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Adoptive Cell Therapy for B-Cell Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation With Costimulated, Tumor-Derived Lymphocytes

Phase 1
18 Years
75 Years
Open (Enrolling)
Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm

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Trial Information

Adoptive Cell Therapy for B-Cell Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation With Costimulated, Tumor-Derived Lymphocytes



- Determine the feasibility of administering ex vivo costimulated, expanded, clinically
relevant numbers of tumor-derived lymphocytes (TDL) from surgically resected tumor
(TDL) and tumor-involved bone marrow (marrow-TDL) in patients with persistent or
recurrent B-cell lymphoid malignancies after prior allogeneic hematopoietic stem cell
transplantation (alloHSCT).

- Determine the safety of TDL, in terms of the incidence of infusion-related toxicities,
hyperacute graft-versus-host disease (GVHD), or acute or chronic GVHD, in these


- Determine antitumor response in patients treated with TDL.

- Investigate methods of characterizing residual tumor after alloHSCT by evaluating
patient tumor and bone marrow tissue samples for tumor viability and inflammatory
infiltrate; assessing residual tumor cells for antigen specificity and gene expression;
and assaying TDL for tumor reactivity and specificity.

- Investigate methods of characterizing the immune phenotypic and functional
characteristics of patient TDL and tumor-selected TDL and compare the in vitro
antitumor efficacy of these two cell products.

- Identify recombinant, graft-versus-tumor (GVT) antigens in tumor samples before and
after administration of TDL to better understand the mechanisms and effectors of GVT
response in these patients.

- Investigate methods of characterizing tumor infiltrate in these patients by evaluating
tumor and bone marrow tissue samples for viability and inflammatory infiltrate;
assessing residual tumor cells for enhanced antigen specificity and gene expression;
and assaying TDL for tumor reactivity and specificity.

- Investigate the effect of immune depletion in these patients on the availability of
homeostatic cytokines and the requirement for exogenous cytokine support of in-vivo
survival and expansion of adoptively transferred cells.

OUTLINE: This is a pilot study.

Patients undergo apheresis to collect peripheral blood mononuclear cells (PBMCs). Patients
then undergo surgical resection of accessible tumor and/or bone marrow is collected.
Tumor-infiltrating T lymphocytes (TILs) are isolated from tumor tissue, costimulated with
PBMCs, and expanded ex vivo to generate tumor-derived lymphocytes (TDLs). Beginning at least
24 days after surgery and within 7 days after tumor assessment, patients receive an infusion
of TDL IV in the absence of disease progression or unacceptable toxicity.

Patients undergo blood, bone marrow, and tissue collection periodically during study for
correlative studies, including the following: phenotypic and functional characterization of
residual tumor and TDL by immunohistochemistry and fluorescent in situ hybridization;
identification of prognostic markers of clinical outcome (i.e., HLA-A, -B, and -C; HLA-DR,
Fas ligand, CD80, and CD86) by flow cytometry; in vitro assessment of tumor-reactive,
selectively expanded T-cell clones by gene expression profiling; and evaluation of immune
response by tumor-specific cytotoxicity assays (immunoenzyme techniques) and DNA sequencing
for recombinant graft-versus-tumor antigens. Chimerism is assessed with a polymerase chain
reaction-based assay and cytogenetics.

After completion of study therapy, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.

Inclusion Criteria


- Histologically confirmed B-cell non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma
chronic lymphocytic leukemia, non T-cell acute lymphoblastic leukemia (B-cell ALL),
or multiple myeloma

- Persistent or recurrent disease after last systemic treatment

- Underwent prior allogeneic hematopoietic stem cell transplantation (alloHSCT) and
failed to respond to the following after a minimum of 4 weeks:

- Withdrawal of immunosuppressive therapy trial, including trials that were
discontinued due to development of graft-versus-host disease (GVHD)

- Administration of ≥ 1 donor lymphocyte infusion (DLI) with a minimum T-cell dose
of 1 x 10^7 CD3-positive cells/kg*

- Evidence of stable or increasing donor engraftment over the past 3 months (≥ 50%
donor chimerism in the bone marrow, whole blood, and/or circulating CD3+
lymphoid pool) NOTE: *Patients who have relapsed after prior alternative donor
alloHSCT (e.g., haploidentical, matched unrelated, umbilical cord blood) without
failing DLI are eligible

- Presence of bone marrow involvement with tumor and/or at least 1 lymph node with ≥
1.5 cm³ of accessible tumor available for resection with minimal surgical morbidity
and hospitalization

- Presence of at least 1 other site of disease that permits monitoring for response to

- Minimal to no clinical evidence (grade 0-1) of acute GVHD or limited-stage chronic
GVHD while off systemic immunosuppressive therapy for ≥ 4 weeks

- No untreated leptomeningeal involvement with malignancy

- Lumbar puncture required for patients with aggressive NHL, history of
leptomeningeal disease, or signs or symptoms suggestive of leptomeningeal


- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)

- Life expectancy > 3 months

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 1 year after
completion of study therapy

- Absolute neutrophil count ≥ 500/mm³ (or < 500/mm³ attributed to tumor )

- Platelet count ≥ 20,000/mm³ (without transfusion) (> 50,000/mm³, if

- Creatinine < 2.5 mg/dL

- Creatinine clearance > 40 mL/min

- Bilirubin ≤ 2.5 mg/dL (≤ 5 mg/dL if attributable to liver involvement by malignancy*)

- AST and ALT < 2.5 times upper limit of normal (ULN) (≤ 5 times ULN if attributable to
liver involvement by malignancy*)

- PT and PTT normal (or demonstrably not related to coagulopathy)

- No PT > 6 seconds attributable to hepatic failure (in the absence of vitamin K
deficiency, pharmacologic anticoagulation, or identifiable clotting abnormality)

- LVEF ≥ 45% by MUGA or 2-dimensional echocardiogram

- DLCO ≥ 50% of predicted (corrected for hemoglobin)

- No active infection that is not responding to antimicrobial therapy

- No active psychiatric illness that would preclude compliance with transplantation
protocol or giving informed consent NOTE: *Provided the patient has no evidence of
impending hepatic failure (i.e., encephalopathy or PT > 2 times ULN)


- See Disease Characteristics

- At least 2 weeks since prior cytotoxic therapy or immunotherapy

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Feasibility (defined as 11 of 15 tumors yielding 1.0 × 10e7 tumor-derived lymphocytes/kg meeting defined release criteria)

Safety Issue:


Principal Investigator

Michael R. Bishop, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Food and Drug Administration

Study ID:

070064, CDR0000532130



Start Date:

August 2007

Completion Date:

Related Keywords:

  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • recurrent small lymphocytic lymphoma
  • splenic marginal zone lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • recurrent mantle cell lymphoma
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult Burkitt lymphoma
  • B-cell chronic lymphocytic leukemia
  • refractory chronic lymphocytic leukemia
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent marginal zone lymphoma
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • stage I multiple myeloma
  • stage II multiple myeloma
  • stage III multiple myeloma
  • refractory multiple myeloma
  • recurrent adult Hodgkin lymphoma
  • recurrent adult acute lymphoblastic leukemia
  • Neoplasms
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Lymphoma, B-Cell



Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office Bethesda, Maryland  20892-1182