Vaccines to promote Tc-1-based targeting of tumor stroma

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DESCRIPTION (provided by applicant): In addition to targeting tumor cells, the supportive tumor microenvironment may be destabilized or destroyed by therapeutic strategies targeting tumor-associated stromal cell types, such as those involved with neoangiogenesis or neovasculogenesis. While formation of blood vessels from the surrounding vasculature is typical of wound healing and peripheral neoangiogenesis, similar structures in progressive tumors may also involve the process of neovascularization. In particular, tumor vascular endothelial tubes and stabilizing perivascular pericytes are typically recruited into tumors as (mesenchymal or hematopoietic) precursors and induced to differentiate and integrate into higher order complexes based on tumor-produced or -induced angiogenic factors, such as VEGF, PDGF, and TGF-¿. Given such operational (and potentially component) differences, it has now become feasible to consider the immune- based targeting of vascular endothelial cells (VEC) or pericytes within the tumor microenvironment (TME), with an expectation for safety (i.e. lack of inhibitory effects on wound-healing or crucial vascular barriers within the blood-brain barrier or the retina). Vaccines designed to elicit T cell-mediated eradication of VEC or pericytes in the tumor microenvironment would conceivably provide durable inhibition of the tumor blood supply with a reduced concern for antigen-loss target variants, as may occur in heterogeneous tumor cell populations under chronic immune-editing/-selection. As a consequence of blunting nascent, and destabilizing existing, vessels in the TME, enhanced tumor cell death and corollary cross-priming of anti-tumor T cells sponsored by host antigen presenting cells (APC) would be expected. Furthermore, the immune-mediated removal of pericytes from tumor blood vessels would be anticipated to result in enhanced vessel hemorrhaging/leakiness yielding elevated vascular permeability and a normalization in the interstitial fluid pressure within the tumor core. Such conditions would favor increased and potentially selective delivery of systemic agents (including pharmacologic compounds or adoptively transferred T cells) into the TME, yielding the possibility for improved therapeutic efficacy. In Preliminary Data, we show that prophylactic and therapeutic vaccines promoting CD8+ T cell responses against pericyte- or VEC-associated antigens prevent the vascularization of murine tumors in vivo, in the absence of detectable autoimmune pathology via a mechanism that prompts normalization in tumor IFP and a reduction in intratumoral hypoxia. Based on this paradigm, we propose to: test the hypotheses that vaccines targeting tumor VEC/pericytes are safe and capable of promoting CD8+ T cell-mediated regression of late-stage tumors in vivo (Specific Aim 1), and that co-therapies integrating such vaccines will improve the (co)delivery of chemo/immunotherapy agents into the TME, yielding enhanced therapy benefit via a broadening in the therapeutic T cell repertoire (Specific Aim 2).