TUMOR VACCINES AFTER NON MYELOABLATIVE ALLOGRAFTING

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D E S C RIPTION (Applicant's Description): A variety of drug-resistant h e m atologic malignancies are effectively treated by high dose c h e m oradiotherapy followed by allogeneic bone marrow transplantation (alloBMT), which is associated with an immune-mediated graft-versus-leukemia (GVL) effect. Unfortunately, conditioning regimen toxicity, graft-versus-host disease (GVHD), and relapse are significant causes of treatment failure. Non- myeloablative alloBMT (NM alloBMT) is a new therapy that reduces conditioning regimen intensity and toxicity and serves as a platform for inducing GVL effects with donor lymphocyte infusions (DLI). The central hypothesis of this proposal is that the antitumor efficacy of NM alloBMT can be augmented by post-transplant administration of tumor cell-based vaccines +/- DLI, thereby circumventing the dysfunction of endogenous T cells that is frequently seen in cancer patients. Accordingly, the specific aims are to: 1) Examine the e f f e cts of donor/recipient histoincompatibility, conditioning regimen intensity, and timing of DLI on the immune response to tumor vaccines after bone marrow allografting. 2) Characterize the effects of tumor vaccine administration on GVHD and antitumor efficacy of DLI after NM alloBMT. 3) Characterize the effects of GVHD and tumor vaccines on the in vivo proliferation, cytokine production, and antitumor efficacy of transgenic T cells specific for a defined tumor antigen. My immediate and long-term goals are to translate laboratory research on tumor vaccines and alloBMT into improved therapies of cancer in the clinic. My mentors are Drs. Ephraim Fuchs and Drew Pardoll, who have expertise in translational immunology research and will support my efforts to achieve independent investigator status. All cancer immunology research at Johns Hopkins is conducted on the fourth floor of the new Bunting-Blaustein Cancer Research Building, which provides state-of-the-art equipment and a fertile intellectual environment. The Johns Hopkins Oncology Center has several clinical trials of tumor vaccines in both solid and hematologic malignancies, and performs over 200 bone marrow transplants per year, approximately half of which employ allogeneic donors.