based on the patient's status after the initial transplant, patients receive CD8+ memory T-cells intravenously (IV) over 10-20 minutes sometime between day 30 and day 60.

After completion of study treatment, patients are followed up periodically.

Arms: arm 1: All participants receive allogeneic CD8+ memory T-cells 30 to 60 days after standard non-myeloablative allogeneic hematopoietic cell transplant (aHCT).
Interventions: intervention 1: Anti-Thymocyte Globulin intervention 2: Cyclosporine intervention 3: Mycophenolate Mofetil intervention 4: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplant intervention 5: Allogeneic Cluster of Differentiation 8 (CD8)+ Memory T-cells intervention 6: Total Nodal Irradiation
Intervention descriptions: intervention 1: Given per standard institutional practice intervention 2: Given PO intervention 3: Given PO intervention 4: Undergo nonmyeloablative allogeneic HSCT intervention 5: Receive CD8+ memory T-cells via IV intervention 6: Undergo TLI

Protocol documents:
Prot_SAP_001.pdf: 
IRB-33058  
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23 August 2019 
  
Post Transplant Infusion of Allogeneic CD8 Memory T-Cells as Consolidative 
Therapy After Non-Myeloablative Allogeneic Hematopoietic Cell 
Transplantation in Patients with Leukemia and Lymphoma  
Coordinating Center 
Stanford Cancer Center 
875 Blake Wilbur Dr 
Stanford, CA 94305 
Protocol Director 
Robert Lowsky, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA 94305  
rlowsky@stanford.edu  
              
  NCT02424968      Version date: 23 August 2019 
 
Co-Investigators 
Wen-Kai-Weng, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
 wkweng@stanford.edu  
Robert Negrin, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr MC5623, Stanford, CA  94305 
negrs@stanford.edu 
Sally Arai, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
sarai1@stanford.edu 
Laura Johnston, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
korb@stanford.edu 
David Miklos, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
dmiklos@stanford.edu 
Judith Shizuru, MD, PhD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA 94305 
Jshizuru@stanford.edu 
Everett Meyer, MD 
Division of Blood and Marrow Transplantation 
and Cellular Therapeutics Facility Laboratory 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
evmeyer@stanford.edu 
Andrew Rezvani, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr , Stanford, CA  94305 
 
arezvani@stanford.edu 
Lori Muffly, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Dr, Stanford, CA  94305 
lmuffly@stanford.edu 
Samuel Strober, MD 
Divisions of Immunology & Rheumatology 
CCSR Building, Stanford, California 94305 
sstrober@stanford.edu 


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23 August 2019  
Michael Spinner, MD 
Division of Blood and Marrow Transplantation 
Stanford University Medical Center 
300 Pasteur Drive, Stanford, CA 94305 
mspinner@stanford.edu 
Philip Lavori, PhD (Biostatistician) 
Department of Health Research and Policy 
Biostatistics Shared Resource, 
Redwood Building, Stanford, CA 94305 
 
lavori@stanford.edu 
 
IRB number: 
IRB-33058  
OnCore number 
BMT288 
Version date: 
 23 August 2019 
IND number: 
IND 014844 
SRC Approval  
 20 April 2019 


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TABLE OF CONTENTS 
 
 
Protocol Synopsis 
4 
Schema 
5 
1. 
Objectives 
6 
2. 
Background 
6 
3. 
Participant Selection and Pre-Enrollment Requirements 
16 
4. 
Treatment Plan 
20 
5. 
Investigational Agent Information 
21 
6. 
Dose Modifications 
23 
7. 
Adverse Events and Reporting Procedures 
23 
8. 
Correlative / Special Studies 
25 
9. 
Study Calendar 
26 
10. 
Measurement and Statistical Methods 
27 
11. 
Regulatory Considerations 
28 
12. 
Statistical Considerations 
28 
References 
30 
Appendices 
34 
 


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Protocol Synopsis 
TITLE  
A post-transplant infusion of CD8 memory donor T-cells as 
consolidative therapy after allogeneic non-myeloablative hematopoietic 
cell transplantation in patients with leukemia and lymphoma. 
STUDY PHASE 
Phase 2 efficacy study 
STUDY SITE 
Stanford University Medical Center, CA 94305 
INDICATION 
Patients with leukemia and lymphoma who are not eligible for full dose 
transplantation 
INVESTIGATIONAL 
PRODUCT  
Allogeneic CD8 memory T-cells infused 30 to 75 days after 
hematopoietic cell transplant 
PRIMARY 
ENDPOINT and 
OBJECTIVE(S) 
To determine the proportion of patients with full dose donor T-cell 
chimerism within 3 months after the CD8+ memory T-cell infusion. 
SECONDARY 
ENDPOINTS AND 
OBJECTIVE(S) 
1. To determine the risk of disease progression, overall and event free 
survival, and non-relapse mortality following treatment with 
allogeneic CD8+ memory T-cells. 
2. To determine the incidence of acute and chronic GVHD following 
infusion of allogeneic CD8 memory T-cells. 
STUDY 
OBSERVATION 
PERIOD 
Patients will be followed for 6 months from the time of transplant 
(about 4 month after the CD8+ memory T-cell infusion) 
TREATMENT 
SUMMARY 
The efficacy of non-myeloablative allogeneic transplantation is 
mediated in part by the establishment of an alloreactive donor T-cell 
compartment following transplant with minimal toxicity.  A 
post-transplant infusion of allogeneic CD8+ memory T-cells may 
facilitate the conversion to full donor chimerism without an increase in 
graft versus host disease.  This is a single institution open-labeled 
single treatment study evaluating the efficacy of allogeneic CD8+ 
memory T-cell infusion derived from HLA-matched sibling donors.   
SAMPLE SIZE  
20 patients plus 20 sibling donors 
SUMMARY OF 
SUBJECT 
ELIGIBILTY 
Patients with the following histologically-confirmed disease: 
1. Acute myeloid leukemia (AML) 
2. Chronic lymphocytic leukemia (CLL) 
3. Non-Hodgkin lymphoma (NHL) 
4. Hodgkin lymphoma (HL) 
5. Myelodysplastic syndrome (MDS) /  
Myeloproliferative disease syndrome  (MPD) 
Patients not undergoing a full dose transplant conditioning 
Patients with HLA-matched or single antigen/allele mismatched related 
donors. 
CONTROL GROUP 
Historically-matched control patients 


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SCHEMA 
 
Day -11 
TLI 1 120 cGy 
ATG 2 1.5 mg/kg 
 
Day -10 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -9 
TLI 120cGy 
ATG 1.5 mg/kg 
 
Day -8 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -9 
TLI 120 cGy 
ATG 1.5 mg/kg 
 
Day -4 
TLI 120 cGy 
 
 
Day -3 
TLI 120cGY 
 
oral CsA 3 
Day -2 
TLI 120 cGy 
 
 
Day -1 
TLI 
120 cGy x 2 
 
 
Day 0 
 
infusion of 
mobilized PBSC 4 
oral MMF 5 
Day 25 to 70 
On study 
enrollment date 
Cyclophosphamide 
1.5 g/m2 IV x1 
 
Day 30 to 75 
 
CD8 memory 
T-cell infusion 
 
 Age ≤ 80 
 Not eligible for a 
myeloablative preparative 
regimen 
 Available HLA-matched or 
single allele/antigen 
mismatched related donor 
 Estimated creatinine clearance 
≥ 50 mL/min 
 LVEF ≥ 30%,  
 DLCO ≥ 40% predicted 
(adjusted for Hgb) 
 TBili < 3mg/dL 
 AST/ALT < 3X ULN 
 KPS ≥ 70 
Screening / Eligibility 
 AML 
 CLL 
 NHL 
 HL 
 MDS/MPD 
HLA-matched or single antigen/allele 
mismatched related donor 
G-CSF 16 mcg/kg x 5 days 
Collection of hematopoietic cells by 
apheresis, desired goal of ≥ 5 million 
CD34+ cells/kg recipient weight for 
infusion on Day 0 
Collection of unstimulated donor lymphocytes by  
apheresis with infusion of fresh column enriched  
CD8 memory T-cells between Days 30 to 75 
post-transplant, desired dose of 5 million/kg recipient 
weight 
1  TLI = total lymphoid irradiation 
2  ATG = anti-thymocyte globulin  
3  CsA = cyclosporine 
4  PBSC = peripheral blood stem 
cells.  The PBSC infusion 
procedure is called a 
hematopoietic cell transplant 
(HCT) or donor leukocyte 
infusion (DLI)  
5  MMF = mycophynelate mofitel 


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1. 
OBJECTIVES 
1.1 Primary Objective 
To determine the rate of conversion to full donor chimerism (FDC) following a post-transplant 
infusion (Day 30 to 75) of freshly enriched allogeneic CD8+ memory T-cells in patients with 
AML, NHL CLL, or HL, who received non-myeloablative TLI ATG transplant conditioning. 
1.2 Secondary Objectives 
1.  To determine the risk of disease progression, overall and event free survival, and non-relapse 
mortality. 
2.  To determine the incidence of acute and chronic GVHD following the infusion of allogeneic 
CD8+ memory T-cells. 
2. 
BACKGROUND 
2.1 Allogeneic Hematopoietic Cell Transplantation 
Allogeneic hematopoietic cell transplantation (HCT) is proven effective therapy for patients with a 
variety of hematolymphoid malignancies.  Following allogeneic HCT, a significant percentage of 
patients who were otherwise considered to have incurable cancers using best of care 
non-transplantation therapies have long-term disease free control and appear cured.  These patients 
are characterized by developing donor type hematopoiesis and have complete resolution of all 
disease-related signs, symptoms and markers.  Generally, patients who undergo allogeneic HCT 
are doing so as a “last ditch” effort for long-term disease control and possibly cure after exhausting 
all chemotherapy, and radiation therapy based treatment strategies.  Often many of the patients 
who undergo allogeneic HCT for treatment of their lymphoma have had disease relapse even after 
high dose chemotherapy and autologous stem cell rescue (autologous HCT). 
2.2 Relapse of Disease following Allogeneic HCT 
The main cause for treatment failure following allogeneic HCT is disease relapse.  Depending, in 
part, on the disease, disease status at the time of transplantation, and the intensity of the 
transplantation regimen, disease relapse occurs in roughly 25 to 80% of patients.  For example, 
following a full dose transplant in younger patients with acute leukemia in 1st or 2nd complete 
remission (CR) and using a graft from an HLA-matched sibling, the 2-year risk of disease relapse 
was < 30% [1-8].  In contrast, the 2-year risk of disease relapse for younger patients with 
refractory acute leukemia who received a full dose transplant was > 70% [9-11].  Older (> 55 years 
of age) patients or younger patients with medical co-morbidities that preclude full dose 
conditioning undergo reduced intensity conditioning (RIC) allogeneic HCT.  The 2-year risk of 
disease relapse in patients with acute leukemia in CR who received RIC allogeneic HCT was 
> 50% [12, 13].  Similarly, disease relapse remains the major cause of treatment failure for patients 
with T-cell, large B-cell and Hodgkin lymphomas and chronic lymphocytic leukemia (CLL) and 
occurs in > 40% who undergo RIC allogeneic HCT with chemotherapy, sub-lethal total body 
irradiation (TBI), or total lymphoid irradiation combined with anti-thymocyte globulin (TLI/ATG) 
[13-18].   
2.3 Treatment for Disease Relapse Following Allogeneic HCT 
Disease relapse following allogeneic HCT remains an ominous clinical event, which usually 
results in progressive disease and death.  Treatment strategies of patients with relapse following 


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allogeneic HCT can often be further complicated by the overall general poor clinical status of the 
patient.  Strategies for the treatment of disease relapse in these patients include the cessation of 
post-transplantation immune suppression medication, salvage chemotherapy with or without 
irradiation, a second allogeneic HCT, or the infusion of donor leukocytes (DLI).  Despite these 
interventions few patients beyond those with chronic myelogenous leukemia (CML) can be 
returned to durable remissions and the overall survival (OS) at 2 years following disease relapse 
was < 20% [19, 20].  Given that disease relapse is relatively common after transplant, and that few 
if any patients can be returned to durable remission once relapse has occurred, a desired goal 
would be to improve the transplant strategy and avoid the serious problem of post-transplant 
disease relapse. 
2.4 Graft Versus Tumor Reactions 
A major mechanism of cancer eradication following allogeneic HCT is the immunological-based 
recognition of residual host tumor cells by donor-derived immune cells contained in the donor 
graft.  This phenomenon, termed graft-versus-tumor (GVT) reactions, is supported by various lines 
of evidence.  The initial observations in support of GVT reactions stemmed from studies that used 
T-cell depleted (TCD) donor grafts whereby graft-versus-host disease (GVHD) was eliminated; 
however, without donor T-cells in the donor inoculum patients suffered a high incidence of disease 
recurrence [21].  The importance of GVT reactions was further demonstrated by improved disease 
control and fewer relapses following HLA identical sibling (allogeneic) transplantation compared 
to syngeneic (identical twin) transplantation for patients with hematologic malignancies [22].  The 
three year probability for relapse of leukemia was substantially higher following syngeneic 
compared to allogeneic HCT in acute myelogenous leukemia (AML) (52% vs 16%) and CML 
(40% vs 7%) following treatment using full dose transplant conditioning regimens [22].  The 
increased risk of relapse in syngeneic transplants counterbalanced the beneficial effect of the lack 
of GVHD.  Perhaps the most compelling evidence comes from the observation that the infusion of 
donor leukocytes obtained from the original donor in patients who have disease relapse following 
allogeneic HCT resulted in a GVT effect (23).   
2.5 Reduced Intensity Transplant Conditioning 
Following the recognition that a main mechanism of disease control after allogeneic HCT is by 
donor derived immune mediated GVT reactions, multiple groups, including our own at Stanford,  
developed reduced intensity transplant conditioning (RIC) regimens that shifted the burden of 
disease control from high doses of chemoradiotherapy to the donor immune system (24-28).  The 
low intensity transplant conditioning has allowed older patients and those with medical 
co-morbidities to proceed with transplant whereas, before these patients were excluded from 
allogeneic transplantation as the full dose conditioning regimens were associated with prohibitive 
toxicities.  As a consequence of the low dose conditioning, host hematopoietic and immune cells 
persist and result in a state of mixed hematopoietic and lymphoid chimerism (MC) that may 
convert to full donor chimerism (FDC) over a variable time course (13, 28-30).  Importantly, the 
achievement of early (before Day 60) FDC appears to be a necessary precondition for disease 
control (13, 28-30).  We and others have reported that irrespective of the specific type of RIC 
regimen used, the relapse risk is significantly higher in patients with persistent MC compared to 
those with FDC, and likely reflects tolerance of donor cells to recipient tissues (13, 28-30).  In a 
report detailing the outcomes of 111 allogeneic HCT recipients from HLA-matched and single 
antigen mismatch donors following TLI-ATG conditioning for leukemia and lymphoma there was 
a very low incidence of severe (Grade 2 to4) acute GVHD (< 5%), and a low incidence of 


