Anti-CTLA-4 Monoclonal Antibody Therapy for Lymphoma

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DESCRIPTION (provided by applicant): Follicular B cell non-Hodgkin's lymphoma (NHL) can be considered the most "immune-responsive" of human cancers based on its capacity for spontaneous regression and substantial response rate following treatment with non-specific immunostimulants, monoclonal antibodies, and therapeutic tumor vaccines. Despite this, tumor immune-escape and physiologic T cell homeostasis mechanisms appear to limit the expansion and effector functions of potentially tumor-reactive T cells. One novel approach to the reversal of T cell hyporesponsiveness towards tumors is blockade of the negative T cell regulatory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4). Administration of blocking anti-CTLA-4 monoclonal antibodies can promote anti-tumor immunity in a wide variety of murine tumor models. Promising clinical activity has been observed in several recent phase I clinical trials utilizing anti-CTLA-4 monoclonal antibodies against melanoma and prostate cancer. Given the unique susceptibility of B cell lymphoma to immunotherapeutic interventions, we hypothesize that anti-CTLA-4 should have significant clinical activity in this disease setting, and could possibly augment the efficacy of other lymphoma immunotherapies such as vaccines. We therefore propose a new clinical trial that will serve to establish the appropriate dosing schedule, toxicity profile, and single agent activity of anti-CTLA-4 in B cell lymphoma patients. Specific Aim 1. Perform a phase I/II clinical trial to characterize the safety and clinical efficacy of anti-CTLA-4 monoclonal antibody in patients with follicular B cell non-Hodgkin's lymphoma. This multi-center study (UCLA & Mayo Clinic) will include up to 36 patients with measurable follicular lymphoma relapsing after or resistant to conventional therapies. Patients who have received prior tumor vaccines will represent one-half of subjects. Specific Aim 2. Determine whether anti-CTLA-4 treatment results in systemic recruitment of anti-tumor immune effector mechanisms in patients with follicular lymphoma. Before and after therapy, peripheral blood will be sampled for measurement of: 1) Tumor-specific cytokine release and cytotoxicity, 2) Responsiveness of memory T cells to stimulation with recall antigens, 3) The numbers and activation state of circulating T cells, including the CD4+CD25+ regulatory T cell population which constitutively expresses CTLA-4, and 4) Tumor-specific antibodies. Specific Aim 3. Investigate whether anti-CTLA-4 therapy can boost number and function of T cell effectors in the tumor microenvironment. Tumors will be biopsied pre- and post-treatment to characterize the number and activation state of tumor infiltrating lymphocyte subpopulations (including CD4+, CD8+, and CD4+CD25+ regulatory T cells), and to evaluate the anti-tumor effects of tumor infiltrating T cells following in vitro expansion.