Authors
Heather K Lin, Dejah A Blake, Ruby Freeman, YuJie Chen, Jaehoon Kim, Andrew M Johnson, Kory Wells, Abhijay Mudigonda, William Liu, Poonam Yadav, Fanyuan Zeng, Abir Muhuri, Kiyoon Min, Srijon Sarkar, Yuou Wang, Subir Goyal, Ronald Christopher Roberts, Elyse Christensen, Antonio B Ward, Brad Heller, Paul Chun, Jodi Dougan, Christopher C Porter, Benjamin G Barwick, Chrystal M Paulos, Lily Yang, Anupam Patgiri, Susan Napier Thomas, Edmund K Waller, Sarwish Rafiq
Published in
Science translational medicine. Volume 18. Issue 859. Pages eadt9565. Jul 22, 2026. Epub Jul 22, 2026.
Abstract
Clinical efficacy with chimeric antigen receptor (CAR) T cells is currently limited by numerous factors including poor initial product phenotypes and lack of engagement of endogenous immunity. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide, and the antagonism of its receptor (VIPR) on T cells potentiates T cell activation. We demonstrated that VIP suppresses CAR T cell function and engineered CAR T cells to secrete a short peptide drug that antagonizes VIPR (CAR/VIPRa). Armored CAR/VIPRa T cells maintained a memory phenotype and were metabolically quiescent after manufacturing yet mounted a strong bioenergetic response after antigen stimulation. Moreover, CAR/VIPRa T cells potentiated endogenous antitumor immunity through the recruitment of host T cells. In syngeneic and xenogeneic mouse models of hematological and solid tumors, CAR/VIPRa T cells exhibited greater tumor infiltration and maintained a less exhausted memory phenotype, resulting in superior antitumor efficacy. Together, these data show that VIPRa peptides produced by armored CAR T cells can enhance T cell function and boost endogenous immunity, thereby improving tumor control.
PMID:
42485431
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.
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