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4806 Antagonizing Vasoactive Intestinal Peptide (VIP) Receptors on CAR T Cells Improves Efficacy and Persistence

Program: Oral and Poster Abstracts
Session: 703. Cellular Immunotherapies: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Biological therapies, Research, Fundamental Science, Translational Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Therapies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Heather Lin1, Dejah Blake1, Abhijay Mudigonda, BS2*, Alysa N Evans, BS2*, Ruby Freeman1*, Tanisha Sinha, BS2*, Fan Fei, BS2*, Elyse Christensen, BS2*, Tenzin Passang Fnu, BS2*, Sruthi Ravindranathan, PhD2*, Tongrui Liu, PhD3*, Lily Yang, MD PhD3*, Edmund K. Waller, MD2 and Sarwish Rafiq, PhD1

1Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA
2Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
3Department of Surgery, Emory University School of Medicine, Atlanta, GA

Vasoactive intestinal peptide (VIP) is an emerging checkpoint pathway for T cell function1. VIP is expressed by both T cells2,3 and tumor cells1 and is upregulated during TCR activation1,4,5. Augmentation of the VIP/VIPR axis during expansion of primary human T cells enhances less differentiated T cell phenotypes, anti-tumor cytotoxicity, and in vivo persistence6. In this work, we elucidate the mechanisms by which the VIP/VIPR axis is a critical and targetable immune checkpoint pathway for chimeric antigen receptor (CAR) T cell therapy. By engineering CAR T cells to secrete novel and potent VIPR antagonistic peptides, these cells can overcome the immunosuppression of VIP-rich tumor microenvironments.

First, we demonstrated that VIP suppresses CAR T cell function as evident by reduced expansion with exogenous VIP supplementation, which can be rescued by the addition of VIPRa peptides. The VIP/VIPR axis is relevant to CAR T cell signaling as these cells produce VIP after antigen stimulation and upregulate VIPR expression. In fact, polyfunctionality and cytotoxic killing is enhanced by VIPR knockout of CAR T cells. Together, these results demonstrate the critical role of the VIP/VIPR axis in CAR T cell function. To harness this axis, CAR T cells were engineered to secrete VIPRa peptides (VIPRa CAR T) to provide continuous and localized delivery of VIPRa peptides.

Continuously delivered VIPR antagonism increases the viability and proportions of less-differentiated and less-exhaustive phenotypes of CAR T cells at baseline. Functionally, VIPRa CAR T cells have a proliferative advantage and enhanced activation compared to parental CAR T cells. RNA sequencing was performed on VIPRa CAR T cells before and after antigen-stimulation to illuminate in-depth phenotypic and functional differences compared parental CAR T cells. Finally, these novel CAR T cells were tested in xenograft and syngeneic mouse models. VIPRa CAR T cells show improved tumor control and persistence as evidence long-lived circulating cells in the peripheral blood. To validate the clinical relevance of this target for CAR T therapy, patient-derived xenograft (PDX) pancreatic tumors were assayed to show robust expression of VIP. VIPRa CAR T cells significantly reduced tumor burden and improved survival in PDX tumor-bearing mice.

Collectively, this data demonstrates that targeting VIP is a novel and successful approach to improving CAR T cell anti-tumor efficacy. VIPR antagonism enhances initial CAR T cell phenotypes and function, which has the potential to improve CAR T cell therapy for a variety of tumor types. The mechanisms by which CAR T cell-mediated delivery of VIPRa peptides can modulate tumor microenvironments in a syngeneic model are currently being evaluated. VIPRa CAR T cells are a uniquely improved cellular therapy capable of enhanced anti-tumor function against clinically relevant tumors.

Disclosures: Waller: Allovir: Consultancy; Cambium Oncology: Current equity holder in private company, Other: Founder; CRISPR: Consultancy; Secura: Research Funding; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; BMS: Research Funding; ORCA: Research Funding; Sanofi: Research Funding; NCI R01: Research Funding; PartnersTherapeutics: Research Funding; Cambium Medical Technologies: Current equity holder in private company, Other: Founder.

*signifies non-member of ASH