Antagonizing vasoactive intestinal peptide (VIP) receptors with Muc16CD-directed armored CAR T cells for pancreatic cancer.
Authors: Heather K Lin, Dejah A Blake, Kory Wells, William Liu, Alysa N Evans, Subir Goyal, Tongrui Liu, Ruby Freeman, Christopher Ronald Funk, Tanisha Sinha, Elyse Christensen, Naeman Mahmood, Brad Heller, Paul Chun, Tenzin Passang, Sruthi Ravindranathan, Anupam Patgiri, Lily Yang, Edmund K. Waller, Sarwish Rafiq
Journal: Journal of Clinical Oncology (2024)

2558 Background: Chimeric antigen receptor (CAR) T therapies for pancreatic ductal adenocarcinoma (PDAC) still face significant immunosuppressive obstacles in the tumor microenvironment (TME). We hypothesize that an optimal CAR T cell for PDAC combines targeting an ideal tumor-associated antigen (TAA) and overcomes unique immunosuppression in the PDAC TME. The retained ectodomain of Muc16 (Muc16CD) is a known TAA in ovarian cancer but has yet to be explored in pancreatic cancer. Vasoactive intestinal peptide (VIP) is an emerging checkpoint pathway for T cell function, which expresses VIP receptors (VIPR) and is abundantly expressed by PDAC. In this work, we present a novel armored CAR T cell that targets Muc16CD and antagonizes VIPRs (CAR/VIPRa) to overcome the immunosuppressive PDAC TME. Methods: Patient expression data was assessed based on data generated by the TCGA Research Network. Primary human T cells from healthy donors or PDAC patients were retrovirally transduced to express Muc16CD-directed CARs with or without secretion of novel, potent VIPR antagonist peptides. In vivo, PDAC PDX tumors were engrafted into SCID/Beige mice and treated with CAR T cells. Results: PDAC tumors have significantly increased expression of Muc16 compared to normal pancreas tissue and patients with high Muc16 expression have a significantly decreased overall survival. PDAC patient-derived tumors show robust expression of both Muc16CD and VIP. CAR/VIPRa T cells reveal that VIPR antagonism metabolically reprograms CAR T cells and drives a memory-rich product. CAR/VIPRa T cells are less activated and less exhausted by the manufacturing process, which lends to better viability and a metabolically quiescent phenotype at baseline. These distinct features allow CAR/VIPRa T cells, when antigen-stimulated, to have enhanced activation and expansion with repeated stimulation. To investigate clinical relevance, CAR/VIPRa T cells manufactured from PDAC patient blood are also significantly enriched for memory phenotypes. In vivo, CAR/VIPRa T cells have enhanced expansion, phenotype, infiltration, and persistence, which ultimately reduces PDAC tumor burden. In a patient-derived PDAC preclinical mouse model where CAR T is typically ineffective, CAR/VIPRa T cells significantly reduce tumor burden. Conclusions: This work demonstrates Muc16CD as a clinically relevant TAA target for CAR T therapy in PDAC. Furthermore, antagonizing the previously undescribed VIP checkpoint pathway in CAR T cells produces enhanced phenotypic and functional profiles. Collectively, this data demonstrates that novel CAR/VIPRa T cells create an advantageous cellular therapy product capable of treating PDAC. The long-term goal of this work is translating CAR/VIPRa T cells for the treatment of PDAC and expanding these preclinical findings of cellular therapies for other VIP-abundant tumors.