Antigen Discovery and Development of Tumor-Specific Lymphoma Immunotherapy

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DESCRIPTION (provided by applicant): The objective of this grant proposal is to provide the candidate, Sattva S. Neelapu, M.D., the experience, dedicated time, and training necessary to develop a career as an independent patient-oriented translational researcher in the study of lymphomas. Dr. Neelapu is a physician scientist with laboratory training in cancer immunotherapy and clinical training in lymphoma medical oncology. This award would allow him to focus 75% of his effort to career development and the proposed research. Active immunotherapy is a promising approach for the treatment of B-cell non-Hodgkin's lymphoma. We have previously demonstrated that customized vaccines made from the unique variable regions of the heavy and light chains of the B-cell lymphoma immunoglobulin molecule, termed idiotype, can induce tumor-specific immunity in greater than 80% of patients with follicular and mantle cell lymphoma. Furthermore, vaccination was associated with significantly prolonged disease-free survival, suggesting that active immunotherapy might induce meaningful clinical benefit in lymphoma patients. However, a problem with using tumor-specific idiotype as a vaccine is that it requires the generation of a custom-made product for each patient that is expensive, laborious, and time-consuming to make. The use of shared lymphoma-specific tumor antigens would obviate these difficulties, but such antigens have not been identified to date and thus have not been tested. We propose to achieve both in the research described here. The central hypothesis that we plan to test is that lymphoma patients vaccinated with a tumor antigen generate broad immune responses against the immunogen as well as other lymphoma-associated antigens and therefore, T cells from these patients can be used as tools for tumor antigen discovery. Tumor-specific T-cell lines and clones generated from idiotype-vaccinated patients recognized several HLA-matched lymphomas obtained from other patients, which suggested that they recognized a shared tumor antigen(s). The specific aims of this proposal are: 1) Identify novel shared lymphoma-specific antigen(s) using a cDNA expression cloning method and T cells from previously vaccinated patients. 2) Define T-cell epitopes in the candidate lymphoma antigen(s) identified in Aim 1. 3) Characterize the expression pattern of the candidate tumor antigen(s) in various lymphomas and normal tissues. 4) Determine the safety, immunogenicity, and clinical activity of peptide vaccinations in patients with mantle cell lymphoma. Our long-term goal is to generate clinically efficacious vaccines from these newly identified tumor-specific antigens in lymphoma patients. In terms of the rationale, the important clinical benefit of these vaccines made from shared immunogenic lymphoma-specific antigens is a treatment that can i) considerably improve the outcome in patients with lymphoma and ii) be used universally in these patients.