Biological Therapy After Chemotherapy in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Biological therapies use different ways to stimulate the immune system and stop cancer cells from growing. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining biological therapy with chemotherapy may kill more cancer cells. PURPOSE: Phase I trial to study the effectiveness of biological therapy after chemotherapy in treating patients who have relapsed or refractory non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the safety and toxicity of cellular immunotherapy with autologous CD8+ cytotoxic T-lymphocyte clones after chemotherapy comprising cyclophosphamide, vincristine, and prednisone in patients with relapsed or refractory CD20+ indolent lymphomas or mantle cell lymphoma. Secondary Determine the duration of in vivo persistence of adoptively transferred CD20-specific CD8+ cytotoxic T-lymphocyte clones in the absence and presence of subcutaneous interleukin-2 in these patients. Assess the trafficking of CD8+ cytotoxic T-lymphocyte clones to lymph nodes in these patients treated with this regimen. Determine immune response and tumor response in patients treated with this regimen. OUTLINE: This is an open-label, pilot study. Leukapheresis: Patients undergo leukapheresis. Selected CD20-specific CD8+ cells are cultured to expand the cytotoxic T lymphocytes (CTL), which are then cloned. Chemotherapy: Patients receive oral cyclophosphamide and oral prednisone on days 1-5 and vincristine IV on day 1. Courses repeat every 3-4 weeks for a total of 6 courses. Immune cell infusion: Beginning 4 weeks after the last course of chemotherapy (and lymph nodes ≤ 5 cm diameter or ≤ 5,000 circulating CD20+ lymphocytes/mm^3), patients receive autologous CD8+ CTL clones IV over 30 minutes. Courses repeat every 2-5 days for a total of 3 courses in the absence of disease progression or unacceptable toxicity. The last 6 patients receive interleukin-2 subcutaneously every 12 hours for 14 days, beginning 2 hours after the last infusion of CD8+ CTL clones. After course 2 or 3 of immune cells, all patients undergo surgical lymph node biopsy to determine if immune cells are moving to the lymph nodes. Patients are followed monthly for 1 year and then annually for 2 years. PROJECTED ACCRUAL: A total of 12 patients will be accrued for this study within 4 years.

Official Title
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A Phase I Study To Evaluate The Safety Of Cellular Immunotherapy Using Genetically Modified Autologous Cd20-Specific Cd8+ T Cell Clones For Patients With Relapsed Cd20+ Indolent Lymphomas

Conditions
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Leukemia, Lymphoma

Intervention / Treatment
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* Biological: aldesleukin
* Biological: therapeutic autologous lymphocytes
* Drug: cyclophosphamide
* Drug: prednisone
* Drug: vincristine sulfate
* Procedure: adjuvant therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Immunohistopathologically documented relapsed or refractory CD20+ indolent lymphomas or mantle cell lymphoma Indolent B-cell lymphomas including any of the following subtypes: Follicular lymphoma (grade I, II, or III) Small lymphocytic lymphoma or chronic lymphocytic leukemia Marginal zone lymphoma (splenic, nodal, and extra-nodal) Lymphoplasmacytoid lymphoma Ineligible for or unwilling to participate in other FHCRC/UWMC protocols Serological evidence of prior exposure to Epstein-Barr virus Must agree to undergo peripheral blood drawing, bone marrow biopsy, lymph node biopsy, and nuclear medicine imaging Must agree to cytoreductive chemotherapy if necessary to reduce lymph nodes to < 5 cm in diameter or circulating B lymphocyte counts to < 5,000/mm^3 No pulmonary involvement No CNS involvement PATIENT CHARACTERISTICS: Age: Any age Performance status: Not specified Life expectancy: At least 90 days Hematopoietic: Not specified Hepatic: No active hepatitis B infection Renal: Not specified Other: No HIV positivity Not pregnant or nursing Fertile patients must use effective contraception No history of hypersensitivity reactions to murine proteins PRIOR CONCURRENT THERAPY: Biologic therapy: At least 4 months since prior rituximab, tositumomab, or ibritumomab No prior allogeneic stem cell transplantation No other concurrent immunotherapy (e.g., interferons, vaccines, or other cellular products) Chemotherapy: At least 2 years since prior fludarabine or cladribine At least 4 weeks since prior chemotherapy and recovered Endocrine therapy: No concurrent systemic corticosteroids except to treat toxicity from chemotherapy or cellular immunotherapy Radiotherapy: Not specified Surgery: Not specified Other: At least 4 weeks since prior immunosuppressive therapy and recovered No concurrent pentoxifylline No other concurrent investigational agents
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: aldesleukin|nan|
|Biological: therapeutic autologous lymphocytes|nan|
|Drug: cyclophosphamide|nan|
|Drug: prednisone|nan|
|Drug: vincristine sulfate|nan|
|Procedure: adjuvant therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and toxicity by NCI CTC toxicity scale in patients w/ recurr. or refract. CD20+ follicular lymphoma who are not candidates for high dose chemoradiotx and stem cell transplant during each infusion, weekly for 4 wks and then monthly for a yr |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of in vivo persistence of adoptively transferred CD20-specific CD8+ T cell clones by flow cytometry and quantitative polymerase chain reaction (qPCR) during each infusion, weekly for 4 weeks, and then monthly for a year |  |  | 
| Trafficking of CD8+ CD20-specific T cell clones to lymph nodes by Gamma camera imaging during each infusion, weekly for 4 weeks, and then monthly for a year |  |  | 
| Development of host anti-scFvFc:zeta (and anti-NeoR) immune responses by ELISA and chromium release assays during each infusion, weekly for 4 weeks, and then monthly for a year |  |  | 
| Tumor responses to cyclophosphamide, vincristine, and prednisone (CVP) and to cytotoxic T-lymphocyte (CTL) infusions by Cheson criteria during each infusion, weekly for 4 weeks, and then monthly for a year |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia