Tumor-Infiltrating Lymphocytes in Treating Patients With Persistent or Recurrent B-Cell Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia or Multiple Myeloma After a Previous Donor Stem Cell Transplant

• Feasibility (defined as 11 of 15 tumors yielding 1.0 × 10e7 tumor-derived lymphocytes/kg meeting defined release criteria) [ Designated as safety issue: No ]
• Safety (defined as having no greater risk of developing acute graft-versus-host disease by day 28 as with standard therapy with unmanipulated donor lymphocyte infusion) [ Designated as safety issue: Yes ]

• Feasibility (defined as 11 of 15 tumors yielding 1.0 × 10e7 tumor-derived lymphocytes/kg meeting defined release criteria)
• Safety (defined as having no greater risk of developing acute graft-versus-host disease by day 28 as with standard therapy with unmanipulated donor lymphocyte infusion)

RATIONALE: Biological therapies, such as cellular adoptive immunotherapy using tumor-infiltrating lymphocytes, may stimulate the immune system in different ways and stop cancer cells from growing.

PURPOSE: This phase I trial is studying the side effects and how well tumor-infiltrating lymphocytes work in treating patients with persistent or recurrent B-cell non-Hodgkin's lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, or multiple myeloma after a previous donor stem cell transplant.

OBJECTIVES:

Primary

• 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 patients.

Secondary

• 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.

• Leukemia
• Lymphoma
• Multiple Myeloma and Plasma Cell Neoplasm

• Biological: graft-versus-tumor induction therapy
• Biological: therapeutic tumor infiltrating lymphocytes
• Genetic: cytogenetic analysis
• Genetic: fluorescence in situ hybridization
• Genetic: microarray analysis
• Genetic: polymerase chain reaction
• Other: flow cytometry
• Other: immunoenzyme technique
• Other: immunohistochemistry staining method
• Other: immunologic technique
• Other: laboratory biomarker analysis
• Procedure: biopsy
• Procedure: conventional surgery

DISEASE CHARACTERISTICS:

• 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 therapy
• 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 involvement

PATIENT CHARACTERISTICS:

• 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 transfusion-dependent)
• 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)

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 2 weeks since prior cytotoxic therapy or immunotherapy