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non-relapse related mortality at 1 year (< 5%) (13).  Whereas almost all patients who failed to 
achieve FDC experienced disease relapse, the actuarial event free survival was more than 55% in 
the patients who achieved > 95% donor type chimerism, with observations extending up to 6 years 
(13).  
2.6 Strategies to Convert MC to FDC 
Attaining FDC relatively early post-transplant is desirable because of its significant association 
with a reduced risk of disease relapse (13, 28-36).  A commonly used strategy to convert MC to 
FDC has involved the use of low dose, or escalating doses, of donor lymphocyte infusions (DLI) at 
designated early time points post-transplant [31-36].  These studies confirmed that prophylactic 
DLI (i.e.  before disease progression) induced conversion to FDC and was associated with a 
reduced risk of disease relapse, yet overall survival was not improved in these trials due to the 
increased risk of significant acute GVHD (31-36). 
In summary, disease relapse is the main cause of treatment failure following allogeneic HCT and is 
an ominous event as most patients cannot be returned to durable remission.  A significant 
percentage of patients who receive reduced intensity conditioning remain as MC for months and 
there is a significant association of MC with increased risk of disease relapse.  Conversion of MC 
to FDC following low dose or escalating doses of DLI was associated with a reduced risk of 
disease relapse yet OS was not improved due to the limiting toxicity of severe acute GVHD.  A 
pre-emptive strategy that would promote conversion of MC to FDC and retain immune mediated 
GVT reactions yet without promoting GVHD has the potential to benefit patients and may improve 
the cure rate in patients following allogeneic HCT. 
2.7 Preclinical Strategies to Overcome GVHD with DLI in a Murine Model Memory T-cells 
Induce Significantly Less GVHD than Naïve T-cells 
Recent murine studies showed that in many strain combinations memory T-cells, including 
memory CD4+, and memory CD8+ T-cells induce significantly less GVHD than naive T-cells 
(CD62LhiCD44lo) or combinations of naive and memory T-cells [37-43]. 
Accordingly, our group at Stanford compared freshly isolated naive CD4+, CD8+, or total T-cells, 
and/or memory CD4+CD44hi, CD8+CD44hi, and total memory T CD44hi cells from unprimed 
donors for their capacity to induce GVHD, and mediate antitumor activity against a naturally 
occurring B-cell lymphoma (BCL1) in an MHC-mismatched model where CD4 is predominant yet 
CD8 also can induce lethal GVHD (44).  Only the CD8+CD44hi memory T-cell subset containing 
both central and effector memory cells was capable of eradicating the lymphoma cells without 
inducing GVHD.  In contrast, CD4+ and CD8+ naïve T-cells, memory CD44hi CD4+ T-cells, 
naive total T-cells, and memory CD44hi total T-cells either induced lethal GVHD or lacked potent 
antitumor activity.  The tumor-bearing recipients of CD8+CD44hi T-cells had a clear survival 
advantage over those given CD8+ naive T-cells because of the lethal GVHD induced by the latter.  
The CD8+CD44hi T-cells were also used in a model of treatment of progressive lymphoma growth 
after BMT, and were able to promote complete chimerism and eradicate the tumor without GVHD. 
In other preclinical murine models of bone marrow transplantation using various MCH-matched 
strain combinations conducted by our group, the only cell subset that we could identify that 
provided GVT reactions against FBL3 leukemia tumor cells without inducing lethal GVHD was 
CD44hiCD8+ memory T-cells [45]. 


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Taken together, our studies and those by others suggest that CD8+ memory T-cells will have 
retained promote donor cell engraftment and retain GVT reactions yet have markedly reduced 
GVHD capacity.  These studies support the hypothesis that a clinical trial of infusing CD8+ 
memory T-cells may be superior to DLI for the conversion of MC to FDC following allogeneic 
HCT. 
2.8 Purification of human CD8+ memory T-cells for use as DLI therapy 
 
Figure 1A, Representative flow analysis of peripheral blood apheresis collections from the 
pre-selection, post-CD45RA depletion, and CD8 enrichment steps and stained for 
expression of CD4, CD8, CD45RA, and CD45RO after gating on CD3+ cells.   
Since we were successful in treating progressive tumor growth after BMT without inducing 
GVHD in mice with enriched donor CD8+ memory T-cells, we attempted to purify a similar subset 
of freshly isolated T-cells from normal humans for use in the currently planned study.  
Accordingly, we used immunomagnetic bead separation on Miltenyi columns to enrich 
CD8+CD45RO+CD45RA- T-cells from PBMCs (46).  First, cells were incubated with Miltenyi 
Unfractionated 
CD45RA Depleted 
1A 
CD45RA depleted 
CD8 selected 
CD8 
 


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GMP grade anti-CD45RA mAb conjugated beads for negative selection.  Thereafter, the 
CD45RA- cells were incubated with Miltenyi GMP grade anti-CD8 mAb conjugated beads to 
positively select the CD8+ cells.  The resultant CD8+CD45RA- T-cells had over 95% purity as 
shown in the FACS pattern in Figure 1A that is representative of 6 independent separations.  
Almost all the CD45RA-CD8+ cells were CD45RO+CD8+.  Yields of the cells were also 
determined using apheresis products from normal HCT donors and the mean post-enrichment cell 
count obtained from a single apheresis product was 5 x 108 with a range of 3 to 8 x 108 
CD45RA-CD8+ cells.  Therefore, following 2 high volume aphereses per donor, the highest 
feasible dose of memory CD8+ T-cells available for infusion will be 10 x 108 cells.  Assuming 
most patients weigh less than 100 kg, attainable numbers of memory CD8+ T-cells for a phase 1 
dose escalation trial are 1 x 106/kg;  5 x 106/kg;  and 10 x 106/kg.  IND 014844 has been submitted 
to the FDA describing the use of manipulated donor lymphocyte infusion (DLI) cells in clinical 
trials. 
 
In further studies the enriched CD45RA-CD8+ human memory T-cells were tested for immune 
reactivity in vitro by stimulation with irradiated allogeneic PBMCs from normal donors.  The 
cultures were monitored for 3H-thymidine incorporation at 7 days and for IFN-γ and IL-2 
concentrations in the supernatants.  The responder T-cells increased the mean 3H-thymidine 
incorporation in cultures with allogeneic stimulator cells as compared to control cultures without 
allogeneic stimulators (data not shown).  In addition, the memory CD8+ T-cell supernatants had a 
marked increase in the concentration of IFN-γ after culture with allogeneic stimulator cells, and 
had a minimal increase in the concentration of IL-2 (Figure 1B).  The results of the human mixed 
Figure 1B, Cytokine secretion assessment in CD8
+/CD45RA
- and 
CD4
+ cells activated by co-culture with or without irradiated allogeneic 
stimulators (Stim).  Supernatants from 7-day cultures were analyzed by 
flow cytometry using Cytokine Bead Arrays for INFγ;  IL-2;  and TNFα 
(n = 4).  Results are shown with +/- standard deviation (SD) 
1B 


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leukocyte response (MLR) experiments were consistent with the responses observed with CD8+ 
memory T-cells from mice.  The murine responder cells also showed a marked increase in 
3H-thymidine incorporation after stimulation with allogeneic cells, and the production of IFN-γ 
was considerably greater than that of IL-2 [46]. 
In summary, these studies demonstrated that an enriched population of CD8+ memory T-cells can 
be obtained from healthy human donors that in MLR experiments were consistent with the 
responses observed with CD8+ memory T-cells from mice and provided evidence for clinical 
safety (limited GVHD) and efficacy (retained GVT reactions).   
2.9 Phase 1 Clinical Trial of CD8+ Memory T-cell Infusion for Disease Relapse after 
Allogeneic HCT 
We conducted a single institution open-labeled single treatment study evaluating the safety and 
potential efficacy of allogeneic CD8+ memory T-cell infusion derived from HLA-matched sibling 
donors.  The phase I study followed a standard 3+3 dose escalation format using a low CD8+ 
memory T-cell dose of 1 x 106 cells/kg, an intermediate dose of 5 x 106 cells/kg and a final dose of 
10 x 106 cells/kg.  The objectives of the protocol were:   
1. To determine the feasibility of purifying allogeneic CD8+ memory T-cells suitable for 
clinical application and to determine the safety and maximum tolerated dose (MTD) of 
these cells in patients with recurrent or refractory hematolymphoid malignancies following 
allogeneic HCT.   
2. To determine disease response, time to disease progression, event-free survival, and overall 
survival following treatment with allogeneic CD8+ memory T-cells.   
3. To assess donor specific chimerism before and at designated time points after treatment 
with allogeneic CD8+ memory T-cells. 
To date, 8 patients with disease relapse after allogeneic HCT have been enrolled on the study and 
were followed for safety and potential efficacy.  The Table below summarizes the patients.  
Pt Dose 
level 
Dx 
DOT 
Date of 
Relapse 
Status at CD8+ 
memory 
T-cell infusion 
Date of CD8+ 
memory 
T-cell  infusion 
AE or GVHD 
Follow-up 
(months) 
Status at last 
F/U 
1.1 
1 
AML 
2-27-09 
8-25-11 
CR2 
4-17-12 
none 
27 
Alive in CR 
1.2 
1 
AML 
4-6-12 
8-1-12 
Not in CR 
8-10-12 
none 
17 
Expired 
1.3 
1 
AML 
08-14-03 4-17-12 
CR3 
10-11-12 
none 
20 
Alive, 
Relapse 
2.1 
2 
AML 
07-17-12 
1-4-13 
CR2 
6-6-13 
none 
14 
Expired 
2.2 
2 
BC- CML 08-29-07 
2-1-13 
CR 
6-27-13 
none 
13 
Alive in CR 
2.3 
2 
CLL 
09-03-10 3-15-12 
Not in CR 
7-17-13 
none 
3 
Expired 
3.1 
3 
AML 
05-31-13 7-10-13 
Not in CR 
10-9-13 
AE*, no GVHD 
1 
Expired 
3.2 
3 
AML 
03-15-13 11-18-13 Not in CR 
4-2-14 
AE*, no GVHD 
6 
Alive, 
Relapse 
* The AE was unrelated to CD8+ memory T-cell infusion. 


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Detailed patient summaries are provided below and are divided by cell dose cohort, 
Cohort 1:  A dose of 1 x 106 CD8+ memory T-cells/kg 
Patient 1.1:  A 66-year-old female with AML relapse 910 days after TLI-ATG conditioned 
allogeneic transplant from her matched sibling donor.  For disease relapse she received 4 cycles of 
myelotarg combined with azacytadine and achieved a complete marrow remission with < 5% 
marrow blasts yet had incomplete count recovery.  She received the donor CD8+ memory T-cell 
infusion on 17 April 2012, and as per visit on 21 October 2014, she was 917 days post CD8+ 
memory T-cell infusion and continues in complete remission with normal blood counts and a 
marrow with no evidence of AML. 
Patient 1.2:  A 71-year-old female with AML who had disease progression 117 days after 
TLI-ATG conditioned allogeneic transplant from her matched sibling donor.  The patient declined 
chemotherapy her post-transplant disease relapse.  Therefore, CD8 memory T-cells were infused at 
a time of the patient had active disease.  Post CD8+ memory T-cell infusion, the patient developed 
stable disease and was transfusion independent for 455 days.  Fifteen months after the cell infusion 
the patient presented with leukemic cutis and declined therapy and she succumbed from 
progressive disease on Day 517 after the cell infusion. 
Patient 1.3:  A 40-year-old female with extra medullary leukemia relapse 3165 days after initial 
allotransplant.  She received involved field radiation therapy to the extra-medullary site of disease 
and 4 cycles of Azacytadine and was returned to remission.  On evaluation on 727 days after the 
CD8 memory T-cell infusion, she was alive yet had disease relapse 650 days after the cell infusion. 
Cohort 2:  A cell dose of 5 x 106 CD8+ memory T-cells/kg 
Patient 2.1:  A 37-year-old with AML who had disease relapse 169 days after allogeneic 
transplant from a matched sibling donor.  The patient received 7+3 re-induction with cytarabine 
and Daunorubicin and failed to achieve a remission.  Thereafter the patient received 2 cycles of 
G-CLAC (G-CSF, clofarabine and cytarabine) and achieved a marrow remission with incomplete 
blood count recovery.  Following the CD8+ memory T-cell infusion the patient continued in 
remission with normal blood counts for 9 months and thereafter had chemorefractory resistant 
recurrence and expired from AML 418 days after the cell infusion. 
Patient 2.2:  A 60-year-old who underwent allogeneic HCT from a matched sibling donor for blast 
crises CML and developed a return of chronic phase CML 1829 days after transplant.  The patient 
was returned to a complete remission with dasatinib and at last follow up continues in complete 
remission, 435 days after the CD8+ memory T-cell infusion. 
Patient 2.3:  A 53-year-old with multiply recurrent high risk CLL who had disease progression 
545 days post allotransplant that progressed on salvage bendamustine-rituximab, and was treated 
to a stable disease using 3 cycles of FCR (fludarabine, cyclophosphamide, and rituximab).  Shortly 
(32 days) after receiving the CD8+ memory T-cell infusion the patient had progressive disease and 
was transitioned to best supportive care and died 89 days after the cell infusion. 
Cohort3:  A cell dose of 10 x 106 CD8+ memory T-cells/kg  
Patient 3.1:  A 61-year-old woman with refractory AML at start of allotransplant conditioning 
despite several attempts to achieve remission using 3 different induction regimens.  The patient 
had progressive AML 65 days post allotransplant and received salvage FLAG (fludarabine, 
high-dose cytarabine, G-CSF) chemotherapy and continued with refractory disease.  For her 


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refractory disease the patient was infused with 7.8 x 106 CD8 memory T-cells/kg, instead of the 
desired cell dose of 10 x 106cells/kg.  The patient continued with progressive disease and was 
transitioned to best supportive care and died 42 days after the cell infusion. 
Patient 3.2:  A 67-year-old man with overlap Myeloproliferative Disease and Myelodysplastic 
syndrome who on azacitidine progressed to AML.  He failed to receive remission despite 2 courses 
of induction cytarabine and daunorubicin and underwent allogeneic HCT using his HLA-matched 
sibling donor.  He had progressive AML 236 days after transplantation and received several cycles 
of re-induction chemotherapy using vorinostat with temozolomide yet his disease failed to 
respond.  He received a CD8 memory T-cell donor lymphocyte infusion for his refractory disease; 
the dose of cells was 8 x 106 CD8 memory T-cells/kg, instead of the desired 10 x 106 CD8 memory 
T-cells/kg.  At last follow-up 185 days after the cell infusion, the patient continues with a stable 
low level of AML and has not received additional chemotherapy.   
Two adverse events, considered unrelated to the infused cell product were noted. 
Patient 3.1 had neutropenia prior to the cell infusion and continued with neutropenia after the cell 
infusion.  The neutropenia was related to active AML.  Eighteen days after the CD8 memory 
T-cell infusion, the patient developed a fever that was treated to resolution with short course broad 
spectrum intravenous antibiotics and anti-fungal therapy.  All cultures were negative.  The reported 
adverse event was most likely UNRELATED to the investigational product.  The serious adverse 
event (SAE) was reported to MedWatch on 6 November 2013.   
Patient 3.2 had neutropenia prior to the cell infusion and continued with neutropenia after the cell 
infusion.  The neutropenia was related to active AML.  The patient developed fevers 33 days after 
the cell infusion.  Imaging studies at the time revealed probable new onset pneumonia.  The 
pneumonia was treated to resolution with broad spectrum antibiotics.  A bronchoscopy revealed 
light growth of MSSA.  The patient completed a full course of rocephin, azithromycin, and 
fluconazole.  The PCP stain was negative.  The patient continues with active AML.  The adverse 
event was most likely UNRELATED to the investigational product. 
2.10 Lymphodepletion with cyclophosphamide to promote CD8+ memory T-cell expansion 
and persistence 
Lymphodepletion with cyclophosphamide administered several days prior to DLI has been shown 
to promote in vivo expansion and persistence of the infused donor lymphocytes by providing 
lymphoid space, eliminating anti-donor immune reactivity, and reducing competition for growth 
factors that promote expansion of the infused T-cells [47-49]. Lymphodepletion with 
cyclophosphamide is thus routinely utilized prior to the infusion of various autologous or 
allogeneic cellular therapies where it has been shown to augment the antitumor activity of 
unmanipulated DLI [50, 51], chimeric antigen receptor-modified T cells [52, 53], and adoptively 
transferred tumor-specific T cells [54, 55]. We therefore propose administering a single dose of 
cyclophosphamide 1.5 g/m2 intravenously 3-5 days prior to the CD8+ memory T-cell infusion in 
order to promote further expansion and persistence of the cells, augment GVT activity, and reduce 
relapse rates.  
 


