A Phospholipid-Derived Nanotherapeutic Platform for Improved Colorectal Cancer Immunochemotherapy

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Project Summary/Abstract While immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer treatment paradigm, the response rate is limited to a small subset of cancer patients (~20%). For colorectal cancer (CRC), the second leading cause of cancer-related deaths in US, only patients (~4%) with mismatch-repair-deficient or microsatellite instability-high tumors can respond to ICIs, leaving the vast majority of CRC patients with limited to no clinical benefit. Chemotherapy has been increasingly manifested to contribute significantly to the overall antitumor efficacy when combined with ICIs via switching the tumors from “immune-cold” to ‘immune-hot’. However, owing to the poor solubility and pharmacokinetics, limited tumor accumulation, and non-specific toxicities to healthy tissues, the utility of chemotherapeutics in enhancing the efficacy of ICIs has been considerably hindered. To render a safer and more efficacious chemotherapy-enabled immune response to cooperate with ICIs, our long- term goal is to develop an innovative and multifunctional liposomal nanotherapeutic platform via conjugating anticancer agents to the backbone phospholipid of liposome. We have developed a phospholipid-derived camptothecin (CPT) liposome (Camptothesome) nanoplatform, which significantly prolonged blood circulation time, enhanced tumor uptake and therapeutic efficacy and minimized systemic toxicities compared to free CPT. Moreover, Camptothesome potentiated the anti-CRC efficacy of PD-L1/PD-1 inhibitors, resulting in partial eradication of tumors in immunocompetent mice. To improve the efficacy of this combined therapy, we used Camptothesome to co-deliver an inhibitor targeting another independent immune checkpoint, Indoleamine 2,3- dioxygenase (IDO1), which markedly enhanced anti-CRC efficacy and immunity. To further strengthen the delivery efficiency and explore the potential of this nanoplatform in enhancing PD-L1/PD-1 blockade therapy, in this proposal we will: Aim 1: Improve the Camptothesome system for enhanced therapeutic delivery. Aim 2: Determine the tumor delivery efficiency and pharmacokinetics of the improved co-delivery system in murine CRC models. Aim 3: Define antitumor effects of the improved co-delivery system with or without PD-L1/PD-1 blockade in murine CRC models. The mechanistic action for the in vivo antitumor efficacy and immune responses of the combined therapy will also be elucidated. Successful completion of this proposal will result in an innovative and multifunctional nanotherapeutic platform for improved and safe CRC immunochemotherapy. Moreover, given that IDO1 is expressed in diverse cancer cells, and the broad applicability of this nanoplatform to other anticancer drugs, our combination nanotherapeutic system has the potential to revolutionize cancer treatment paradigms.