Murine tumor models have contributed much to our understanding of immune rejection processes and afford an opportunity for rapidly monitoring the in vivo therapeutic effects of cancer vaccines, adoptively transferred T cells (ATC), and bone marrow transplantation (BMT). We have shown that murine tumor lysate- pulsed dendritic cells (TP-DC) can elicit tumor-specific CD4+ and CD8+ T cell reactivities in vitro and in vivo. This observation has been made in a variety of histologically-distinct murine tumors, including sarcoma, carcinoma, and melanoma. We have also shown that syngeneic hosts can be effectively immunized in vivo to reject aggressive, weakly-immunogenic sarcomas, a breast carcinoma, and a poorly-immunogenic subline of the B16 melanoma by immunization with TP-DC, which is dependent upon host-derived CD8+ and, to a lesser extent, CD4+ T cells. TP-DC treatments could also result in regression of well-established s.c. and lung metastases, which could be further enhanced by the systemic administration of low-dose IL-2. The experimental studies outlined in this renewal application are designed to continue our successful preclinical efforts to generate more potent immunization strategies against cancer based on potent antigen- presenting dendritic cells. We will now extend our efforts on novel approaches to use TP-DC in the setting of BMT. The rationale for doing so is based on the accepted dogma that certain preparative regimens for BMT can debulk tumor load, that it can reduce tumor-induced immunosuppression, and that antigen- pulsed DC may potently """"""""educate"""""""" the developing T cell lineage to tumor-associated antigens post-BMT. The effects of TP-DC immunization on the antitumor immune response will be evaluated in the setting of BMT and the developing lymphomyeloid system upon reconstitution. We propose the following Specific Aims: 1. To determine the therapeutic efficacy of the combination of tumor-pulsed dendritic cell immunizations, recombinant cytokine administration, and BMT in mice with solid tumors; 2. To analyze the specificity, function, and repertoire of the host T cell response induced by tumor-pulsed dendritic cell immunization; 3. To determine the therapeutic efficacy of ex vivo expanded antitumor effector T cells in tumor-bearing mice with BMT and tumor-pulsed dendritic cell immunizations. The range of therapeutic strategies will be tested and compared in settings of minimal residual disease and advanced disease. The overall goal of our research effort will be to develop and optimize a new strategy that combines BMT with TP-DC vaccines, recombinant cytokines, and ATC transfer for the treatment of cancer.
Showing the most recent 10 out of 19 publications