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The Cell Processing and Quality Assurance data are highlighted below.  
Cell Processing Summary 
 
CD8+ memory T-cell Quality Assurance Assessment 
 
 


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From the clinical trial the following observations are made 
1. The CD8 memory T-cell infusion was not associated with any infusion related toxicities, or 
related adverse events such as the development of GVHD, or other. 
2. The CD8 memory T-cell infusion appeared to have some efficacy albeit patients who have 
relapse of disease after allogeneic transplant have a poor overall survival at < 20% at 
2 years [19, 20].  Among the 8 patients treated, one patient continues in CR more than 
2 years after the CD8 memory T-cell infusion, one patient with untreated relapse continued 
with disease that did not progress and transfusion independence for > 1 year, and 
2 additional patients remain alive but with disease relapse with observations extending to 
beyond a year. 
3. Although no toxicities were observed at any dose, the maximum cell dose of 
10 x 106 CD8+ memory T-cells/kg is not a feasible dose for use in a clinical trial due to our 
inability to obtain this high number of CD8 memory T-cells.  Rather, a dose of 
5 x 106 cells/kg is readily obtainable from all donors. 
2.11 Study Rationale 
The administration of CD8+ memory T-cells at doses of ≤ 10 x 106 cells/kg did not result in 
GVHD, or other related adverse events.  The persistence of mixed hematopoietic cell chimerism is 
associated with a significantly high risk of disease relapse after allogeneic HCT [13, 28-36].  Once 
the patient’s disease has relapsed after allogeneic HCT, the likelihood for long-term survival is 
poor.  Therefore, a strategy that can help promote conversion of mixed to complete hematopoietic 
cell chimerism prior to disease relapse, and does not promote significant GVHD has the potential 
to help improve the outcomes of allotransplant recipients by reducing the risk of disease relapse.  
The goal of the current proposed trial will be to determine if CD8+ memory T-cells administered 
prophylactically and prior to disease relapse can convert patients with mixed chimerism at 
30 to 75 days after transplant to complete chimerism.  We hypothesize that patients who convert 
from mixed to complete chimerism will have a reduced rate of relapse similar to patients who are 
complete chimeras.  This study will follow a single arm Simon 2-stage trial principle.  In 
Simon stage 1, we will enroll 8 patients, and if 3 or fewer patients respond, defined as the 
conversion from mixed to complete chimerism within 90 days of the CD8+ memory T-cell 
infusion, we will stop for futility.  If 4 or more respond in Simon stage 1, then in stage 2 we will 
continue to enroll a full sample of 20 patients and declare success if a total of 11 or more patients 
respond.  The time frame for the CD8+ memory T-cell infusion will be between 30 to 75 days after 
transplant, and all patients will continue with the planned immune suppression drug taper to 
discontinuation at 6 months after transplant providing no GVHD is observed.  The primary 
endpoints will be safety and determination of the rate of conversion from mixed to complete donor 
chimerism.  If > 2 patients among the first 6 enrolled experience any new Grade 3 to 4 toxicities or 
> 2 patients develop Grade 3 to 4 GVHD during the 60 days following the CD8+ memory T-cell 
infusion, we will de-escalate the dose to 1 x 106 CD8+ memory T-cells/kg.  Based on our 
preclinical data that CD8+ memory T-cells do not aggravate GVHD, and the data from the clinical 
phase 1 trial we do not expect toxicities at a dose of 5 x 106/kg.  Secondary endpoints will include 
the risk of acute and chronic GVHD, freedom from disease progression, event-free and overall 
survival, and the relapse rate.  The goal is to improve the rate of attaining complete chimerism 
without increasing the risk of GVHD.  If following the Simon 2-stage trial the results are 


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lncouraging, we will expand our experience to a broader trial to determine if the infusion of CD8+ 
memory T-cells is associated with significantly lower rates of disease relapse. 
Study Design 
This is a single institution open-labeled single treatment study evaluating the safety and efficacy of 
allogeneic CD8+ memory T-cell infusion derived from HLA-matched sibling donors.  Enrollment 
of 18 patients is expected to be completed in less than 3 years.  The study will involve a single 
non-randomized intervention arm of administering 5 x 106 cells/kg CD8+ memory T-cells 
30 to 75 days after allogeneic HCT using TLI ATG conditioning.  The total duration of patient 
study participation is 6 months.  Patients will be followed indefinitely for all outcomes including 
survival, event-free survival and late complications such as but not limited to late chronic GVHD 
and infections. 
3. PARTICIPANT SELECTION AND PRE-ENROLLMENT REQUIREMENTS 
Refer to the Participant Eligibility Checklist in Appendix A. 
3.1  
Patient Inclusion Criteria for Transplant (patients must have all of the following). 
3.1.1  Between 18 and 80 years of age, inclusive. 
3.1.2  Has a HLA-matched or single allele-mismatched adult sibling serving as donor. 
3.1.3 Has a myeloid or lymphoid malignant disease that is treated with TLI and ATG 
reduced-intensity conditioning for allogeneic transplant [any of the following:  acute 
myeloid leukemia (AML);  chronic lymphocytic leukemia (CLL);  B or T-cell 
non-Hodgkin lymphoma (NHL);  Hodgkin lymphoma (HL);  Myelodysplastic syndrome 
(MDS);  or Myeloproliferative disease syndrome  (MPD)] 
3.1.4  Patients who due to age, pre-existing medical conditions, or, prior therapy are considered to 
be at high-risk for regimen-related toxicity associated with fully ablative transplant 
conditioning, and therefore reduced intensity conditioning is recommended. 
3.1.5  Ability to understand and the willingness to sign a written informed consent document.  
Patients must have signed informed consent to participate in the trial. 
3.2  
Patient Exclusion Criteria for Transplant (excluded if any of the following) 
3.2.1.   Uncontrolled bacterial, viral or fungal infection defined as currently taking medication and 
progression of clinical symptoms. 
3.2.2.  Progressive hemato-lymphoid malignancy despite conventional therapy 
3.2.3.  Acute leukemia not in remission 
3.2.4.  Chronic myelogenous leukemia (CML)  
3.2.5.  Active CNS involvement of the underlying malignancy 
3.2.6.  HIV-positive 
3.2.7.  Pregnant or lactating  
3.2.8.  Prior malignancy (EXCEPTION:  diagnosed > 5 years ago without evidence of disease, OR 
treated ≤ 5 years ago but have a greater than 50% chance of life expectancy of ≥ 5 years for 
that malignancy). 
E.2.9.  Have a psychiatric disorder(s) or psychosocial circumstance(s) which in the opinion of the 
primary physician would place the patient at an unacceptable risk from transplant. 


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3.2.10. Organ dysfunction defined as follows: 
i.  Ejection fraction < 30%, or uncontrolled cardiac failure 
ii.  DLCO < 40% predicted 
iii.  Total bilirubin > 3 mg/dL 
iv.  SGOT or SGPT > 4 x ULN 
v.  Creatinine > 2 mg/dL and an estimated creatinine clearance < 40 mL/min  
j.  Poorly controlled hypertension despite multiple antihypertensive medication 
k.  KPS < 60% 
l.  Note:  Patients positive for hepatitis B and C will be evaluated on a case-by-case basis 
3.3  
Donor Inclusion/Exclusion Criteria (To be eligible to participate in this trial, donors must 
meet the following criteria): 
3.3.1 HLA-matched or single allele mismatched sibling of enrolled transplant patient 
3.3.2 18 to 80 years of age, inclusive 
3.3.3 In a state of general good health and have completed a donor evaluation with history, 
medical examination and standard blood tests within 60 days of starting the hematopoietic 
cell collection procedure.  In order to fairly represent the interests of the donor, the donor 
evaluation and consent will be performed by a study team member other than the 
recipient’s attending physician.  
3.3.4 White blood cell count >3.5 x 109/liter, platelets >150 x 109/liter and hematocrit > 35% 
3.3.5 Capable of undergoing leukapheresis 
3.3.6 Able to understand and sign informed consent 
3.3.7 Hepatitis A, B and C, HIV-1 and -2, HTLV, VZV, EBV, HSV, West Nile virus, Syphilis 
Treponema, T cruzi (Chagas), CMV, and the MPX NAT IDT (HIV/HCV/HBV) will be 
tested as per national standard of care guidelines for transplant donors.  Donors who are 
HIV-positive will be excluded.  Donors who are positive by serology for Hepatitis B or C 
are eligible as long as PCR for RNA/DNA is negative.  
3.3.8 Females must not be pregnant or lactating 
3.3.9 
No psychological traits or psychological or medical conditions which make them unlikely to 
tolerate the procedure 
3.3.10 Has not developed a new malignancy requiring chemotherapy or radiation in the interval since 
apheresis for initial HCT 
3.4 
Patient Criteria for Proceeding with CD8+ Memory T-cell Infusion:  On Study 
enrollment date. 
3.4.1 Patients must be beyond Day 30 and before Day 75 after transplant. 
3.4.2 Patients must have evidence of mixed CD3 T-cell chimerism based on the Day +28 
(+/- 7 days) blood sample showing ≥ 30% and <90% donor type cells. 
3.4.3 Patients must have no evidence of active graft-versus-host disease at the time of the CD8+ 
memory T-cell infusion.  Patients with a history of acute GVHD overall Grade 2 based on 
skin only involvement or upper GI tract involvement only will be eligible.  Patients with a 
history of Liver or lower GI tract GVHD will not be eligible. 


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3.4.4 Patient must not have clinical evidence of disease progression prior to the CD8+ memory 
T-cell infusion. 
3.4.5 Patients must be on single immune suppression therapy with either Tacrolimus or 
Cyclosporine at the time of CD8+ memory T-cell infusion.  Prednisone at a physiologic 
dose of 5mg per day or less is allowed. 
3.4.6 Patients must have a Karnofsky performance status of ≥ 60% at the time of the CD8+ 
memory T-cell infusion. 
3.4.7 Patients must not have an uncontrolled bacterial, fungal or viral infection, defined as 
progressive symptoms despite therapy, at the time of the CD8+ memory T-cell infusion.  
Asymptomatic viremia is allowed. 
3.4.8 Patients must have adequate organ function and performance status at the time of the CD8+ 
memory T-cell infusion, defined by the following: 
i. Total bilirubin ≤ 4 mg/dL 
ii. SGOT or SGPT ≤ 4 x ULN 
iii. Creatinine ≤ 3 mg/dL or estimated creatinine clearance ≥ 40 mL/min  
3.5 Donor Evaluation for CD8+ Memory T-Cell Collection 
Donors must be the HLA-matched sibling who served as the donor for the allogeneic transplant.  
Within 7 days of cell collection, donors will be screened to confirm eligibility.  Screening will 
consist of the following evaluations and procedures.   
- 
A transplant physician together with the study coordinator will review the prior medical 
record that was performed for the initial transplant. 
- 
Under the direction of the study coordinator, donors will fill out a standard Stanford BMT 
self-assessment form that highlights all new medications prescribed from the time of initial 
donation, as well as any new medical diagnosis or surgeries. 
- 
Any newly prescribed medication, new medical diagnosis, or surgery since the time of the 
initial collection for transplant will initiate a formal medical re-evaluation. 
- 
If no new medications or new diagnosis have occurred, and no surgery, then just as what is 
done for the NMDP and collection of a DLI, the prior medical evaluation will suffice 
providing it is ≤ 120 days from date of initial medical evaluation to the date of starting the 
CD8+ memory T-cell collection. 
Documentation of vital signs (temperature, blood pressure, pulse rate, weight). 
Donors will be evaluated with the following laboratory tests within 14 days of starting apheresis 
for the collection of CD8+ memory T-cells:   
• CBC with complete blood count. 
• Clinical chemistry assessments including sodium, potassium, chloride, creatinine, random 
glucose, total calcium, total protein, albumin, total bilirubin, alkaline phosphatase, SGOT, 
SGPT.   
• A coagulation profile including PT and PTT  
• Female donors of child-bearing potential will undergo serum HCG testing which must be 
negative to proceed. 


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Donors will be screened within 7 days of the CD8 memory T-cell collection to confirm eligibility 
by undergoing repeat testing for: 
• Hepatitis A, B and C, HIV-1 and -2, HTLV, VZV, EBV, HSV, West Nile virus, Syphilis 
Treponema, T cruzi (Chagas), CMV, and the MPX NAT IDT (HIV/HCV/HBV) will be 
tested as per national standard of care guidelines for transplant donors.  Donors who are 
HIV-positive will be excluded.  Donors who are positive by serology for Hepatitis B or C 
are eligible as long as PCR for RNA/DNA is negative. 
• ABO/Rh will be performed. 
Once donors have been appropriately screened, they will proceed to cell harvest.   
3.6 Informed Consent Process 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for treatment of the underlying disease.  The attending physician will conduct 
the conference.  All potential risks associated with the use of TLI, ATG, immunosuppressive drugs 
and allogeneic hematopoietic cell infusions including and CD8+ memory T-cell cells will be 
discussed as objectively as possible.  It will be explained that patients offered this protocol have an 
underlying malignancy that render them either at high risk of relapse or that will result in life 
expectancies of several months to no more than one to two years with conventional treatments.  
These patients would be unlikely to benefit from, or tolerate an autologous transplant, and are at 
high risk of early transplant mortality from conventional allogeneic transplant.  Informed consent 
from the patient will be obtained using a form approved by the Administrative Panel on Human 
Subjects in Medical Research of the Stanford University Medical Center.  The participant will 
receive a copy of the signed and dated consent document.  The original signed copy of the research 
consent document must be retained in the subject’s research file.   
3.7 Study Timeline 
It is expected the study will accrue 7 patients per year and therefore the target goal of 20 patients 
will be completed within 2.5 years of the study opening. 
Patients will be followed for 6 months after the mobilized PBSC infusion on Day 0.  Patients’ 
End-of-Study Visit will be scheduled for approximately Day 180 post-PBSC infusion, +/- 3 weeks.  
Therefore, it is expected the study will be complete within 36 months of opening.  All patients will 
be followed for outcomes beyond the 6 months study observation period for determination of 
secondary outcome measures and as per institutional standards for transplant patients. 


