Local anti-PD-1 delivery prevents progression of premalignant lesions in a 4NQO-oral carcinogenesis mouse model.

While the principle of systemic treatment to prevent the progression of oral premalignant lesions (OPLs) has been demonstrated, there remains a lack of consensus about an optimal approach which balances clinical efficacy with toxicity concerns. Recent advances in cancer therapy using approaches targeting the tumor immune micro-environment (TIME) including immune checkpoint inhibitors indicate that these agents have significant clinically activity against different types of cancer including oral cancer and therefore they may provide and effective oral cancer prevention strategy for patients with OPLs. Our past work showed that systemic delivery of a monoclonal antibody to the PD-1 immune checkpoint can inhibit the progression of OPLs to oral cancer in a syngeneic murine oral carcinogenesis model. Here we report a novel approach of local delivery of a PD1 immune checkpoint inhibitor loaded using a hydrogel, which significantly reduces the progression of OPLs to carcinomas. In addition, we detected a significant infiltration of regulatory T cells associated with oral lesions with p53 mutation, and a severe loss of expression of STING which correlated with a decreased infiltration of dendritic cells in the oral lesions. However, a single local dose of PD1 inhibitor was found to restore STING and CD11c expression and increase the infiltration of CD8 T cells into the TIME irrespective of the p53 mutational status. Overall, we provide evidence for the potential clinical value of local delivery of biomaterials loaded with anti-PD-1 antibodies to prevent malignant progression of OPLs.