Protocol Number: 07-C-0064

Title:

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

Number:

07-C-0064

Summary:

Background:

-After allogeneic (donor) stem cell transplantation, a new immune system grows in the patient from the transplanted donor stem cells and lymphocytes (type of immune cell). Donor lymphocytes, unlike the patient's own lymphocytes, often can recognize the patient's tumor cells as being foreign and destroy them.

-It is thought that tumor shrinkage after stem cell transplantation is the result of donor T lymphocytes, or T cells. Some studies show that patients with tumors that have T cells are better able to keep tumor growth in check.

-Patients who have had donor stem cell transplantation may have donor T cells in their tumors that can recognize and fight their cancer. Compared with donor T cells taken directly from the donor and infused into the patient, donor T cells found in patients' tumors may be specific for the cancer cells and thus better able to attack tumor. Also, because the T cells found their way to the tumor, they may be less likely to recognize and attack non-tumor tissues than the T cells given in donor lymphocyte infusions.

-The T cells may be especially effective at controlling tumor if they are given an additional stimulus to become active. Costimulation is the name of the body's natural process for providing an extra stimulus, and can be performed on cells in the laboratory. Costimulation can produce large numbers of activated cells that may be able to attack cancer cells and shrink tumors.

Objectives:

-To evaluate the ability of lymphocytes found in tumors from patients who have received donor stem cell transplants to control their tumor growth.

Eligibility:

-Patients between 18 and 75 years of age with a B-cell cancer that has continued to grow or recurred after remission following allogeneic stem cell transplantation. This includes patients who have received transplants from unrelated donors and cord blood.

Design:

-Immune cells are collected from patients' blood and blood from their stem cell donor.

-Patients undergo surgery to remove their tumor and a small piece of skin. In the laboratory, donor T cells are isolated from the tumor and costimulated to expand the number of cells and activate them.

-The expanded, activated T cells as infused into the patient.

-Patients have a needle biopsy and possibly surgery to remove a sample of remaining tumor for research studies.

-Patients are followed at the NIH clinic 48 hours after the cell infusion, and again at 1, 2, 4, 8 and 12 weeks after the infusion. Tumor size is monitored every month with CT scans, and possibly also with a PET or bone marrow aspiration and biopsy, for the first 3 months after the cells are infused. Thereafter, visits are less frequent (every 3 months, then every 6 months, and then yearly) during a minimum 5-year follow-up.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Inclusion Criteria: Recipient

1. Patients must have received allogeneic HSCT for B-cell malignancies, specifically non-Hodgkin's lymphomas, chronic lymphocytic leukemias, and multiple myeloma, and must have disease that has failed to respond after a minimum of four weeks to:

Evidence of established full-donor T cell engraftment (greater than 90% chimerism of the T cell compartment and a circulating T cell population)

A trial of withdrawal of immunosuppressive therapy, including trials that are discontinued due to development of GVHD

Receiving at least one DLI with a minimum T cell dose of 1 x 10(7) CD3+ cells/kg.

2. Patients who have relapsed after treatment with an alternative donor alloHSCT (e.g., haploidentical, matched unrelated, umbilical cord blood) or any patient for whom the donor is no longer available may be included without failing DLI.

3. Presence of at least one resectable lymph node or other tumor focus that is a minimum of 1.5 cm(3) (estimated size from which at least 1.0 x 10(6) TNC/kg can be generated):

- Resectable defined on a case-by-case basis, in collaboration with the Surgical Consult Service.

-For surgical tumor resection, the expected procedure must be associated with minimal morbidity and minimal hospitalization.

-In addition to a resectable lesion, there must be at least one other site of disease that permits monitoring for response to therapy.

4. Patients must be 18 - 75 years of age.

5. ECOG performance status less than or equal to 2 (Karnofsky performance status greater than or equal to 60%).

6. Life expectancy greater than 3 months.

7. Minimal to no clinical evidence (Grade 0 to 1) of acute GVHD or limited-stage chronic GVHD while off of systemic immunosuppressive therapy for at least four weeks. Subjects who require continued prophylaxis with steroid-sparing agents, e.g., cyclosporine, or whose disease is controlled with local therapy, e.g., topical steroids or budesonide, will be eligible for enrollment.

8. Provision for a Durable Power of Attorney.

9. Ability to give informed consent.

Inclusion Criteria Donor:

10. Donor must be the same individual whose cells were used as the source for the patient's original stem cell transplant

11. Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.

12. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody negative.

EXCLUSION CRITERIA:

Exclusion Criteria Recipients:

1. Active infection that is not responding to antimicrobial therapy.

2. Evidence of infection with HIV, Hepatitis B or Hepatitis C. Patients must be HIV-, HbsAg-, and Hepatitis C antibody negative. The high degree of immune suppression that may be used in this study may lead to the activation or progression of these viral illnesses.

3. Active psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent (as determined by Principal Investigator and/or his designee).

4. Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the immunosppressive medications that could be required to treat GHVD are likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to an infant.

5. Serum total bilirubin greater than 2.5 mg/dl, serum ALT and AST values greater than or equal to 2.5 times the upper limit of normal. If the abnormal liver function is attributable to liver involvement by malignancy, patients may be eligible with serum total bilirubin up to 5.0 mg/dl, and serum ALT and AST values up to 5.0 times the upper limit of normal, provided the patient has no evidence of impending hepatic failure (encephalopathy or prothombin time greater than 2 time the upper limit of normal).

6. Minimum absolute neutrophil count of 500 cells/microL Active leptomeningeal involvement with malignancy.

7. Coagulation status: PT and PTT normal or demonstrably not related to coagulopathy; platelet count of greater than 50,000; if transfusion-dependent, able to sustain platelets of above 50,000, however, final determination of surgical candidacy will be determined by the NCI Surgical Consult Team.

Exclusion Criteria: Donors

8. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.

9. History of hypertension that is not controlled by medication, stroke, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.

10. Donors must not be pregnant. Donors of childbearing potential must use an effective method of contraception.

11. Anemia (Hb less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per microL). However, potential donors with Hb levels less than 11 gm/dl that is due to iron deficiency will be eligible as long as the donor is initiated on iron replacement therapy. The NIH Clinical Center, Department of Transfusion Medicine will determine the appropriateness of individuals as donors.

Special Instructions:

Currently Not Provided

Keywords:

Adoptive Immunotherapy

Tumor Infiltrating Lymphocytes

Refractory Tumor

Resection

B-cell malignancies

Recruitment Keyword(s):

Chronic Lymphocytic Leukemia

B-cell malignancies

B-cell Lymphoid Malignancy

BCL

Condition(s):

Chronic Lymphocytic Leukemia

Investigational Drug(s):

Allogeneic Cell Therapy w/ Tumor-derived Lypho

Investigational Device(s):

None

Intervention(s):

Drug: Allogeneic Cell Therapy w/ Tumor-derived Lypho

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11810-3

Russell NH, Byrne JL, Faulkner RD, Gilyead M, Das-Gupta EP, Haynes AP. Donor lymphocyte infusions can result in sustained remissions in patients with residual or relapsed lymphoid malignancy following allogeneic haemopoietic stem cell transplantation. Bone Marrow Transplant. 2005 Sep;36(5):437-41

Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Aug 19;329(8):581; author reply 581-2.

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