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4. 
TREATMENT PLAN 
4.1 
Study Treatment Schedule 
Transplant Schedule 
Week 1 
Monday 
Day -11 
Tuesday 
Day -10 
Wednesday 
Day -9 
Thursday 
Day -8 
Friday 
Day -7 
Saturday 
Day -6 
Sunday 
Day -5 
TLI 120 cGy 
TLI 120 cGy 
TLI 120 cGy 
TLI 120 cGy TLI 120 cGy 
Rest 
Rest 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
ATG  
1.5 mg/kg + 
solumedrol 
1.0 mg/kg 
 
 
Week 2 
Monday 
Day -4 
Tuesday 
Day -3 
Wednesday 
Day -2 
Thursday 
Day -1 
Friday 
Day 0 
Saturday 
Day +1 
Wednesday 
Day 25-70 
Friday 
Day 30-75 
TLI 
120cGy 
TLI  
120 cGy 
TLI  
120 cGy 
TLI  
120cGy  
x 2 doses 
Mobilized 
PBMC 
 
Cytoxan 
1.5 g/m2 IV 
x1  
CD8+ 
memory 
T-cell 
infusion 
 
Start Oral 
CSP 
CSP 
CSP 
CSP 
CSP 
CSP 
CSP 
 
 
 
 
Start Oral 
MMF 
MMF 
MMF 
stopped     
Day +28 
 
4.2 Apheresis 
HLA-matched donors will undergo unmobilized apheresis for collection of CD8+ memory T-cells.  
Sufficient numbers of cells will be obtained following 1 to 2 apheresis procedures on consecutive 
days such that the target cell dose at the end of the selection will be achieved.  Plasmapheresis, 
including volumes and frequency of collections, will be in accordance with 21CFR§640.65.  
4.3 Cyclophosphamide lymphodepletion 
Patients will receive a single dose of cyclophosphamide 1.5 g/m2 intravenously over 2 hours as 
lymphodepletion 3-5 days prior to the CD8+ memory T-cell infusion in order to promote further 
expansion and persistence of the infused T cells (see section 2.10). 
4.4 Administration of Study Drug  
Selected CD8+ memory T-cells meeting the release criteria (described below) will be infused no 
more than 48 hours after the harvest.  CD8+ memory T-cells will be taken to the recipient and 
infused fresh without cryopreservation.  The cells will be infused through a central venous catheter 
or peripheral IV of at least 19 gauge.  CD8+ memory T-cell infusion will take place over 10 to 20 
minutes, just like unmodified DLI.  


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IN Patients will be monitored for vital signs (temperature, blood pressure, pulse rate) every 
30 minutes following infusion and for at least two hours afterwards with evaluation every 
30 minutes.  WHO toxicity will be performed as described.  Recipients will be monitored for 
infusion related toxicities and treated as needed.  Premedication is not required and, if possible, 
should be avoided.  If clinically indicated, Benadryl and Tylenol can be given as needed.  Benadryl 
and will be utilized should a reaction occur and epinephrine and solumedrol will be available at the 
bedside. 
4.5 Criteria for Removal from Study and not proceeding with the Planned CD8+ memory 
T-cell Infusion 
All adverse events will be reviewed by Stanford Cancer Institute Data and Safety Monitoring 
Committee (DSMC) and patients will be removed from the study for the following reasons: 
• Excess toxicities are observed such as acute GVHD beyond Grade 2 skin or upper GI tract 
only GVHD, uncontrolled infection or organ performance status not meeting criteria for 
cell infusion. 
• Any other cconcurrent illness that prevents further administration of CD8 + memory T-cell 
Infusion 
• Non-compliance with the protocol (defined as inability to receive all scheduled treatments, 
follow-up appointments, and tests) 
• Patient request to withdraw from the study 
The number of patients who do not receive the planned CD8 memory T-cell infusion will be 
followed.  If for any reason more than 1 of the first 3 patients, or more than 2 of the first 6 patients, 
or more than 3 of the first 10 patients do not receive the planned infusion, the trial will temporarily 
close pending a DSMC audit to determine the cause.  A patient enrolled on the trial but who does 
not proceed with the planned infusion will be replaced with another enrolled patient as the goal is 
to evaluate 20 patients who receive the CD8+ memory T-cell product. 
4.6 Alternatives 
Alternative therapies will be discussed with each patient and would potentially include allogeneic 
transplantation using TLI and ATG conditioning without a planned CD8+ memory T-cell infusion 
or allogeneic transplantation using other transplant conditioning or other investigational therapies, 
or best of care non-transplantation therapy. 
4.7 Compensation 
There will be no compensation for participation on study. 
5. 
INVESTIGATIONAL AGENT INFORMATION 
5.1 
 Investigational Agent  
CD8+ Memory T-Cell Selection 
The patient’s original HLA-matched donor will undergo apheresis with collection of blood 
mononuclear cells as for standard DLI.  No mobilization agents will be administered.  Donor 
CD8+/CD45RA- T-cells will be isolated by tandem immunomagnetic selection using the 
CliniMACS Cell Selection System (Miltenyi Biotec).  Depletion of CD45RA expressing cells uses 
CliniMACS CD45RA Reagent (BB-MF-11872).  The CD45RA depleted fraction is enriched for 


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CD8 expressing cells by positive cell selection with CliniMACS CD8 Reagent (BB-MF-11704).  
In our phase 1 study, we evaluated the CD45RA-CD8+ cell yield from 8 normal donors that 
underwent either 1 or 2 aphereses.  The mean starting TNC count was 6.8 x 1010, the mean 
post-CD45RA depletion cell count was 4.5 x 1010, and the mean post-CD8 enrichment cell count 
was 6.6 x 108 with a range of 1.5 to 18.0 x CD45RA-CD8+ cells.  The lower end range cell yields 
were in donors who underwent 1 apheresis and the higher end range cell yields were following 
2 consecutive days of apheresis.  In combination, we completed 4 validation runs, combined with 
8 donor runs for the phase 1 protocol, our efficiency of percent CD8+ memory T-cell recovery has 
dramatically increased from < 20% to > 50%.  Therefore, following 1 or 2 consecutive days of 
aphereses per donor, we have data to validate that we will achieve the target cell dose of 5 x 106 
CD8+ memory T-cells/kg for all patients, assuming most patients weigh less than 120 kg.  If the 
number of CD8+ memory T-cells be below the desired threshold of 5 x 106/kg, the infusion will 
proceed as planned as the aggregate data support the importance of conversion from mixed to 
complete chimerism to decrease the risk of post-transplant disease relapse (13, 28-36).  Therefore 
we believe it is in the patient’s best interest to receive the additional cell infusion as this has the 
potential to help achieve complete chimerism.  It is expected that a cell yield of less than the 
desired cell dose will be obtained less than 10% of the time. 
Stability 
Prior to initiating the phase 1 study we completed four validation runs and found > 90% viability 
based on the immediate post selection viability.  We also have stability data on the 4 validation 
runs that extend to 48 hours of storage and found minimal loss in cell viability and all validation 
products continued with > 90% viability.  The phase 1 study added stability data from an 
additional 8 donors that extended to 48 hours of storage and confirmed > 94% viability in all cases.   
Reagents for cells for immediate release and conditions for storage 
For post selection products infused the same day the Miltenyi Biotech Selection Buffers that 
contain PBS with 1mmolar EDTA and 0.5% HSA will be used.  The CD8 and CD45 reagent 
systems are pharmaceutical grade and both have Master Files which are BB-MF-11704 and 
BB-MF-11872, respectively.  For post selection products that will be stored for 24 or 48 hours 
prior to infusion, the product will be diluted for storage with 1 volume of Normosol-R with 
2% HSA.  For patient comfort the volume will be reduced to < or equal to 200 mL and the 
CD8+memory T-cell concentration will range between 1 x 106 to 1 x 108 cells/mL.  The overnight 
storage temperature will be 4 degrees Celsius. 
Release Requirements of the Product 
Release of the selected cell products for fresh infusion includes: 
• negative Gram staining (no organisms detected) 
• endotoxin levels ≤ 0.5 EU/milliliter of infused product volume 
• > 90% cell viability 
• ≥ 80% of the CD3+ cells express the CD8 memory T-cell phenotype, here defined as 
CD8+/CD45RA-/CD45RO+ 
• ≤ 5% of cells with the CD3+/CD45RA+/CD45RO- phenotype 
• sufficient cells with the CD8 memory T-cell phenotype to meet the desired dose, or at least 
the minimum dose of > 2 x 106 CD8+ memory T-cells/kg 


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Release Criteria for products stored 24 or 48 hours:  due to the logistics of donor cell collection, 
cell processing and patient schedule, it is possible that some products may be stored for 24 or 48 
hours before their infusion.  Cell viability >90% is required for infusion of products not being 
stored.  Release criteria for products stored 24 or 48 hours require >80% viability as assessed by 
trypan blue or 7-AAD dye exclusion. 
In addition, post-selection sterility cultures in accordance with sterility testing guidelines 
(21CFR§610.12) will be conducted to confirm the sterility of the selected cells.  Any positive 
growth results obtained will be documented in the processing record of the selection and 
immediately communicated to the patient’s attending physician in accordance with the plan of 
action for the infusion of cellular products with microbial contamination.  Ancillary studies may 
include phenotypic analysis of the selected cells and cytokine secretion profiles from MLR assays 
may be used to further our understanding of the CD8+ memory T-cell population characteristics 
but do not constitute release criteria at this time. 
If the cell product does not meet release criteria after manipulation, the product will not be infused.  
In the case(s) where the manipulated cell product does not meet release criteria, the donor may 
undergo subsequent apheresis procedure(s) to collect a new product in an attempt to achieve a 
releasable fresh product for infusion.  If at any dose level the minimum cell dose is not achieved 
the patient and donor may be taken off study.  A patient removed from the study due to a failure to 
achieve the minimum CD8+ memory T-cell dose will be replaced with another patient. 
5.2 
Availability 
CD8+ memory T-cell products will be prepared in the Stanford Blood and Marrow Transplantation 
Cellular Therapy Facility under the direction of laboratory director, Kevin Sheehan, PhD.  
Dr Sheehan oversaw the manufacturing of the CD8+ memory T-cells for the phase 1 trial. 
5.3 
Agent Accountability 
CD8+ memory T-cells meeting the release criteria will be administered according to the 
instructions specified in the approved study protocol.  Infusions will be prepared and administered 
by a trained person designated by the investigator in response to orders written by the investigator. 
6. 
DOSE MODIFICATIONS 
The primary endpoints will be safety and determination of the rate of conversion from mixed to 
complete donor chimerism.  In the first 6 enrolled patients (i.e., infused with CD8+ memory 
T-cells), if > 2 patients experience any new Grade 3 to 4 toxicities, or > 2 develop Grade 3 to 4 
GVHD during the 60 days following the CD8+ memory T-cell infusion, we will de-escalate the 
dose to 1 x 106 CD8+ memory T-cells/kg.  In the first 12 enrolled patients, if > 3 patients develop 
Grade 3 to 4 GVHD during the 60 days following the CD8+ memory T-cell infusion, or after the 
first  12 enrolled patients if > 4 patients develop Grade 3 to 4 GVHD during the 60 days following 
the CD8+ memory T-cell infusion, the dose will be de-escalated as per above.  
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Adverse Events 
Hematopoietic cell transplantation (HCT) is an aggressive therapy for the treatment of a number of 
life-threatening disorders, including cancer.  In this setting, a very large number of Grade 1 and 2 
adverse events (AEs) are expected to occur, regardless of whether or not a patient is participating 
in a research study.  In order to minimize the “background noise” and to focus on 


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clinically significant, impactful adverse events useful in the assessment of treatment effect, the 
following AE reporting schema is proposed.  This schema is intended to capture all AEs that are 
clinically significant and/or impactful, but minimize “not informative” AE collection.  
• Grade 3 and higher AEs will be collected and documented with causality attribution 
(see Section 7.2 Adverse Event Attribution) on an adverse event log (AE log).   
• In addition, all AEs meeting the criteria of “serious” as defined at 21CFR§312.32(a), 
including any that are otherwise Grade 1 or 2,  will be collected;  identified as serious; and 
documented on an AE log, including causality attribution.   
o An adverse event is considered serious if it fulfills one of the following criteria per 
21CFR§312.32(a): 
▪ Results in death 
▪ Life-threatening (patient at risk of death at the time of the event) 
▪ Requires inpatient hospitalization or prolongation of existing hospitalization 
▪ Results in persistent or significant disability 
▪ Other medical events that may not be immediately life-threatening or result in death 
or hospitalization by may jeopardize the patient or require intervention to prevent 
one of the outcomes listed above 
• Laboratory values without a clinical consequence or outcome will not be tracked as 
adverse events, unless deemed serious. 
• Grade 1 and 2 AEs not meeting these criteria will not be collected, except as follows.  
Grade 1 and 2 AEs resulting in subject dose modification (including dose termination) or 
withdrawal from the study will be collected. 
All Serious Adverse Events (SAEs) will be tracked until resolution or at least 60 days after the last 
dose of the study treatment.  
Vital signs for all subjects enrolled on the trial will be monitored for infusion-related toxicities 
(AEs) during the CD8 memory T-cell infusion, and every 30 minutes for 2 hours afterwards.  
Observed events will be recorded on the AE log.  In particular, subjects will be observed for 
hemodynamic instability, allergic reactions (eg, hives, rashes, angioedema), and fevers 
(> 38.3º po).  
The development of acute GVHD, its date of onset and overall grade, is a key secondary outcome 
measure for patients on this trial.  Please refer to Section 6 “Dose Modifications” that highlight the 
safety rules with respect to GVHD development.  Acute GVHD will be recorded on an AE log.  
7.2 
Adverse Event Attribution 
As noted, HCT is an aggressive therapy for the treatment of cancer, and a large number of AEs are 
expected in this setting, including a number of specific AEs that are associated with the underlying 
disease;  therapies administered prior to HCT;  health status of the transplant recipient including 
co-existing conditions;  the preparative regimen for transplant;  concomitant therapies intended to 
reduce transplant-related complications (eg,  immunosuppressants for the prevention of GVHD);  
and treatment for complications of HCT.   


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The Protocol Director (PD) or designee will assess each Adverse Event (AE) to determine whether 
it is unexpected according to the Informed Consent, Protocol Document, or 
Investigator’s Brochure, and related to the investigation.  Unless specifically determined otherwise 
by the investigator, the following events are considered anticipated in this setting.  
• Alopecia  
• Anemia  
• Anorexia  
• Bleeding, including requiring transfusions  
• Cardiac arrhythmias   
• Central venous catheter infections  
• Constipation  
• Diarrhea  
• Edema  
• Fatigue  
• Febrile episodes  
• Gastritis  
• Graft failure  
• Graft versus host disease  
• Hematuria   
• Hypertension  
• Hypotension  
• Hypoxia  
• Incontinence  
• Infections, including sepsis 
• Insomnia  
• Laboratory abnormalities  
• Mental status changes and mood alterations  
• Mucositis  
• Nausea  
• Neutropenia  
• Pain  
• Pleural effusion  
• Pneumonitis  
• Rash  
• Seizures  
• Sinusoidal obstructive syndrome  
• Tachycardia  
• Thrombocytopenia  
• Thrombotic microangiopathy  
• Tremor  
• Vomiting 
7.3 
Adverse Event Reporting 
All serious adverse events (SAEs) related to study procedures will be collected from signing of 
informed consent through CD8+ Memory T-cell infusion.  Adverse events, both non-serious and 
serious, will be collected as outlined in Section 7.1 from date of CD8+ Memory T-cell infusion 
through 60 days.  Beyond 60 days post-cell infusion, SAEs related to study treatment will be 
collected through the Week 20 follow-up visit. 
All serious adverse events (SAEs) will be reported to the IRB;  to the IND;  and to the DSMC, 
either in an annual review or as an expedited report, in accordance with the applicable guidelines 
and regulations.  
AEs meeting the criteria specified for an IND Safety Report as defined at 21CFR§312.32(c)(1) 
will be collected;  documented in the adverse event log;  and reported to the IND (on a 
MedWatch 3500A form) in the timeframe specified. 
The IND annual report will include summaries of the collected AEs, as specified by 
21CFR§312.33.  
8. 
CORRELATIVE/SPECIAL STUDIES  
N/A 


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9. 
STUDY CALENDAR 
Pre enrollment 
requirements  
                           HCT 
                          Day = 0 
On study 
enrollment = 
CD8+ Memory 
T-cell Infusion 
Weeks from on study 
enrollment 
 
±5 days 
Weeks from on study 
enrollment 
 
±2 weeks 
(Day 30-75) 
Wk 1 
Wk 2 
Wk 4 
Wk 8 
Wk 12g 
Wk 20g 
HCT Infusion 
 
X 
 
 
 
 
 
 
 
Infusion of CD8+ 
memory T-cells 
 
 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
X 
X 
X 
X 
X 
X 
Concurrent meds 
X 
 
X 
X 
X 
X 
X 
X 
X 
Donor Evaluation 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs a 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry b 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse 
Event evaluation 
 
 
X 
Disease Status 
Assessment c 
X 
 
X 
B-HCG d 
X 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
Xf 
 
 
 
 
 
 
STR analysis e 
X 
 
X 
 
a: 
Temperature, blood pressure, and pulse.  On day of infusion, vital signs to be taken any time prior to infusion, then 
immediately after infusion and every 30 minutes thereafter until 2 hours post-infusion. 
b: 
Albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, glucose, potassium, total protein, AST, 
ALT, sodium 
c 
Response assessment as per disease histology, and may include CT, PET, and/or MRI imaging, and bone 
marrow biopsy or aspiration (refer to Appendix C), and is typically performed around Day 90 post transplant 
(Day 0)  
d: 
Women of childbearing potential only 
e: 
Short tandem repeat (STR) analysis relative to transplant date Day 0.  Therefore, performed on Day 28 +/- 7 days, 
Week 8 +/- 2 weeks, Week 12 +/- 2 weeks, and Week 20 +/- 2 weeks, and thereafter as per standard of care  
f: 
A single dose as lymphodepletion given 3-5 days prior to the CD8+ memory T-cell infusion 
g: 
As necessary, data for the Week 12 or Week 20 visit, which is considered part of routine medical care for 
post-transplant patients, may be collected by phone contact to the subject and/or their regular physician. 


