IMMUNOTHERAPY OF BREAST CANCER WITH TUMOR ANTIGEN SPECIFIC CYTOTOXIC T CELLS

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This proposal is based upon the premise that an effective cell mediated immune response against "non-immunogenic" spontaneously arising breast tumors can be elicited by activation of tumor associated antigen (TAA) specific cytotoxic T lymphocytes (CTL). We have demonstrated in vitro that we can activate and expand TAA specific CTL from lymphocytes infiltrating human breast carcinomas. The practical aspects of adoptive immunotherapy with CTL would be greatly enhanced if CTL precursors (CTLp) could be harvested from patient peripheral blood mononuclear cells (PBMC) rather than tumor infiltrating lymphocytes (TIL) due to the limited availability of the latter. To apply this therapeutic modality to human use, we have developed methods using a novel gene delivery system that allows for activation and ex vivo expansion of TAA specific CTL using autologous stimulator cells. Initial studies will examine PBMC populations for the presence of anti-HBR2/neu and anti-MAGE-I CTL. Based on the relative frequency of these TAA specific CTL quantitated by limit dilution analysis (LDA) present in PBMC, the second series of experiments will seek to increase overall peripheral CTL reactivity by specific cellular immunization with canary pox constructs expressing HER2/neu or MAGE-l in the context of a phase I clinical trial. The overall goal of this proposal is to develop and perform phase I clinical studies of immunotherapy with ex vivo activated and expanded autologous TAA specific CTL in patients with breast cancer and provide an analysis of the effectiveness of TAA specific CTL using objective phenotypic and functional markers of immune reactivity. We then propose to develop phase II clinical trials in patients with minimal tumor burden following high dose cytoreductive chemotherapy and autologous bone marrow transplant (ABMT) based on the clinical and biologic data from the phase I study. The proposed clinical trials are facilitated by the Duke Multidisciplinary Breast Clinic, the Duke Bone Marrow Transplant Program and the Duke Oncology Consortium, which are designed to implement clinical trials of novel therapeutic strategies and insures the availability of an adequate number of patients with breast cancer eligible for this study.