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

Area of Science:

• Immunology
• Cell Therapy
• Cancer Research

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise but faces limitations like poor T cell function and lack of endogenous immune engagement.
• Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that inhibits T cell activity by binding to its receptor (VIPR).

Purpose of the Study:

• To engineer CAR T cells to overcome VIP-mediated immunosuppression and enhance their antitumor functions.
• To evaluate the efficacy of engineered CAR T cells secreting VIPR antagonists (CAR/VIPRa) in preclinical cancer models.

Main Methods:

• CAR T cells were engineered to secrete a peptide drug antagonizing the VIP receptor (VIPR).
• The function, phenotype, and metabolic response of armored CAR/VIPRa T cells were assessed post-manufacturing and upon antigen stimulation.
• 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 responded robustly to antigen stimulation.
• CAR/VIPRa T cells demonstrated enhanced tumor infiltration and a less exhausted memory phenotype in vivo.
• These cells potentiated endogenous antitumor immunity by recruiting host T cells, leading to superior tumor control.

Conclusions:

• VIPR antagonism by engineered CAR T cells enhances their function and persistence.
• CAR/VIPRa T cells improve antitumor efficacy by boosting both direct cell killing and endogenous immune responses.
• This strategy offers a promising approach to overcome immunosuppression and improve CAR T cell therapy outcomes.