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10. 
MEASUREMENT and STATISTICAL METHODS 
Our extensive experience with the TLI ATG conditioning for allogeneic HCT in cancer patients 
showed a 30% incidence of FDC at Day 90, with a 95% confidence interval of 10 to 49%.  The 
non-relapse mortality (NRM) was 3% (95% CI:  0 to 14%) at 100 days and 6% (95% CI:  
1 to 28%) at 1 year.  The incidence of acute GVHD by Day 100 was 6% (0.7 to 22%). 
10.1  Primary and Secondary Outcome measures 
Following the infusion of CD8+ memory T-cells to promote the conversion of mixed chimerism to 
full donor chimerism and ultimately reduce the risk of disease relapse a variety of outcome 
measures will be followed. 
The primary outcome is to determine the proportion of patients with full dose donor chimerism 
within 3 months of receiving the CD8+ memory T-cell infusion.  Successful conversion from 
mixed to complete chimerism is defined as achieving ≥ 95% donor type in the CD3+ lineage or 
whole blood within 90 days of cell infusion.    
The secondary outcome measures include the 1 year time-to-disease progression;  
overall survival (OS);  and event-free survival (EFS);  and non-relapse mortality.  The incidence of 
acute and chronic GVHD following the infusion of allogeneic CD8+ memory T-cells will be 
determined. 
Recipients will be monitored for infusion related toxicities and the rates of GVHD or marrow 
aplasia.  Typically following an unmanipulated DLI the timing for acute GVHD or marrow 
hypoplasia onset is about 30 days post-infusion [32-38].  GVHD, if it occurs, will be treated 
promptly.  First line therapy will include corticosteroids at a dose of 1-2 mg/kg depending upon 
severity.  Additional immunosuppressive medications will be added as clinically indicated.   
Evaluations will be performed to assess infusion related toxicity according to the following:   
• Post-infusion toxicity evaluations (including physical exam, vitals, and weight) will be 
performed on days +7;  +14;  +28;  and weeks 8;  12;  20;  and 26 (+/- 5 days for the first 
4 weeks post-infusion;  +/- 14 days for dates thereafter) using CTCAE v4.0.   
• STR analysis will be performed prior to the CD8+ memory T-cell infusion (within 35 days 
prior) and then will follow the scheduled events calendar assessment visits until 6 months 
post-transplant. 
• GVHD will be according to Appendix B for GVHD Grading.   
• CBC performed within 7 days prior to the CD8+ memory T-cell infusion and then will follow 
the scheduled events calendar until 6 months. 
• Chemistries including Albumin, alkaline phosphatase, total bilirubin, calcium, chloride, 
creatinine, glucose, potassium, total protein, AST, ALT, and sodium will be performed within 
7 days prior to the cell infusion and thereafter follow the scheduled events calendar until 6 
months.   
• The level of tumor burden will be evaluated at 3 and 6 months after transplant by standard 
imaging and blood evaluation procedures specific for the patient disease (refer to 
Appendix C). 
Beyond 6 months all patients will be followed as per standard as per our institutional practice for 
HCT recipients (on average about every 6 weeks until 12 months post-transplant and regularly 


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thereafter) and data and laboratory tests including disease burden assessment will be recorded to 
determine the 1 year overall survival and event-free survival, NRM and for the development of 
infections and chronic GVD. 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the informed consent and all forms of participant information related to the study 
(eg, advertisements used to recruit participants) will be reviewed and approved by the Stanford 
IRB and Stanford Cancer Center Scientific Review Committee (SRC).  Any changes made to the 
protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.  The Protocol Director will disseminate the protocol amendment information to 
all participating investigators. 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Center Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  In addition, the DSMC will 
regularly review serious adverse events and protocol deviations associated with the research to 
ensure the protection of human subjects.  Results of the DSMC audit will be communicated to the 
IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
11.3 
Data Management Plan 
The Protocol Director, or his designee, will prepare and maintain adequate and accurate participant 
case histories with observations and data pertinent to the study.  The Stanford BMT data 
monitoring team along with the study coordinator will collect the information required in the Study 
calendar of events and maintain records for data analysis.  The data will be reviewed by the study 
PI for accuracy against source document data. 
11.4 Confidentiality  
Patient records will be kept in a secure location at Stanford University Medical Center accessible 
only to research authorized personnel.  Patient identity will be kept as confidential as possible as 
required by law.  The patient will not be identified by name, social security number, address, 
telephone number, or any other personal direct identifier.  Study patients will be assigned an 
identification code.  Information about the code will be kept in a secure location and access limited 
to research study personnel.  The results of this study may be presented at scientific or medical 
meetings or published in scientific journals, however patient identity will not be disclosed.  
Personal data included in the investigators’ database will be maintained in compliance with all 
applicable laws and regulations. 
12. 
STATISTICAL CONSIDERATIONS 
Statistical Analysis 
Analysis of 50 consecutive previous patients with persistent mixed chimerism after HCT using 
TLI-ATG conditioning confirmed the observed rate of conversion to complete chimerism without 


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an additional cell infusion was 25% (n = 12), and assume the upper limit of conversion is likely 
35%.  The sample size determination for the clinical trial will follow a single arm Simon 2-stage 
trial principle, with a null hypothesis of 35% (p0), and an alternative hypothesis of 70% (p1).  We 
will use a significance level of 0.05 () and power of 0.9 (1-).  In Simon stage 1, we plan to 
enroll 8 patients and if 4 or more patients respond by converting to complete chimerism we will 
proceed to stage 2 where we will continue to enroll a full sample of 20 patients and declare success 
if a total of 11 or more patients respond.  We will not start enrollment in Simon stage 2 until at 
least 3 successes are observed. 
Patients will receive a CD8+ memory T-cell infusion 30 to 75 days after their initial HCT.  The 
desired dose of CD8+ memory T-cells will be 5 x 106 cells/kg.  It is fully expected this dose will 
be safe and not provoke or increase the risk of GVHD or other complications.  In the phase 1 trial 
we infused this dose, or exceeded it, in 5 patients and observed no infusion related, early or late 
toxicities. 
Patients will be evaluated for toxicities, defined as new Grade 3 to 4 toxicities, according to the 
Common Toxicity Criteria v.4 and Grade 3 to 4 GVHD (Appendix B) during the 60 days 
following the CD8+ memory T-cell infusion.  If 2 of the first 6 patients develop DLTs, the dose 
will be lowered to 1 x 106 CD8+ memory T-cells/kg.  If 2 of the first 6 patients infused with this 
lower dose develop DLTs, then the trial will be stopped for safety reasons. 
For the first 3 enrolled patients, the CD8+ memory T-cell infusion will be staggered by at least a 
30-day interval between patients to allow for an assessment of DLTs for each patient.  Thereafter, 
if no DLTs are observed, the CD8+ memory T-cell infusion will be staggered by 10-day intervals 
between patients.  For added safety, if there is any incidence of a DLT observed the wait period 
will be extended to 60 days between the patients.   
If a Grade 5 toxicity or death occurs and is at least likely related to the cell infusion, the trial will 
stop.  Consideration for trial modifications will depend on institutional IRB and DSMC reviews.  
The appropriate regulatory offices including FDA will be notified within 5 business days of such 
an event. 
Statistical considerations for the revised protocol  
 
We have infused phenotypic CD8+ memory T cells in a total of 29 patients (as a treatment in 15 
patients who had disease relapse after transplant, and as a prophylactic intervention in 14 patients 
with mixed chimerism to convert to  complete chimerism to reduce the risk of subsequent disease 
relapse).  We have confirmed the safety; there have been no infusion reactions, and no grade 3 or 
higher adverse events attributable to the infusion, and no aggravation or precipitation of acute 
GVHD. 
 
We now propose to amend the protocol by administering a single dose of cyclophosphamide 
(1500mg/m2 BSA) 2-5 days prior to the CD8+ memory T cell infusion. The primary reason to 
amend the protocol to include cyclophosphamide is the desire to take advantage of the new clinical 
and pre-clinical information available that strongly suggests an increase in efficacy (success rate) 
with the addition (see section 2.10 in the revised Protocol). In addition to the obvious ethical 
impetus to provide trial participants with the optimal version of an experimental treatment, we note 
a scientific rationale: since the use of cyclophosphamide in this context will very likely become the 
new standard prior to infusing a cellular therapy, it is advisable to adapt our protocol to that reality.  


IRB-33058  
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The compelling ethical and scientific rationale notwithstanding, we must remain attentive to the 
extra assumptions required for statistical integration of the data from the patients treated without 
Cyclophosphamide early in the study and those treated with Cyclophosphamide after the change. 
Here is a review of the new design, the main issues it raises, and the analysis that led us to our new 
strategy: 
 
1. The original Simon optimal, 2-stage design was predicated on a historical control success rate of 
35% and an alternative success rate of 70%. There is no reason to alter the historical assumption. 
We propose a new embedded but independent 2-stage design (see below for details) with a single 
arm treated with the addition of Cyclophosphamide to the current regimen, predicated on an 80% 
alternative. The 10% increase in the alternative is based on the pre-clinical and clinical results 
cited above.  The original design entertained a Type 1 error rate of 5% and a Type 2 error rate of 
10%; in the new embedded trial we allow a 10% Type 1 error rate (which is more usual in phase 2) 
and retain the 10% Type 2 error rate.  
 
2. We considered simply finishing the trial with the remaining 6 patients in the original design now 
being treated with cyclophosphamide, which would address the ethical dimension. However, the 
interpretation of a positive result would rest on an assumption that the alternative under 
Cyclophosphamide cannot be less than that without Cyclophosphamide. This is a reasonable 
assumption, but at the end of the trial we would likely not have strong evidence to support it, so the 
interpretation would still rely on a largely untested assumption. In addition, we would have little 
new evidence for safety, always an important consideration. By adding only 2 patients to the entire 
study, we are able to treat up to 8 patients with the Cyclophosphamide-containing regimen, which 
leads to the 2-stage design (details below) predicated on the 80% alternative assumption.  
 
Why is this better? We have converted an assumption necessary for interpretation of a positive 
overall result into an assumption that drives the design of the embedded trial whose results will test 
the assumption at high power (90%). A positive result in the embedded trial is statistically definite, 
once it is completed, since the design assumption has been subject to test.  A positive independent 
result in the embedded trial will buttress the overall result obtained by pooling the initial 14 and 
new 8 patients and calculating the one-sided 95% lower confidence limit for the success rate. It 
should be noted that because the embedded trial “stands alone” and does not include the initial 
cohort of patients treated without Cyclophosphamide, the fact that the interim results in the initial 
patients are known does not affect the type 1 error of the embedded trial.  
 
3. The details of the embedded trial: Assuming a 35% historical control rate, and an 80% 
alternative, for 10% Type 1 and 2 error rates, the Simon optimal 2-stage design calls for a first 
stage with 2 patients, going on if there is at least 1 success, to the second stage with a cumulative 
total of 8 patients, rejecting the historical control rate (declaring a positive result) if there are at 
least 5 successes out of 8. 
 
The output for the file is: 
 
clinfun::ph2simon(pu=0.35,pa=0.80,ep1=0.1,ep2=0.1) 
 Simon 2-stage Phase II design  


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Unacceptable response rate:  0.35  
Desirable response rate:  0.8  
Error rates: alpha =  0.1 ; beta =  0.1  
 
                r1 n1 r n EN(p0) PET(p0) 
Optimal  0  2 4 8  5.465  0.4225 
 
 
 
12.1  Sample Size and On-Study Enrollment Date  
At least 20 patients will be required to complete the study (plus two additional patients as per 
above)  The on-study enrollment date for this trial will be the day the recipient is infused with 
CD8+ memory T-cells.  Prior to this date transplant recipients will be in a screening phase.  
12.2 
Accrual estimates 
Approximately 6 to 7 patients will be enrolled annually.  Time to complete enrollment will be 
3 years.  Time to complete the trial will be about 3.5 years. 


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120(8):  p. 646-52. 
23. Kolb, H, et al.  Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow 
grafted patients.  European Group for Blood and Marrow Transplantation Working Party 
Chronic Leukemia.  Blood, 1995.  86(5):  p. 2041-2050. 
24. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, et al.  
Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional 
bone marrow transplantation with lethal cytoreduction for the treatment of malignant and 
nonmalignant hematologic diseases.  Blood.  1998 Feb 1;91(3):756-63. 
25. Giralt S, Estey E, Albitar M, van Besien K, Rondon G, Anderlini P, et al.  Engraftment of 
allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy:  
harnessing graft-versus-leukemia without myeloablative therapy.  Blood.  1997 Jun 
15;89(12):4531-6. 
26. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al.  
Hematopoietic cell transplantation in older patients with hematologic malignancies:  replacing 
high-dose cytotoxic therapy with graft-versus-tumor effects.  Blood.  2001 Jun 
1;97(11):3390-400. 
27. Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, Laport GG, 
Stockerl-Goldstein KE, Johnston LJ, Hoppe RT, Bloch DA, Blume KG, Negrin RS, Strober S.  
Protective conditioning for acute graft-versus-host disease. N Engl J Med.  2005 Sep 
29;353(13):1321-31. 
28. Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S, et al.  Engraftment 
kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation:  full 
donor T-cell chimerism precedes alloimmune responses.  Blood.  1999 Nov 1;94(9):3234-41.  


