In order to develop new and more effective immune-based cancer treatments, relevant, small animal models continue to play a necessary role in understanding the underlying biology of such therapies, which are designed to modulate the immune system to recognize a neoplasm as """"""""foreign"""""""". We have shown that murine tumor lysate-pulsed dendritic cells (TP-DC) can elicit tumor-specific 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 further shown that synegeneic hosts can be effectively immunized in vivo to reject aggressive, weakly-immunogenic sarcomas, a breast carcinoma, and a poorly-immunologic subline of the B16 melanoma by immunization with TP-DC, which is dependent upon host-derived CD8+ and CD4+ T cells. TP-DC treatments can also result in regression of both established subcutaneous tumor nodules and lung metastases., which can be further enhanced by the systemic administration of IL-2. The experimental studies outlined in this application are designed to continue our preclinical efforts to generate more potent immunization strategies against cancer based on potent antigen-presenting DC. We will now extend our efforts on novel approaches to use TP-DC in the setting of a powerful chemoattractant cytokine, denoted secondary lymphoid tissue chemokine (SLC). The rationale for doing so is based on our recent data demonstrating that SLC is a unique, potent chemokines selective for the recruitment of naive T cells and immature DC. It is our hypothesis that concomitant expression of SLC at the immunization site of TP-DC will result in increased tumor reactivity through elevated levels of host immune cell recruitment and activation. We propose the following Specific Aims: 1. To evaluate the efficacy of SLC to attract T cells and DC to primary immunization sites in vivo; 2. To evaluate the capacity of immunization of tumor-bearing mice with SLC gene-modified TP-DC to mediate a therapeutic anti-tumor response in vivo; 3. To determine the mechanism of tumor response in mice immunized with SLC gene- modified TP-DC; 4. To evaluate the combination of SLC and additional recombinant cytokines to enhance therapeutic efficacy in vivo; and 5. To evaluate the clinical use of SLC in the treatment of patients with advanced melanoma. The range of therapeutic strategies will be tested and compared in settings of minimal and advanced disease states. The overall goal of our research effort will be to develop and optimize a new strategy that combines a chemokine with DC-based vaccine approaches for the treatment of cancer.
Showing the most recent 10 out of 103 publications
