Nanoscale Coordination Polymers of Cyclic-di-nucleotides and Peptide Antigens for Effective Therapy of Metastatic Colorectal Cancer - Project Summary: New approaches, such as the emergence of immune checkpoint blockade over the past decade, hold great promise for patients with metastatic cancer. Indeed, PD-1/PD-L1 blockade has enjoyed remarkable clinical success for immunogenically “hot” tumors such as subsets of melanoma and non-small cell lung cancer patients; however, for patients with immunologically “cold” tumors, such as most advanced colorectal cancers, patient response rates can be as low as 5%. With the advent of whole genome sequencing and sophisticated bioinformatics techniques, patient-specific neoantigens in tumors can now be identified and provide the basis for many therapeutic vaccines in preclinical and clinical development. Neoantigen-based cancer vaccines can be tailored to individual patients by identifying their unique neoantigens. We have pioneered the development of nanoscale coordination polymers (NCPs), which are a class of hybrid nanoparticles formed by the self-assembly of metal ions and polydentate bridging ligands. NCPs preferentially accumulate in tumor tissues by taking advantage of the enhanced permeability and retention effect and possess several advantages over existing nanocarriers. The long-term goal of our collaborative research is to establish a new treatment paradigm for metastatic colorectal cancer, through the development and characterization of effective NCPs that can be delivered systemically. The overall goal of the proposed studies is to develop robust NCPs, namely, ZnCDN, for the systemic delivery of a neoantigen and hydrophilic cyclic dinucleotide (CDN) STING agonists, including CDA, ADU-S100, and MK-1454, to potentiate the antitumor immune effect of anti-PD-L1 immunotherapy for the effective treatment of mCRC. Increased understanding of the mechanisms involved in this combination therapy will provide critical insights to enhance the response rates and durability of immunotherapies for mCRC. We have designed ZnCDN NCP with a core of CDA and Zn2+ ions and a hydrophilic shell of PEG2000 to resist plasma protein absorption and clearance by the monocytic phagocytic system. As a result, ZnCDN can be administered to mice via intravenous injection to significantly accumulate in the TME. We will study three ZnCDN formulations with CDA, ADU-S100, and MK-1454 to obtain the best ZnCDN and evaluate its effects on tumor vasculature and intratumoal retention. We will evaluate immune activation in mouse models of mCRC, and elucidate the mechanisms of ZnCDN-mediated STING activation in the tumor microenvironment. In order to evaluate the delivery of tumor-specific antigens, we will incorporate tumor antigen peptides into NCPs to facilitate cross-priming of CD8+ T cells and enhance antitumor efficacy. Finally, we will elucidate the mechanism of STING activation with ZnCDN-antigen to overcome resistance to PD-1/PD-L1 blockade. Our labs have been working together on this project in the Ludwig Center for Metastasis Research for most of the past decade. This interdisciplinary endeavor could lead to a transformation in the treatment of mCRC.