IRB-33058  
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29. Reshef R, Hexner EO, Loren AW, Frey NV, Stadtmauer EA, Luger SM, Mangan JK, Gill SI, 
Vassilev P, Lafferty KA, Smith J, Van Deerlin VM, Mick R, Porter DL.  Early donor 
chimerism levels predict relapse and survival after allogeneic stem cell transplantation with 
reduced-intensity conditioning. Biol Blood Marrow Transplant.  2014 Nov;20(11):1758-66. 
30. Koreth J, Kim HT, Nikiforow S, Milford EL, Armand P, Cutler C, Glotzbecker B, Ho 
VT, Antin JH, Soiffer RJ, Ritz J, Alyea EP 3rd.  Donor chimerism early after reduced-intensity 
conditioning hematopoietic stem cell transplantation predicts relapse and survival.  Biol Blood 
Marrow Transplant. 2014 Oct;20(10):1516-21. 
31. Solomon SR, Sizemore CA, Zhang X, Brown S, Holland HK, Morris LE, Bashey A.  
Preemptive DLI without withdrawal of immunosuppression to promote complete donor 
T-cell chimerism results in favorable outcomes for high-risk older recipients of 
alemtuzumab-containing reduced-intensity unrelated donor allogeneic transplant:  a 
prospective phase II trial.  Bone Marrow Transplant. 2014 May;49(5):616-21.  doi:  
10.1038/bmt.2014.2. 
32. Rujkijyanont P, Morris C, Kang G, Gan K, Hartford C, Triplett B, Dallas M, Srinivasan A, 
Shook D, Pillai A, Pui CH, Leung W.  Risk-adapted donor lymphocyte infusion based 
on chimerism and donor source in pediatric leukemia. Blood Cancer J.  2013 Aug 30;3: 
33. Dey BR, McAfee S, Colby C, Sackstein R, Saidman S, Tarbell N, Sachs DH, Sykes M, Spitzer 
TR.  Impact of prophylactic donor leukocyte infusions on mixed chimerism, graft-versus-host 
disease, and antitumor response in patients with advanced hematologic malignancies treated 
with nonmyeloablative conditioning and allogeneic bone marrow transplantation.  Biol Blood 
Marrow Transplant. 2003 May;9(5):320-9. 
34. El-Cheikh J, Crocchiolo R, Furst S, Ladaique P, Castagna L, Faucher C, Calmels B, Oudin C, 
Lemarie C, Granata A, Devillier R, Vey N, Bouabdallah R, Chabannon C, Blaise D.  Donor 
CD3(+) lymphocyte infusion after reduced intensity conditioning allogeneic stem cell 
transplantation:  single-center experience. Exp Hematol.  2013 Jan;41(1):17-27. 
35. Liga M, Triantafyllou E, Tiniakou M, Lambropoulou P, Karakantza M, Zoumbos NC, 
Spyridonidis A.  High alloreactivity of low-dose prophylactic donor lymphocyte infusion in 
patients with acute leukemia undergoing allogeneic hematopoietic cell transplantation with an 
alemtuzumab-containing conditioning regimen. Biol Blood Marrow Transplant.  2013 
Jan;19(1):75-81. 
36. Bloor AJ, Thomson K, Chowdhry N, Verfuerth S, Ings SJ, Chakraverty R, Linch 
DC, Goldstone AH, Peggs KS, Mackinnon S.  High response rate to donor lymphocyte 
infusion after allogeneic stem cell transplantation for indolent non-Hodgkin lymphoma.  Biol 
Blood Marrow Transplant. 2008 Jan;14(1):50-8. 
37. Anderson, B.E, et al.  Memory CD4+ T-cells do not induce graft-versus-host disease.  The 
Journal of Clinical Investigation, 2003.  112(1):  p. 101-108. 
38. Dutt, S, et al.  Naive and Memory T-cells Induce Different Types of Graft-versus-Host 
Disease.  The Journal of Immunology, 2007.  179(10):  p. 6547-6554. 
39. Zheng, H, et al.  Effector memory CD4+ T-cells mediate graft-versus-leukemia without 
inducing graft-versus-host disease.  Blood, 2008.  111(4):  p. 2476-2484. 
40. Zhang, Y, et al.  Dendritic cell¬ñactivated CD44hiCD8+ T-cells are defective in mediating 
acute graft-versus-host disease but retain graft-versus-leukemia activity.  Blood, 2004.  
103(10):  p. 3970-3978. 


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41. Chen, B.J, et al.  Transfer of allogeneic CD62L¬ñ memory T-cells without graft-versus-host 
disease.  Blood, 2004.  103(4):  p. 1534-1541. 
42. Chen, B.J, et al.  Inability of memory T-cells to induce graft-versus-host disease is a result of 
an abortive alloresponse.  Blood, 2007.  109(7):  p. 3115-3123. 
43. Zheng, H, et al.  Central Memory CD8+ T-cells Induce Graft-versus-Host Disease and Mediate 
Graft-versus-Leukemia.  The Journal of Immunology, 2009.  182(10):  p. 5938-5948. 
44. Dutt, S, et al.  CD8+CD44(hi) but not CD4+CD44(hi) memory T-cells mediate potent graft 
antilymphoma activity without GVHD.  Blood, 2011.  117(11):  p. 3230-9. 
45. Kohrt, H.E, et al.  Donor immunization with WT1 peptide augments anti-leukemic activity 
after MHC-matched bone marrow transplantation.  Blood, 2011. 
46. Armstrong, R, et al.  Immunomagnetic Selection of CD8+ Memory Cells for Therapeutic 
Applications.  Biology of Blood and Marrow Transplantation, 2011.  17(2, Supplement 1):  p. 
S220-S220. 
47. Maine, GN, et al.  Making room for T cells.  J Clin Invest, 2002. 
48. Klebanoff, CA, et al.  Sinks, suppressors and antigen presenters: how lymphodepletion 
enhances T cell-mediated tumor immunotherapy.  Trends Immunol, 2005. 26: p. 111-117. 
49. Gattinoni, L, et al.  Removal of homeostatic cytokine sinks by lymphodepletion enhances the 
efficacy of adoptively transferred tumor-specific CD8+ T cells.  J Exp Med, 2005. 202: p. 907-
912. 
50. Warlick, ED, et al.  Successful Remission Rates and Survival after Lymphodepleting 
Chemotherapy and Donor Lymphocyte Infusion for Relapsed Hematologic Malignancies 
Postallogeneic Hematopoietic Cell Transplantation.  Biol Blood Marrow Transplant, 2012. 
18(3): p. 480-486. 
51. Chang, X, et al.  New strategies of DLI in the management of relapse of hematological 
malignancies after allogeneic hematopoietic SCT.  Bone Marrow Transplant, 2016. 51: p. 324-
332. 
52. Turtle, CJ, et al.  Anti-CD19 Chimeric Antigen Receptor-Modified T Cell Therapy for B Cell 
Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Fludarabine and 
Cyclophosphamide Lymphodepletion Improves In Vivo Expansion and Peristence of CAR-T 
Cells and Clinical Outcomes.  Blood, 2015. 126:184. 
53. Turtle, CJ, et al.  Rate of durable complete response in ALL, NHL, and CLL after 
immunotherapy with optimized lymphodepletion and defined composition CD19 CAR-T cells.  
J Clin Oncol, 2016. 34:102. 
54. Wang, LX, et al.  Host lymphodepletion augments T cell adoptive immunotherapy through 
enhanced intratumor proliferation of effector cells.  Cancer Research, 2005. 65(20): p. 9547-
9554. 
55. Wrzesinski, C, et al.  Increased intensity lymphodepletion enhances tumor treatment efficacy 
of adoptively transferred tumor-specific T cells.  J Immunother, 2010. 33: p. 1-7. 


IRB-33058  
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23 August 2019  
APPENDICES 
APPENDIX A:  Participant Eligibility Checklist  
Protocol Title: 
Post Transplant Infusion of Allogeneic CD8 Memory T-Cells as 
Consolidative Therapy After Non-Myeloablative Allogeneic Hematopoietic 
Cell Transplantation in Patients with Leukemia and Lymphoma. 
Protocol Number: 
IRB-33058 / BMT288 
Principal Investigator: 
Robert Lowsky, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Inclusion/Exclusion Criteria 
Transplant Patient Inclusion Criteria 
(From IRB-approved protocol) 
Must have all of the following 
Yes 
No 
Supporting Documentation* 
1. Between 18 and 80 years of age, inclusive 
 
 
      
2. Has a HLA-matched or single allele-mismatched 
adult sibling serving as donor 
 
 
      
3. Has a myeloid or lymphoid malignant disease that 
is treated with TLI and ATG reduced-intensity 
conditioning for allogeneic transplant [any of the 
following:  acute myeloid leukemia (AML);  
chronic lymphocytic leukemia (CLL);  B or T-cell 
non-Hodgkin lymphoma (NHL);  
Hodgkin lymphoma (HL);  Myelodysplastic 
syndrome (MDS);  or Myeloproliferative disease 
syndrome  (MPD)] 
 
 
      
4. Patients who due to age, pre-existing medical 
conditions, or, prior therapy are considered to be at 
high-risk for regimen-related toxicity associated 
with fully ablative transplant conditioning, and 
therefore reduced intensity conditioning is 
recommended. 
 
 
      
5. Ability to understand and the willingness to sign a 
written informed consent document.  Patients must 
have signed informed consent to participate in the 
trial. 
 
 
      


IRB-33058  
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23 August 2019  
Transplant Patient Exclusion Criteria 
Excluded if any of the following are yes 
 
 
 
1. Uncontrolled bacterial, viral or fungal infection 
defined as currently taking medication and 
progression of clinical symptoms. 
 
 
      
2. Progressive hemato-lymphoid malignancy despite 
conventional therapy. 
 
 
      
3. Chronic myelogenous leukemia (CML)  
 
 
      
4. Acute leukemia not in remission 
 
 
      
5. Active CNS involvement of the underlying 
malignancy 
 
 
      
6. HIV-positive 
 
 
      
7. Pregnant or lactating  
 
 
      
8. Patients with a prior malignancy (EXCEPTION:  
diagnosed > 5 years ago without evidence of 
disease, OR treated ≤ 5 years ago but have a 
greater than 50% chance of life expectancy of 
≥ 5 years for that malignancy) 
 
 
      
9. Has a psychiatric disorder(s) or psychosocial 
circumstance(s) which in the opinion of the 
primary physician would place the patient at an 
unacceptable risk from transplant. 
 
 
      
10. Organ dysfunction defined as follows: 
i. Ejection fraction < 30%, or uncontrolled 
cardiac failure 
ii. DLCO < 40% predicted 
iii. Total bilirubin > 3 mg/dL 
iv. SGOT or SGPT > 4 x ULN 
v. Creatinine > 2 mg/dL and an estimated 
creatinine clearance ≤ 40 mL/min  
vi. Poorly controlled hypertension despite 
multiple antihypertensive medication  
vii. KPS < 60% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
      
      
      
      
 
      
 
      


IRB-33058  
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23 August 2019  
Donor Eligibility Criteria 
(From IRB-approved protocol) 
 
 
 
1. HLA-matched or single allele-mismatched sibling of 
enrolled transplant patient 
 
 
      
2. 18 to 80 years of age, inclusive 
 
 
      
3. State of general good health with completed donor 
evaluation with history, medical examination and 
standard blood tests within 60 days of starting the 
hematopoietic cell collection procedure 
 
 
      
4. White blood cell count  
> 3.5 x 109/liter,  
platelets > 150 x 109/liter and  
hematocrit > 35% 
 
 
 
 
 
 
 
 
 
      
      
      
5. Capable of undergoing leukapheresis 
 
 
      
6. Able to understand and sign informed consent 
 
 
      
7. Hepatitis A, B and C, HIV-1 and -2, HTLV, VZV, 
EBV, HSV, West Nile virus, Syphilis Treponema, 
T cruzi (Chagas), CMV, and the MPX NAT IDT 
(HIV/HCV/HBV) will be tested as per national 
standard of care guidelines for transplant donors.  
Donors who are HIV-positive will be excluded.  
Donors who are positive by serology for 
Hepatitis B or C are eligible as long as PCR for 
RNA/DNA is negative. 
 
 
      
8. Females must not be pregnant or lactating 
 
 
      
9. No psychological traits or psychological or medical 
conditions which make them unlikely to tolerate the 
procedure 
 
 
      
10. Has not developed a new malignancy requiring 
chemotherapy or radiation in the interval since 
apheresis for initial HCT 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The method 
of confirmation can include, but is not limited to, laboratory test results, radiology test results, 
subject self-report, and medical record review.   
IV.  Statement of Eligibility 
This subject is [ 
 eligible / 
 ineligible ] for participation in the study. 
 
Signature: 
Date: 
Printed Name: 
 


IRB-33058  
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23 August 2019  
Signature: 
Date: 
Printed Name: 
 
Signature: 
Date: 
Printed Name: 
 


IRB-33058  
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23 August 2019  
APPENDIX B:  Glucksberg clinical stage and grade of acute GVHD 
 


IRB-33058  
Page 41 of 43 
23 August 2019  
APPENDIX C. 
RESPONSE CRITERIA by DISEASE HISTOLOGY 
 
AML Response Criteria (Cheson, et al.  2003) 
 
  In this study day of assessment is 12 weeks and 24 weeks post stem cell infusion.  For patients who are in a pathologically confirmed remission 
prior to infusion, a bone marrow biopsy and/or aspirate are not required; disease can be followed by confirmatory CBCs 
 
NHL Response Criteria (Cheson, et al.  2007) 
 
    In this study day of assessment is 12 weeks and 24 weeks post stem cell infusion. 
 


IRB-33058  
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23 August 2019  
CLL Response Criteria (Hallek, et al.  2008) 
 
  In this study day of assessment is 12 weeks and 24 weeks post stem cell infusion. 


IRB-33058  
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23 August 2019  
MDS Response Criteria (Cheson, et al. 2006) 
 
  

ICF_000.pdf: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 1 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
RECIPIENT consent form for allogenic CD8 memory T-cells  
IRB-33058 / BMT288 
 
Are you participating in any other research studies?   _____ Yes   _____No 
 
INTRODUCTION TO RESEARCH STUDIES 
 
You are invited to voluntarily participate in a research study of a type of immune cells 
called “donor CD8 memory T-cells” being studied as an experimental (“investigational”) 
treatment for cancer, being conducted by Robert Lowsky, MD at the Stanford Cancer 
Center.  You were selected as a possible participant in this study because you have a 
“blood cancer” that is suitable to be treated with a hematopoietic cell transplant from a 
sibling donor  “Hematopoietic cells” are the blood-making cells that live in your 
bone marrow.  The types of cancer that are eligible for this study are:  
• Acute myeloid/myelogenous leukemia (AML)  
• Chronic lymphocytic leukemia (CLL)  
• Hodgkin’s lymphoma (HL) 
• Non-Hodgkin’s lymphoma (NHL), either B- or T-cell  
• Myelodysplastic syndrome (MDS)  
• Myeloproliferative disorder (MPD)  
 
Being in a research study is different from being a patient.  When you are a patient, you 
and your personal doctor have a great deal of freedom in making decisions about your 
health care.  When you are a research subject, the Protocol Director and the research 
staff will follow the rules of the research study (protocol) as closely as possible, without 
compromising your health.  
 
