Modulating the Vasoactive Intestinal Peptide (VIP) Pathway Reprograms Superior CAR T Cells

Chimeric antigen receptor (CAR) T cell therapy is a highly potent cellular immunotherapy that still faces significant obstacles that limit clinical success. Novel immunomodulatory approaches to improve the CAR T cell phenotype, metabolic fitness, and the engagement of endogenous immunity are necessary to create effective CAR T products. Vasoactive intestinal peptide (VIP) is a neuropeptide that dampens adaptive immune responses and is abundantly produced by several hematologic malignancies. Here, we have engineered CAR T cell therapies that secrete a synthetic short peptide drug that antagonizes VIP receptors (CAR/VIPRa).

CAR/VIPRa T cells are less activated and less exhausted by the manufacturing process, which lends to better viability and preservation of memory phenotypes. Furthermore, VIPR antagonism increases the number of mitochondria and enriches the utilization of oxidative phosphorylation. This metabolic reprogramming results in quiescent CAR/VIPRa T cells that have greater potential and plasticity to achieve improved energetic profiles after antigen stimulation. In vivo, CAR/VIPRa T cells demonstrate significantly greater expansion with less exhausted phenotypes and are enriched for memory phenotypes in xenograft tumor models. Additionally, the small peptide drug produced by CAR/VIPRa T cells increases the number of endogenous tumor-infiltrating T cells in syngeneic tumor models. To investigate clinical relevance, CAR/VIPRa T cells manufactured from patient-derived T cells recapitulated lower activation profiles and enrichment for memory phenotypes.

Collectively, this approach to antagonize the VIP/VIPR pathway serves to improve CAR T cell phenotype and function before and after tumor engagement to drive enhanced anti-tumor efficacy. Therefore, CAR/VIPRa T cells are uniquely equipped to overcome many key obstacles that are required for success of CAR T therapy in the clinic.

Waller:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biolinerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forte Bioscience: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cambium Medical Technologies: Current equity holder in private company; Cambium Oncology: Current equity holder in private company; Doximity: Current equity holder in private company.