Designing Lymph Nodes for Cancer Immunotherapy

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DESCRIPTION (provided by applicant): We have shown that murine tumor-loaded dendritic cells (TL-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 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 TL-DC, which is dependent upon host-derived CD8+ and CD4+ T cells. TL-DC treatments can under certain circumstances also result in regression of both established subcutaneous tumor nodules and lung metastases. We have translated these experimental studies to a series of human clinical trials in cancer patients. Recently, we showed for the first time that gene-modification of TL-DC to produce a chemokine, CCL-21, can enhance vaccine efficacy and inhibit tumor growth by priming tumor-reactive T cells extranodally. The new experimental studies outlined in this application is intended to extend our work to identify additional candidates from a panel of 48 known chemokines to further improve tumor vaccine potency, by creating "designer lymph node-like" structures at injection sites. It is our hypothesis that concomitant expression of certain chemokines at the immunization site of TL-DC will result in the formation of functioning, ectopic "lymph nodes" and in substantial increases in tumor reactivity through elevated levels of host immune cell recruitment and activation within these structures. We propose the following Specific Aims: 1. To screen recombinant chemokines in vitro for specific, positive biologic activities on immune cell subtypes; 2. To evaluate the capacity of treatment of tumor-bearing mice with selected chemokine(s) gene-modified TL-DC to mediate an enhanced therapeutic antitumor response in vivo; and 3. To determine the mechanism of tumor response in mice treated with chemokine(s) gene-modified TL-DC. The range of therapeutic chemokine 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 chemokines with DC-based vaccine approaches for the treatment of cancer. PUBLIC HEALTH RELEVANCE: Immunotherapy is showing much promise as a fourth modality for the treatment of cancer. Cancer vaccines are a significant part of the immunotherapy armamentarium. The proposed investigations should provide important insights into the mechanisms of action of and improvements in the potency of therapeutic cancer vaccines.