This document is to be used as a guide for a discussion between you and your 
Study Doctor and the study team.  This form, called an informed consent document, was 
designed to help you understand why this study is being done; what part of the study is 
“research” or “experimental;” what will be asked of you if you choose to participate; 
possible risks; any inconveniences or discomforts you may experience; and other 
important information.  This form may also be helpful as a reference if you choose to 
participate, as a reminder of what your role in the study is, and who to contact if you have 
questions at any time during your participation.  You are urged to discuss any and 
all questions you have about this study with members of the study team.  If you wish, you 
can also discuss this study and your role with your family doctor or medical provider. 
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 2 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
PURPOSE OF RESEARCH 
 
This study involves adding an infusion of donor cells that have been concentrated or 
“enriched” for a type of blood cell called T-cells that have a certain marker on the surface 
known as CD8, and do not have another marker called CD45RA (these enriched cells are 
called “CD8 memory T-cells”).  The treatment with CD8 memory T-cells is unproven, and 
may or may not benefit you.  The infusion of CD8 memory T-cells will occur 30 to 75 days 
after your transplant. .  If at 1-2 months after the transplant test confirm that your blood 
shows a mixture of your (recipient) and donor blood cells (called “mixed chimerism”), 
there is a significant association with increased risk of disease 
(leukemia/lymphoma/MDS) relapse compared to patients who have achieved 100% (full 
donor chimerism) donor blood cells by 1-2 months after transplant.  The study is 
designed to help determine if giving donor CD8 memory T-cells to patients with mixed 
chimerism will help convert them to complete chimerism and subsequently reduce their 
risk of relapse.  Before receiving the CD8 memory T-cells you will receive a single dose 
of chemotherapy called cyclophosphamide (Cytoxan).  The cyclophosphamide will help 
the CD8 memory T-cells work better.   
 
One of the benefits of allogeneic transplant is the donor’s cells are capable of recognizing 
residual tumor and destroying the tumor. This is called graft versus tumor effect.  A risk of 
allogeneic transplant is the donor’s cells can attack your body tissues and cause graft 
versus host disease, which can be a serious and life threatening problem.  This study is 
trying to find a better balance between the anti-cancer benefit  effect and the risk of graft 
versus host disease. .  
 
Your recovery after treatment; symptoms; functional abilities; changes in the extent of 
disease; and laboratory results obtained after you receive the infusion will help the 
research team determine if CD8 Memory cells are  safe for patients with your condition.  
A main cause for treatment failure following allogeneic transplantation (is 
disease relapse.  The study team hopes to learn if the addition of the 
CD8 memory T-cells from your sibling donor will result in a decrease risk of relapse 
without increasing the risk of graft versus host disease or other transplant-related 
side effects.  
 
If you do not participate in this study, you can still receive the transplant from your sibling 
donor but will not receive the CD8 Memory T cells.   Other transplant researchers may 
use other investigational treatments to decrease the risk of disease relapse after 
allogeneic HCT that may involve the addition of a 2nd cell infusion that is not 
CD8 memory T-cells; additional radiation therapy; chemotherapy; and/or other 
investigational study drugs not approved by the FDA.  At this point in time, it is unclear 
what treatment or combination of treatments is the most likely to achieve long-term 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 3 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
control of your cancer.  The right treatments, and the right amounts of those treatments, 
are not completely understood.  Of the currently available treatments, none are better 
than any other at controlling your cancer, and all have associated side effects 
(“toxicities”).  
 
The infusion of CD8 memory T-cells is an investigational procedure.   The word 
“investigational” means that CD8 memory T-cells are not approved by the US Food and 
Drug Administration (FDA) to treat cancer.  This study is being conducted under an 
application submitted to the FDA, called an “Investigational New Drug Application” or 
“IND.”  
 
If you decide to terminate your participation in this study, you should notify either 
Dr. Robert Lowsky or the study coordinator at  xxx-xxx-xxxx or xxx-xxx-xxxx ; or your 
primary BMT doctor.  
 
This research study is looking to treat 22 individuals with an infusion of CD8 Memory T 
Cells.    This study is only being conducted at Stanford.  
 
This study is being paid for by a National Institute of Health (NIH) program grant that 
has been peer-reviewed and endorsed by experts in the field. 
 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to participate will 
not have any negative effect on you or your medical care.  You can decide to participate 
now, but withdraw your consent later and stop being in the study without any loss of 
benefits or medical care to which you are entitled. 
 
You will be informed of any significant new information about this study or 
CD8 memory T-cells that might affect your willingness to participate in this 
research study.  
 
You will be told the results of tests that are part of your medical care, but you may not be 
told the results of the research tests.   
 
DURATION OF STUDY INVOLVEMENT  
 
Your participation in this research study is expected take about 6 months, but the 
study team will follow your health status indefinitely.   
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 4 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
You may withdraw your agreement to continue to take part in this research study at 
anytime.  
 
It is possible that you may not be able to receive the CD8 memory T-cell infusion.  This 
might happen if:   
 Your cancer becomes worse (tumor progression) shortly after the transplant, 
but before the CD8 memory T-cell infusion You have an adverse event such as 
significant graft versus host disease; uncontrolled infection; or organ toxicity 
before the planned CD8 T-cell infusion. 
 
In general, your treatment in this study can continue until one of the following occurs:   
 Your cancer becomes worse (tumor progression); 
 You need a treatment that is not allowed in this study;  
 You have a different illness that prevents study treatment;  
 You or your doctor decides that the side effects are too severe;  
 You are a woman and have become pregnant;  
 The study is terminated; or  
 
You are removed from the research study for any of the following reasons:  
o You  are unable to complete the required parts of the study.  
o You do not follow the study team’s instructions for the study.  
o Your Study Doctor determines it is in your best interest. 
Other unanticipated; appropriate; and/or administrative reasons as determined by 
your doctor or the study sponsor. 
 
When your participation in this study ends, you may be asked to return for a final visit to 
have some end-of-study evaluations or tests.  Your Study Doctor will follow your 
progress, in accordance with good medical care, for as long as it is felt to be necessary 
by both you and the doctor, unless you ask otherwise.  Many if not all of these 
procedures will be part of your continued regular medical care.  In addition, 
further treatment outside the study will be discussed with you.  
 
PROCEDURES 
 
It may be harmful to enter this study while receiving some medications; therefore, you 
may need to stop taking certain medications.  Your Study Doctor will review your 
medications and provide you with specific instructions. 
 
Before you begin the study, you will need to have certain medical examinations, tests, 
or procedures to find out if you can be in the study.  This is called “Screening.”  These 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 5 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
examinations, tests, or procedures are generally part of your regular medical care, and 
are done even if you do not join the study. 
 
Before you join this study, the Protocol Director Dr Lowsky and/or the research study staff 
will review this document with you, and ask you to sign this informed consent document.  
After you have signed this document, and received a signed copy, your enrollment in the 
study will begin the day you receive cyclophosphamide that is being given in order to 
prepare you to receive the CD8 memory T-cells.   
 
General information:  Information about you, such as date of birth; gender (sex); and 
ethnic origin (“demographic information”) is obtained.  
 
Medical history:  Your  eligibility will be determined based on a variety of routine 
standard blood tests that confirm mixed and not complete chimerism and no active 
infection or GVHD.   This information will come from a review of your electronic medical 
record in combination with discussions with the medical team involved in your care.   
 
Location:  The location of your follow-up will be at the Stanford Cancer Institute in the 
BMT clinic area.  The testing to check your progress after the transplant and for your care 
during the first 100 days after transplant will be done at Stanford.  These before and after 
transplant examinations, tests, or procedures are part of your regular medical care, and 
are done even if you do not join the study.  
 
The Study Team will let you know which Stanford locations you may need to go to and 
may include any of the following: 
Stanford Hospital 
Stanford Cancer Center,  
MRI department, ground floor  
Blake Wilbur Building 
300 Pasteur Dr  
Radiology, ground floor  
Stanford, CA  94305 
900 Blake Wilbur Dr  
Phone XXX-xxx-xxxx  
Palo Alto, CA 94306 
  
Phone (xxx-xx-xxxx  
Stanford Medicine Outpatient Center 
Stanford Medicine Imaging Center 
Pavilion B 
451 Sherman Ave 
450 Broadway St 
Palo Alto, CA  94306 
Redwood City, CA  94063 
Phone xxx-xxx-xxxx) 
Stanford Cancer Institute 
Infusion Therapy Center 
875 Blake Wilbur Dr 
Stanford, CA 94306 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 6 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
 
Women of Childbearing Potential 
If you are pregnant or currently breast-feeding, you may not participate in this study.   
   
Study Treatment and Schedule 
This study adds an infusion of CD8 memory T-cells to a standard allogeneic sibling 
transplant (HCT), which is an established medical procedure.  There are no additional 
planned clinic visits as a result of participation in this trial that are above and beyond the 
standard number of clinic visits for a standard transplant patient.  There are no 
additional study specific blood tests needed beyond standard of care. 
 
Twenty-five to seventy days post transplant:  In order to prepare you to receive 
the donor CD8 memory T-cells you will receive an intravenous infusion of 
cyclophosphamide administered over 90-120 minutes.  Because cyclophosphamide 
may be associated with some nausea during or shortly after the infusion, you will 
receive some anti-nausea medications.  Three to five days after the 
cyclophosphamide you will receive the donor CD8 memory T-cells. 
 
Thirty to seventy-five days post transplant:  You will receive the 
CD8 memory T-cells as an infusion over about 20 minutes.  The study team will tell 
you the exact date, which will be based on your status after the initial HCT transplant.  
The CD8 memory T-cells will be infused through a central venous catheter or as a 
peripheral IV infusion.  The infusion of CD8 Memory T cells  is investigational.  You 
will be monitored for side effects for at least 2 hours.  If necessary, you may receive 
medications to minimize the potential for an allergic reaction.  .  
 
Further Study Rationale 
A standard transplant does not include the infusion of CD8 memory T-cells. A main 
reason for the transplant “not working” or “not being successful” is because at some 
point in time after transplant the cancer recurs and/or progresses (disease relapse).  If 
your cancer should relapse/progress after transplant it may be difficult for your doctors 
to gain long-term control of your cancer.  A goal of the current research study is to 
determine if an infusion of CD8 memory T-cells will decrease the risk of cancer 
recurrence/progression, and not cause significant graft versus host disease reactions or 
other toxicity. 
 
Prior studies done at Stanford have shown that the infusion of CD8 memory T-cells in 
patients who suffered disease relapse after transplant were safe and did not cause graft 
versus host disease reactions. The CD8 Memory T cells  were associated with apparent 
meaningful graft versus tumor reactions in some patients. The idea in the current trial is 
not to wait for disease relapse to occur, but instead to infuse the CD8 memory T-cells 
shortly after transplant (30-75 days) and before disease relapse. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 7 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
 
This study attempts to provide a benefit to patients, but this is not known and is 
not guaranteed.  
 
The dose of CD8 memory T-cells infused will be adjusted to 5 x 106 per kg body weight 
and the cells will be collected from your sibling donor 1 to 2 days before the planned 
infusion.  Your sibling will not be required to receive any medications or treatments prior 
to the cell collection.  The cells are collected from the blood during a 3-hour apheresis 
which is similar to what was involved for the collection of cells for initial transplant. 
 
If, at any time, you have any symptom, side effect, or injury affecting you physically or 
mentally during the study, you should tell your transplant doctors and team right 
away, even if you do not think it was caused by the study medication (infusion of 
CD8 memory T-cells). 
 
PARTICIPANT RESPONSIBILITIES  
 
As a participant, your responsibilities include:   
• Follow the instructions of the Protocol Director and study staff.   
• Be sure to tell the study staff all of your present and past diseases, allergies 
and any drugs or medications you are taking.  This is for your safety.  Other 
drugs or medications includes all prescription drugs; over-the-counter drugs; 
herbal preparations; and nutritional supplements.  These may interact with the 
treatments you will receive.  If any other medical provider prescribes new 
medications for you while you are on this study, please contact the study staff 
before taking the new medicine, or have that medical provider contact the 
study staff before prescribing it to you.  You should not take any new 
non-prescription medicine while you are on this study unless you first check 
with the study staff.  Come to the Study Visits as scheduled.  
 Take the medications as instructed.  
 Ask questions as you think of them. 
 Keep your study appointments.  If it is necessary to miss an appointment, please 
contact the transplant team or research study staff to reschedule as soon as you 
know you will miss the appointment. 
 Tell the Protocol Director or study team if you change your mind about staying in the 
study.  
 Tell the Protocol Director or study team about any side effects, doctor visits, or 
hospitalizations that you may have. 
 Tell the Protocol Director or study team if you believe you might be pregnant or gotten 
your partner pregnant. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 8 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
o You must use a medically-approved method of birth control, preferably a 
barrier method, for the duration of the treatment period and for at least 1 month 
after the last day you receive the injection of Study Drug. 
 
About Pregnancy  
In order to participate in this study, you must agree to avoid sexual intercourse, or to use 
a birth control method that the Study Doctor agrees will be effective at preventing 
pregnancy, and that will not interfere with the proposed research.  The Study Doctor can 
discuss with you what methods of birth control are considered adequate.   
Your signature on this document means you agree to these requirements.  
 
There is a risk that pregnancy could still result despite the responsible use of a reliable 
method of birth control.  You agree to notify the investigator as soon as possible of any 
failure of proper use of your birth control method, or if you become pregnant, either of 
which may result in your being withdrawn from the study.   
 
Women of Childbearing Potential:  If you are a woman capable of having children and 
choose to have sex, it is expected that you will use an effective method of birth control to 
prevent exposing a fetus to the known risks of radiation as well as a potentially 
dangerous agent with unknown risk.  The only certain way to be 100% certain you will not 
get pregnant is to not have sex.  You understand that if you are pregnant, if you become 
pregnant, or if you are breast-feeding during this study, you; the fetus (unborn child); or 
the child may be exposed to unknown risks as well as the risks of birth defects due to the 
radiation therapy and treatment drugs.  To confirm that you are not pregnant, you agree 
to have a pregnancy test done before beginning this research study.   
 
During the study, if you become pregnant, or you think you may be, you must 
immediately tell your Study Doctor.  If you become pregnant during the study, the CD8 
Memory T cells  may involve unforeseeable risks to the unborn baby, and your pregnancy 
will be followed to determine the outcome.   
 
Men:  If you are a man, you must 
• Prevent pregnancy in your female partners  
• You should inform your female partners of the potential for harm to her or a fetus.  
They should know that if pregnancy occurs, they should promptly notify their 
doctors  
• If your partner becomes pregnant, you need to tell the Study Team and her 
physician immediately 
 
Your doctor will discuss with you whether your preference for birth control is considered 
adequate.   
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 9 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
WITHDRAWAL FROM THE STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your decision will 
not affect your ability to receive medical care for your disease and you will not lose 
any benefits to which you would otherwise be entitled.   
 
If you decide to withdraw your consent to participate in this study, you should notify 
Dr. Lowsky or the study coordinator at.  To help you safely finish your participation in the 
study, the Study Doctors may ask you to have more tests and you will be asked to come 
into the clinic for a final Study Visit.  The Study Doctor will discuss your treatment options 
with you at this time.   
• If you withdraw from the study after receiving the transplant on Day 0, but before 
receiving the CD8 memory T-cell infusion, Dr Lowsky or his designate will discuss 
your medical options with you.  
 
The Protocol Director may also withdraw you from the study and the CD8 memory T-cell 
infusion may be not be administered, without your consent for one or more of the 
following reasons:  
 Failure to follow the instructions of the Protocol Director and study staff. 
 The Protocol Director decides that continuing your participation could be 
harmful to you. 
 The initial transplant on Day 0 failed to show any donor cells by day 28 after 
transplant (failure to engraft).   
 You have active graft versus host disease reactions before the planned 
CD8 memory T-cell infusion. 
 Test results taken on days 28 or 56 after transplant that confirm you have 
achieved > 90% donor-type cells. 
 You are not strong or healthy enough. 
 You have other medical conditions that prevent the CD8 memory T-cell 
infusion. 
 The sibling donor is unable to or unavailable to provide cells for the 
CD8 memory T-cell collection. 
 If your tumor worsens (tumor progression). 
 You have become pregnant.  
 You need, or have received, treatment not allowed in the study. 
 The study is stopped by the study sponsor Dr Lowsky; the Stanford Institutional 
Review Board (the IRB, a group of people who review the research to protect 
your rights); or by a regulatory agency such as the US FDA. 
 Other administrative reasons. 
 Unanticipated circumstances. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 10 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research study.  
This section describes the reasonably foreseeable risks; discomforts; and 
inconveniences that you may experience.  These deserve careful thought.  While the 
transplant is considered a standard of care procedure, it is also a part of this research 
study and is associated with risks. 
 
