Development of a Novel Armored CAR-T Immunotherapeutic for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) represents a major challenge in oncology, the third leading cause of cancer-related death, and a 5-year survival rate of only 11%. The dense, immunosuppressive tumor microenvironment (TME) of PDAC significantly hinders the efficacy of current therapeutic strategies, including the innovative CAR T cell therapies that have shown promise in hematologic malignancies. A significant contributor to this immunosuppression is the secretion of vasoactive intestinal peptide (VIP) within the PDAC TME by cancer cells and immune cells that limits the efficacy of adoptive T cell therapies. Addressing this urgent need, Cambium Oncology proposes a novel approach to enhance CAR T cell therapy's potency against PDAC by countering the immunosuppressive effects of VIP prevalent in PDAC tumors. Our pioneering strategy involves engineering CAR T cells that target the extracellular domain of Muc16 (Muc16CD), a marker abundant in PDAC tumors and stroma, to secrete an optimized form of the VIP receptor (VIPR) antagonist, ANT308Fc. Preliminary findings indicate that CAR T cells endowed with the capability to secrete VIPR antagonists demonstrate enhanced metabolic flexibility, a predominance of memory T cell subsets, and superior anti-tumor activity. This project is structured to validate the ANT308-Fc fusion as a secreted agent from CAR T cells to disrupt the VIP-mediated immunosuppression within the PDAC TME, thereby enhancing T cell functionality and persistence, remodeling the PDAC TME, and facilitating the eradication of PDAC cells. The proposed “Fast-track” SBIR research and develop plan is divided into two phases: Phase 1 aims to develop and validate ANT308Fc for secretion by CAR T cells (Aim 1) and to identify the form of VIPR antagonism that exhibits the most potent anti-tumor effects in PDAC models (Aim 2). A go/no- go decision based on the in vivo efficacy of ANT308 variants will determine the progression to Phase 2. Phase 2 is focused on evaluating the toxicity and biodistribution (Aim 3), and mechanism of action of the selected CAR/VIPRa T cells (Aim 4), alongside preparing for IND submission (Aim 5). Our aims are rooted in solid preliminary data and leverage a clinically validated CAR target (Muc16CD), positioning this work at the forefront of translational research for PDAC. This project stands to significantly impact the treatment landscape for PDAC by providing a novel, efficacious therapy option. The successful development and clinical translation of CAR/VIPRa T cells could not only revolutionize PDAC treatment but also serve as a platform technology applicable to a broad range of cancers, underscoring the potential of CAR T cell therapies in solid tumors. Impact: Cambium Oncology's endeavor into commercialization of CAR T cells that secrete a VIP Receptor antagonist is aligned with the company’s core competency in developing novel immune-oncology drugs and addresses the pressing need for innovative, effective treatments for PDAC. Results from the proposed SBIR can dramatically improve patient outcomes in this high-mortality cancer.