Modulating the VIP-VIPR pathway reprograms CAR T cells for superior antitumor efficacy in preclinical cancer models

Area of Science:

• Immunotherapy
• Cancer Research
• Cellular Engineering

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise but faces limitations like poor T cell function and inadequate engagement of the host immune system.
• Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that hinders T cell activity, particularly CAR T cells.
• Antagonizing the VIP receptor (VIPR) on T cells can enhance T cell activation and function.

Purpose of the Study:

• To engineer CAR T cells to overcome VIP-mediated immunosuppression and enhance their antitumor capabilities.
• To investigate the impact of secreting a VIP receptor antagonist (VIPRa) on CAR T cell phenotype, function, and endogenous immune engagement.
• To evaluate the efficacy of engineered CAR/VIPRa T cells in preclinical models of various cancers.

Main Methods:

• CAR T cells were engineered to secrete a short peptide drug targeting the VIP receptor (VIPRa).
• The phenotype, metabolic response, and function of armored CAR/VIPRa T cells were assessed post-manufacturing and upon antigen stimulation.
• The ability of CAR/VIPRa T cells to potentiate endogenous antitumor immunity was examined.
• Antitumor efficacy of CAR/VIPRa T cells was evaluated in syngeneic and xenogeneic mouse models of hematological and solid tumors.

Main Results:

• Engineered CAR/VIPRa T cells maintained a memory phenotype and metabolic quiescence post-manufacturing, with robust bioenergetic responses upon antigen stimulation.
• CAR/VIPRa T cells demonstrated enhanced tumor infiltration and a less exhausted memory phenotype in both hematological and solid tumor models.
• These engineered T cells effectively potentiated endogenous antitumor immunity by recruiting host T cells.
• Superior tumor control and antitumor efficacy were observed with CAR/VIPRa T cells compared to control CAR T cells.

Conclusions:

• Secretion of VIPRa peptides by armored CAR T cells effectively enhances T cell function by counteracting immunosuppression.
• CAR/VIPRa T cells exhibit improved persistence, enhanced tumor infiltration, and potentiation of endogenous immunity.
• This strategy offers a promising approach to improve the clinical efficacy of CAR T cell therapy for various cancers.