The broad and long-term objectives of this proposal are: (1) the development of effective immunotherapeutic strategies against human melanoma; and (2) the identification of potent anti-tumor effector T cells. Our hypothesis is that pre-effector cells against autologous melanoma may be induced in the draining lymph nodes by active specific immunotherapy. However, these pre-effector cells may not be active unless they become activated in vitro to become effector cells. This study is meant to induce specific pre-effector cells in vivo by active specific immunotherapy and to activate and expand these pre-effector cells in vitro to become anti-tumor effector cells for adoptive immunotherapy.
The specific aims are: (1) to study the immune response of patients undergoing T cell immunotherapy; (2) to study mechanisms of GM-CSF as an immune adjuvant sensitizing lymph node T cells in vivo with special attention to the role of antigen-presenting cells; and (3) to correlate between immunologic characteristics and in vitro reactivities of lymph node T cells with their in vivo anti-tumor efficacy. Stage IV melanoma patients will be immunized with irradiated autologous tumor ells mixed with GM-CSF as an adjuvant to boost the immune response. Tumor vaccine draining lymph nodes harvested surgically 7 days later will be activated and expanded in vitro with a bacterial super- antigen followed by anti-CD3. A large number of these activated T cells will be infused intravenously to the patient for adoptive immunotherapy. In this research-driven clinical trial, immunological characteristics of these activated T cells will be studied in detail using ELISA and ELISPOT for cytokine production, 51/chromium release assay for T cell cytotoxicity, flow cytometry and immunohistochemical staining for T cell markers and polymerase chain reactions for T cell receptor usage. Skin tests will be performed and analyzed. The in vitro reactivities of these cells will be correlated with their in vivo anti-tumor efficacy and skin test reactivity. It is hoped that this study will allow us to have a better understanding of host-tumor interactions and to improve methods for the generation of therapeutically potent effector T cells. If the criteria to generate specific T cells against autologous melanoma can be established, the health relatedness of the project is a significant therapeutic breakthrough for patients with metastatic melanoma as there is no effective treatment for these patients to date.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Subcommittee G - Education (NCI)
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Xie, Heng
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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