Possible Side Effects of Cyclophosphamide (Cytoxan) 
Cyclophosphamide is a chemotherapy drug that will be administered intravenously (into 
your catheter), given 3-5 days prior to receiving the donor CD8+ memory T cells.  Side 
effects may include nausea, vomiting, diarrhea, sores in the mouth and throat, skin 
changes, loss of appetite, irritation and possibly bleeding of the bladder lining and 
lowered blood counts.  Cyclophosphamide may also damage the heart which in rare 
instances can be fatal.  
 
Possible Side Effects of the CD8 T-cell Infusion  
The CD8 memory T-cell infusion is planned for 30 to 75 days after transplant.  The risks 
of the CD8 memory T-cell infusion may include nausea; discomfort in the chest; facial 
flushing; or lightheadedness. These side effects if they occur generally resolve quickly.  
In rare instances, it is possible that a severe life-threatening allergic reaction may occur. 
In addition, you may develop graft versus host disease because of the 
CD8 memory T-cell infusion.  It will be difficult to know how much of graft versus host 
disease will be due to the CD8 memory T-cells versus how much was from the initial 
transplant..  Overall, the risk of developing graft versus host disease reactions within 
120 days of transplant following a standard transplant using TLI/ATG is generally low 
(less than 20%).  If graft versus host disease is seen more frequently for the 22 transplant 
recipients on this study (more than about 7 or 8 participants of the 22) than it is 
reasonable to assume this higher risk would be a result of the CD8 memory T-cell 
infusion.  
 
Late graft versus host disease (late is typically defined as more than 180 days after 
transplant) may occur anytime in the next few years, and may involve problems with the 
eyes; mouth; lips; skin; throat; lungs; lining of the heart and lungs; vagina; muscles; 
nerves; and/or liver.   
 
Both early and late graft versus host disease  may become severe enough to result in 
death.  If you develop GVH reactions, you will be given drugs to help manage the 
symptoms by weakening the immune system.  Just as with the early graft versus host 
disease, late graft versus host disase may be a consequence of transplant or from the 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 11 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
CD8 memory T-cell infusion.  About 35% of patients develop late graft versus host 
disease after a standard transplant using TLI/ATG.  
 
In addition, there are other risks and possible discomforts you might experience from 
the study procedures, including: 
• Blood draws:  A blood draw may cause fainting; inflammation of the vein; stinging, 
discomfort, or pain; bruising; discomfort; redness; burning; or bleeding at the site 
where the needle is placed to draw the blood.  There is a slight chance of infection.  
You may feel dizzy or you may faint.  If you feel faint, you should immediately lie 
down to avoid falling 
• Personal anxiety:  Following are some common concerns that research subjects 
may have. 
o You may be asked sensitive or private questions which you normally do not 
discuss.  It may be necessary to answer some of these questions related to your 
health and medical status. 
o You may feel embarrassed during the physical exam.  You may request that the 
physical exam be done by a clinician of the same gender.  
o You may be concerned about your personal information being revealed.  
Although the Study Team, the NCI, and FDA does their best to protect your 
personal information, this cannot be absolutely guaranteed.  
• Other risks:  Since CD8 memory T-cell infusions are investigational, there may be 
other risks that are unknown (“unforeseeable”) at this time.   
 
It is important that you report all symptoms and side effects that you experience 
as soon as they occur, whether or not you think they are caused by the Study.  If 
you are unable to reach anyone at the number(s) listed above, and you feel you may 
need medical attention, call 911 or go to the nearest emergency room.  
 
POTENTIAL BENEFITS  
 
It is possible that the infusion of donor CD8 memory T-cells may reduce or completely 
eradicate your cancer.  
 
We cannot and do not guarantee or promise that you will receive any benefits from this 
study. 
 
ALTERNATIVES 
 
You do not have to be in this study to receive treatment for your cancer.  Possible 
alternative treatments and side effects of these treatments depend on the characteristics 
of your cancer, and the stage and location of your cancer.  The effectiveness and side 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 12 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
effects of other treatments may be different for different people.  Instead of taking part in 
this study, you may choose:  
 To receive allogeneic transplantation (cells form another person) using TLI and 
ATG conditioning but without the second infusion of CD8 memory T-cells. 
 To receive allogeneic transplantation using other agents, ie, not TLI plus ATG, 
to attack the cancer and prepare you for the transplantation. 
 To receive treatment with other investigational therapies. 
 While your type of cancer is/may be treatable with currently approved and 
available medications and procedure, another alternative is to receive only 
comfort care, also called “palliative care,” like painkillers.  These types of 
treatments do not treat your cancer (ie, “are not curative”), and only make you 
comfortable (“symptom relief).  If you think you might prefer comfort care, 
please discuss this with your family, friends, and doctor.  NOTE:  The 
Study Doctors do not recommend this decision for you at this time, although it 
is and will remain your decision.  
 
The Study Doctors will discuss with you the risks and benefits of these alternatives, 
including which other treatments might be suitable for you. 
If you decide that you do not wish to take part in this study and wish to pursue any of 
these, or other alternatives, this will not change your regular medical care or the other 
treatment choices in any way.  
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate.  Your questions should be answered 
clearly and to your satisfaction.  If you decide not to participate, tell the Protocol Director.   
 
You can also tell any other member of the study staff. 
 
You will be told of any important new information that is learned during the course of this 
research study, which might affect your condition or your willingness to continue 
participation in this study.  After you hear about this information, you have the right to 
withdraw from the program. 
 
ClinicalTrials.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by US Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 13 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
CONFIDENTIALITY 
 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  Your identity and/or your personal health information will 
not be disclosed except as authorized by you or as required by law.  However, there is 
always some risk that even de-identified information might be re-identified.   
 
Your research records may be disclosed outside of Stanford, but in this case, you will be 
identified only by a unique code number.  Information about the code will be kept in a 
secure location and access limited to research study personnel.   
 
Patient information may be provided to Federal and other regulatory agencies 
as required.  The US FDA, for example, may inspect research records and learn your 
identity if this study falls within its jurisdiction. 
 
The purpose of this research study is to obtain data or information on the safety and 
effectiveness of donor CD8 memory T-cells.  The results will be provided to the Food and 
Drug Administration (FDA); and other federal and regulatory agencies as required. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 14 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
Authorization To Use Your Health Information  
For Research Purposes 
Because information about you and your health is personal and private, it 
generally cannot be used in this research study without your written 
authorization.  If you sign this form, it will provide that authorization.  The 
form is intended to inform you about how your health information will be 
used or disclosed in the study.  Your information will only be used in 
accordance with this authorization form and the informed consent form and 
as required or allowed by law.  Please read it carefully before signing it.   
 
What is the purpose of this research study and how will my health 
information be utilized in the study? 
This study may help determine if donor CD8 memory T-cells are a good 
medical therapy.  Information from this study will be submitted to the FDA 
and possibly international regulatory agencies.  The results from this 
research study are expected to be presented at scientific or 
medical meetings or published in scientific journals.  You will not be 
personally identified in the publications, although representatives of 
the sponsor and FDA and other international regulatory agencies may 
need to know who you are.   
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you will 
not be able to participate in this research study, including receiving any 
research-related treatment.  Signing the form is not a condition for receiving 
any medical care outside the study.  
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 
discontinue any other participation in the study) at any time.  After any 
revocation, your health information will no longer be used or disclosed in 
the study, except to the extent that the law allows us to continue using your 
information (eg, necessary to maintain integrity of research).  If you wish to 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 15 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
revoke your authorization for the research use or disclosure of your health 
information in this study, you must write to:  
Robert Lowsky, MD  
300 Pasteur Drive, H0101 
Stanford, CA  94305 
 
What Personal Information Will Be Obtained, Used or Disclosed? 
Your health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to identifiers 
such as your name and initials; address including ZIP code; phone 
 numbers; dates including date of birth; age; sex; race; ethnicity; and 
medical record number (MRN).  During the study, researchers will also 
obtain information about your health status, life-style choices,  medical 
history, and medical diagnoses, including family medical history and 
allergies; your current and past medications or therapies; your physical 
examination results including height and weight, blood pressure readings, 
heart rate, breathing rate and temperature; your laboratory test results 
including blood, urine, and pregnancy tests; results of procedures, such as 
cancer assessments, any medical scans; and medical reports, such as the 
discharge summary and radiology, post-operative, and pathology  reports.   
 
The researchers will also get information from your medical record 
(includes hospital record from the Stanford Cancer Institute and your 
referring physician’s records).  
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
 The Protocol Director Robert Lowsky, MD  
 Research Staff 
 The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as 
necessary 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 16 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study:  
 The Office for Human Research Protections (OHRP) in the 
US Department of Health and Human Services (DHHS) 
 The Food and Drug Administration (FDA) and/or other state or 
international regulatory authorities 
 Stanford Data Safety Monitoring Committee (DSMC) 
 International Bone Marrow Transplant Registry (IBMTR)  
 Autologous Bone Marrow Transplant Registry (ABMTR) 
 Foundation for the Accreditation of Cellular Therapy 
 National Institutes of Health (NIH)  
 
Your information may be re-disclosed by the recipients described above, if 
they are not required by law to protect the privacy of the information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information 
will end on 31 December 2065 or when the research project ends, 
whichever is earlier.  
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access to 
any health information developed as part of this study until it is completed.  
At that point, you would have access to such health information if it was 
used to make a medical or billing decision about you (eg, if included in your 
official medical record).  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 17 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
 
 
___________________________________ 
 
______________ 
Signature of Adult Participant 
 
 
 
 
Date 
 
 
___________________________________ 
Print Name of Adult Participant 
 
 
___________________________________ 
 
______________ 
Signature of Legally Authorized Representative (LAR) 
Date 
(e.g., parent, guardian or conservator) 
 
 
___________________________________ 
Print Name of LAR 
 
 
________________________________________________________ 
LAR’s Authority to Act for Participant (e.g., parent, guardian or 
conservator).  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 18 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
FINANCIAL CONSIDERATIONS 
 
Costs 
If you participate in this study, the study will pay for those services, supplies, procedures, 
and care associated with the study that are not a part of your routine medical care.  
However, there may be additional costs to you.  These include basic expenses like 
transportation and the personal time it will take to come to the study visits.  You and/or 
your health insurance must pay for services, supplies, procedures, and care that are 
required during this study for routine medical care.  You will also be responsible for 
any co-payments and/or deductibles as required by your insurance.  Participation in 
this study is not a substitute for health insurance.  
 
Payments 
You will not be paid to participate in this research study.  There is no reimbursement 
offered for any expenses related to your participation in this study.  
 
The National Institutes of Health (NIH) are providing some financial support for the facility 
and staff where part or all of the study is taking place. 
 
Consultative or Financial Relationships   
None  
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop medical 
complications from participating in this study.  If such complications arise, the Protocol  
Director and the research study staff will assist you in obtaining appropriate medical  
treatment.  In the event that you have an injury or illness that is directly caused by your 
participation in this study, reimbursement for all related costs of care first will be sought 
from your insurer, managed care plan, or other benefits program.  You will be 
responsible for any associated co-payments or deductibles as required by 
your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, 
managed care plan or other benefits program, you may be responsible 
for these costs.  If you are unable to pay for such costs, the Protocol Director will 
assist you in applying for supplemental benefits and explain how to apply for patient 
financial assistance from the hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 19 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
CONTACT INFORMATION  
 
Questions, Concerns, Complaints, or to Report an Injury or Side Effect:  If you 
have any questions, concerns or complaints about this research study, its procedures, 
risks and benefits, or alternative courses of treatment, you should ask the 
Protocol Director, Dr Lowsky at You should also contact him at any time if you feel you 
have been hurt by being a part of this study.  
 
If you are unable to reach anyone at the number(s) listed above, and you fell you may 
need medical attention, call or go to the nearest emergency room.  
 
Independent Contact:  If you are not satisfied with how this study is being conducted, 
or if you have any concerns, complaints, or general questions about the research or 
your rights as a participant, please contact the Stanford Institutional Review Board (IRB) 
to speak to someone independent of the research team at You can also write to the 
Stanford IRB, Stanford University,  
xxxxEl Camino Real, Palo Alto, CA 94306 
. 
 
Appointment Contact:  If you need to change your appointment, please contact the 
study staff at (xxx-xxx-xxx)  
 
Alternate Contact:  If you cannot reach the Protocol Director, please contact the 
study staff at xxx-xxx-xxxx) 
  
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but are 
not limited to the participant's right to: 
• 
Be informed of the nature and purpose of the experiment;  
• 
Be given an explanation of the procedures to be followed in the 
medical experiment, and any drug or device to be utilized;  
• 
Be given a description of any attendant discomforts and risks reasonably 
expected;  
• 
Be given an explanation of any benefits to the subject reasonably to be expected, 
if applicable;  
• 
Be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits; 
• 
Be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 20 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
• 
Be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
• 
Be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
• 
Be given a copy of the signed and dated consent form; and  
• 
Be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, duress, 
coercion or undue influence on the subject's decision. 
 
May we contact you about future studies that may be of interest to you? ___Yes ___No 
 
Signing your name means you agree to be in this study and that you are given a 
copy of this signed and dated consent form.  
 
 
______________________________________ 
 
____________ 
Signature of Adult Participant 
 
 
 
 
 
Date 
 
 
______________________________________ 
Print Name of Adult Participant 
 
 
______________________________________ 
 
____________ 
Signature of Legally Authorized Representative (LAR)  
 
Date 
(e.g., parent, guardian or conservator) 
 
 
______________________________________ 
Print Name of LAR 
 
 
________________________________________________ 
LAR’s Authority to Act for Participant (e.g., parent, guardian or conservator) 
 
 
______________________________________ 
 
____________ 
Signature of Person Obtaining Consent  
 
 
 
Date 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Robert Lowsky, MD                          ep   33058 
Protocol Title:  
Post-transplant Infusion of Allogeneic CD8 Memory T-cells as Consolidative Therapy After 
Non-myeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with 
Leukemia and Lymphoma 
 
 
 
 
Page 21 of 21 
 
 
 
 Lowsky / IRB-33058 ICF RECIPIENT 18 February 2020 
IRB Use Only 
Approval Date:   March 11, 2020 
Expiration Date: March 11, 2021 
Participant MRN:                                                   
Participant ID: 
______________________________________ 
Print Name of Person Obtaining Consent 
 
The following witness line is to be signed only if the consent is provided as a summary form and 
accompanied by a short form foreign language consent. 
 
 
______________________________________ 
 
____________ 
Signature of Witness 
 
 
 
 
 
 
Date 
 
 
______________________________________ 
Print Name of Witness 
(e.g., staff, translator/interpreter, family member, or other person who speaks both English 
and the participant's language) 
 
• Translated short form must be signed and dated by both the participant (or their LAR) AND the 
witness. 
• The English consent form (referred to as the "Summary Form" in the regulations): 
o Must be signed by the witness AND the Person Obtaining Consent (POC). 
o The non-English speaking participant/LAR does not sign the English consent. 
o The non-English speaking participant/LAR should not sign the HIPAA participant line 
o If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) must 
ensure that 1) the LAR's Description of Authority is completed and 2) that any questions or options 
presented by the consent form are documented and initialed by the POC on the Summary Form, per 
the participant's wishes, as they are understood during the consent process.