Project 1: Developing immune checkpoint controlled-release biomaterials for cancer immunotherapy

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PROJECT SUMMARY: PILOT RESEARCH PROJECT Immunotherapies can provide effective cancer therapy, but only in a minority of patients. The clinical success of immune checkpoint inhibitors in some malignancies has not translated to ovarian cancer. Objective response rates for single-agent immune checkpoint inhibitor (CPI) immunotherapy clinical trials in ovarian cancer are 6- 15%. Also, treated patients experience the consequences of dysregulated immunity from systemic administration of these agents. For cancers in which primary disease is accessible/resected, or in metastatic disease in which lesions are accessible, controlled release immunotherapy delivered locally may provide powerful – and systemic – anti-cancer immunity. Most anti-cancer therapies, including CPI immunotherapies, possess dose-limiting toxicities in non-target tissues that compromise outcomes. Restricting delivery of these therapeutic agents has demonstrated benefit with the reduction in cardiotoxicity and significant improvement in therapy through formulation of paclitaxel into Abraxane as a clinically powerful example. We propose to develop the first controlled release biomaterials to enable local delivery of high dose immunotherapies that would be intolerable if systemically administered. We aim to significantly improve the frequency and durability of response following CPI immunotherapy. We hypothesize that lower intraperitoneal immune checkpoint inhibitor concentration in humans, relative to rodents, contributes to the low efficacy observed for ovarian cancer immunotherapies in clinical trials. Our proposed controlled-release CPI will allow assessment in mice of the intraperitoneal dosing concentrations relevant to humans using a novel core/shell delivery system for sustained and controlled release. The overarching objective of this pilot project is to test improved response to cancer immunotherapy through sustained release of immune checkpoint ligands from biomaterials that are applied locally/regionally (not systemically). Our multi-PI complementary team aims to test this hypothesis in a rodent model of human ovarian cancer that aligns with the exploratory and feasibility objectives of this Pilot Research Project mechanism and appropriate to lead to a full competitive project within 3 years. Aim 1 will synthesize and characterize biomaterials that enable the sustained release of anti-PD-L1 and can be retained locally following intraperitoneal injection to improve immunotherapy while minimizing undesirable side effects. Aim 2 will characterize ovarian cancer progression, immune responses, toxicity and overall survival from the sustained release of anti-PD-L1 in the intraperitoneal cavity of rodent models that replicate aspects of human disease.