Clinical Trial for Lymphoma: 07-C-0064: 1.888.NCI.1937

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

Protocol # 07-C-0064

Why is this trial important?
Who is eligible for this trial?
What types of drugs or therapies are being used?
What is the treatment plan?
What is the frequency and duration of the visits?
What are the costs?
Who is the Principal Investigator?
Where is this trial taking place?
Who are the contacts for this trial?
Where can additional information be found?

Why is this trial important?

The prognosis for patients with B-cell lymphoid malignancies (BCL) with relapse or refractory disease after allogeneic hematopoietic stem cell transplantation (AlloHSCT) is poor. Effective therapy for patients who fail withdrawal of immune suppression and administration of donor lymphocyte infusions (DLI) has not been identified. Further, in the setting of recurrent or refractory BCL, the immunologic graft-versus-tumor (GVT) effect generated by unmanipulated donor lymphocytes is often not durable and can be accompanied by graft-versus-host disease (GVHD). Generation of donor lymphocytes that mediate more potent and specific GVT effects is a major goal of transplantation research. We have hypothesized that lymphocytes found in tumor after alloHSCT are of donor origin, and because they are tumor-derived, they may be tumor-specific in their homing and antigen specificity characteristics. Further, activation and expansion of these cells through CD3/CD28 costimulation may yield a more effective form of cell therapy after AlloHSCT, with enhanced GVT effects and less GVHD.

Who is eligible for this trial? (PDQ)

Histologically confirmed B-cell non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia or multiple myeloma
Persistent or recurrent disease after alloHSCT and the following post-transplant therapeutic maneuvers:

A trial of withdrawal of immunosuppressive therapy
Administration of ≥ 1 DLI with a minimum T-cell dose of 1 x 10⁷ CD3-positive cells/kg*
Evidence of established full-donor T-cell engraftment (> 90% chimerism of the circulating T-cell compartment)

Presence of at least one tumor ≥ 1.5 cm³ that is surgically accessible with minimal surgical morbidity
Presence of at least one other site of disease that permits monitoring for response to therapy
Minimal to no clinical evidence (grade 0–1) of acute GVHD or limited-stage chronic GVHD while off systemic steroid therapy for ≥ 4 weeks
No active leptomeningeal involvement with malignancy

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

ECOG 0–2
Absolute neutrophil count ≥ 500/mm³ (without transfusion)
Platelet count ≥ 20,000/mm³ (without transfusion) (> 50,000/mm³, if transfusion-dependent)
Creatinine < 2.5 mg/dL
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) 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
HIV, hepatitis B surface antigen, and hepatitis C antibody negative
No active psychiatric illness that would preclude compliance with transplantation protocol or giving informed consent
Not pregnant or nursing; fertile patients must use effective contraception during and for 1 year after completion of study therapy

*Patients whose donors are unavailable, including those who received alternative donor alloHSCT (e.g., haploidentical, matched unrelated, umbilical cord blood) do not require DLI to be eligible.
**Provided the patient has no evidence of impending hepatic failure (i.e., encephalopathy or PT > 2 times ULN).

What types of drugs or therapies are being used?

Patients who have had previous alloHSCT will have tumor lesions surgically resected. Lymphocytes will be liberated from the tumor tissue and expanded using a co-stimulatory approach with anti-CD3/CD28 magnetic beads to generate tumor-derived donor lymphocytes (TDL). The TDL product will be assessed to confirm that the lymphocytes are of donor origin. A cell dose of 1.0 x 10⁷ – 1.0 x 10⁸ TDL will be administered.

What is the treatment plan? (PDQ)

This is a pilot study.

Patients undergo apheresis to collect plasma for cell culture and peripheral blood mononuclear cells (PBMCs) for research evaluation
Patients then undergo surgical resection of accessible tumor; tumor-infiltrating lymphocytes (TILs) are isolated from tumor tissue, costimulated, and expanded ex vivo to generate TDL
Beginning at least 24 days after surgery and within 7 days after tumor assessment, patients receive an infusion of TDL
Patients undergo blood, bone marrow, and tissue collection periodically during study
After completion of study therapy, patients are followed periodically for up to 5 years

What is the frequency and duration of the visits?

Patients will be screened for eligibility over a 3 day period. After enrollment, patients will be scheduled for surgery for tumor resection. The tumor resection visit will vary in duration depending on the site of tissue harvest. The site of harvest will be chosen with preference given to the most accessible lesion with the least expected surgical morbidity and hospital stay. Approximately four weeks after harvest, patients will return for TDL administration, after which they will be monitored for the development of infusion reactions (requiring an in-hospital stay of 24 hours), GVHD (requiring clinic visits weekly for four weeks then monthly), and tumor responses (requiring a 1–2 day restaging evaluation and clinic visit monthly).

What are the costs?

There is no charge for medical care received at the National Institutes of Health (NIH) Clinical Center. Patients will be responsible for travel costs for their initial screening visits. In most cases, once patients are enrolled in a trial, the National Cancer Institute (NCI) will pay the transportation costs for all subsequent trial-related visits for patients who do not live in the local area. In addition, these patients will receive a small per diem to help offset the costs of meals and lodging if they are being treated as outpatients.

It will be important to maintain your current insurance plan to cover all medical care that is provided away from the NIH Clinical Center.

No U.S. citizen or permanent U.S. resident residing in the U.S. who otherwise meets the eligibility requirements will be denied enrollment in clinical research protocols because of their inability to pay the costs of travel and subsistence.

Who is the Principal Investigator?

Dr. Michael R. Bishop received his M.D. from the University of Illinois in 1985. He completed clinical training in internal medicine at Northwestern University in 1988 and a fellowship in hematology and oncology at Loyola University Medical Center in 1991. He was an assistant professor of medicine at the University of Kentucky Medical Center from 1991 to 1992 and an associate professor of medicine at the University of Nebraska Medical Center from 1992 to 1999, where he served as director of the Leukemia and Allogeneic Stem Cell Transplantation Programs. Dr. Bishop joined the Medicine Branch in March 1999 to serve as the clinical head of the Stem Cell Transplantation Program.

Where is this trial taking place?

NIH Clinical Center
National Institutes of Health
NCI Medical Oncology Branch and Affiliates,
Experimental Transplantation and Immunology Branch
10 Center Drive
Bethesda, Maryland 20892

Who are the contacts for this trial?

Michael Bishop, M.D.
Principal Investigator
Phone: 301-435-2764
mbishop@mail.nih.gov

Nancy Hardy, M.D.
Protocol Chair
Phone: 301-451-1406
hardyn@mail.nih.gov

Referrals:

Bazetta (Zetta) Blacklock, R.N., B.S., B.S.N.
Transplant Coordinator
Phone: 301-594-2056
Fax: 301-435-6830
bblacklock@mail.nih.gov