The goal of this proposed research is to develop a targeted delivery platform for checkpoint inhibitors. The platform will contain a targeting ligand, an enzyme-responsive linker, and a peptide- based checkpoint inhibitor. We recently discovered several peptide-based PD-L1 inhibitors that can be potentially used for cancer immunotherapy. In this study, we will evaluate the platform in an advanced prostate cancer model. Particularly, we propose to link a PSMA-specific ligand to the anti-PD-L1 peptides via a PSA-cleavable linker. The overall objectives of this project are: 1) to develop a targeted anti-PD-L1 peptide for cancer immunotherapy; 2) to evaluate its therapeutic effect using humanized mice implanted with human castration-resistant prostate cancer (CRPC) cells. The long-term goal of the project is to develop a targeted peptide-based platform for cancer immunotherapy. Our central hypothesis is that cancer growth and metastasis can be effectively inhibited by targeted delivery of anti-PD-L1 peptides to cancer cells. At the completion of this project, we expect to pave the way for the future development of a targeted PD-L1 inhibitor for cancer immunotherapy. Successful completion of the proposed studies is also expected to provide a peptide-based platform (by changing the targeting ligand and the tissue-specific linker) for other peptide-based checkpoint inhibitors.
Immunotherapy using checkpoint inhibitors, such as PD1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, all the current checkpoint inhibitors have a large size and can nonspecifically attack normal cells. We therefore propose a novel platform using a checkpoint inhibitor with small size to enhance the therapeutic efficacy of immunotherapy drugs.