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Abstract

While the advent of checkpoint blockade antibodies has provided a powerful means to reinvigorate pre-existing T cell responses in the treatment of cancer, therapies capable of priming or expanding endogenous antitumor immunity are notably lacking within the current clinical cancer immunotherapy “toolbox”. Neoantigen peptide vaccines, dendritic cell-based vaccines, small molecule adjuvants, oncolytic viruses, and GM-CSF secreting tumor cells have demonstrated striking efficacy in murine tumor models yet, thus far, have failed to broadly impact the clinical treatment of advanced cancer. Difficulties faced translating success from the lab to the clinic have highlighted the need for further development of strategies to ignite effective antitumor immunity in formats which are cheaper, more tumor agnostic, and readily available in off-the-shelf formulations. With this aim in mind, we engineered tAb-pManTLR7, comprised of tumor cell-binding antibodies (tAbs) covalently linked to our pManTLR7 agonist, to localize and sustain delivery of a powerful adjuvant to the tumor microenvironment while endowing existing anti-tumor antibodies with a heightened vaccinal effect. Upon intratumoral injection, pManTLR7-armed antibodies bind and opsonize tumor cells, increase the residence time of pManTLR7 in the tumor microenvironment, and functionally link the delivery of endogenous tumor antigens with strong TLR7 activation. Increased tumor-specific cellular responses and intratumoral T cell accumulation upon tAb-pManTLR treatment mirror the salient outcomes of a traditional subunit or peptide vaccine but here, the tumor itself provides an endogenous source of antigen. In aggressive ‘cold’ models of melanoma and triple-negative breast cancer, tAb-pManTLR treatment slowed or eradicated established tumors in a CD8+ T cell-dependent manner and generated antitumor memory which protected mice against subsequent abscopal tumor challenge. Our engineered approach exemplifies a modular, off-the-shelf immunotherapy capable of activating systemic antitumor immunity with the sufficient magnitude and functionality required for therapeutic efficacy. This work provides a strong proof-of-principle for the further development of tAb-pManTLR as a therapeutic platform to treat numerous malignancies.

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