Modulating the VIP-VIPR pathway reprograms CAR T cells for superior antitumor efficacy in preclinical cancer models
(1) Lin HK (2) Blake DA (3) Freeman R (4) Chen Y (5) Kim J (6) Johnson AM (7) Wells K (8) Mudigonda A (9) Liu W (10) Yadav P (11) Zeng F (12) Muhuri A (13) Min K (14) Sarkar S (15) Wang Y (16) Goyal S (17) Roberts RC (18) Christensen E (19) Ward AB (20) Heller B (21) Chun P (22) Dougan J (23) Porter CC (24) Barwick BG (25) Paulos CM (26) Yang L (27) Patgiri A (28) Thomas SN (29) Waller EK (30) Rafiq S
Inspired by clinical data that the neuropeptide vasoactive intestinal peptide (VIP), acting through its receptor (VIPR), was correlated with poor response in patients undergoing CAR therapy, Lin et al. used alpha-fold to design a similarly sized antagonistic peptide (VIPRa) for this immunosuppressive axis, and expressed it with a CAR. During manufacturing, VIPRa-expressing CAR T cells were less activated, but highly activatable, less exhausted, and had a memory phenotype, translating to improved tumor infiltration and in vivo efficacy. CAR/VIPRa T cells were metabolically superior, and more effectively engaged endogenous immunity.
Contributed by Ute Burkhardt
(1) Lin HK (2) Blake DA (3) Freeman R (4) Chen Y (5) Kim J (6) Johnson AM (7) Wells K (8) Mudigonda A (9) Liu W (10) Yadav P (11) Zeng F (12) Muhuri A (13) Min K (14) Sarkar S (15) Wang Y (16) Goyal S (17) Roberts RC (18) Christensen E (19) Ward AB (20) Heller B (21) Chun P (22) Dougan J (23) Porter CC (24) Barwick BG (25) Paulos CM (26) Yang L (27) Patgiri A (28) Thomas SN (29) Waller EK (30) Rafiq S
Inspired by clinical data that the neuropeptide vasoactive intestinal peptide (VIP), acting through its receptor (VIPR), was correlated with poor response in patients undergoing CAR therapy, Lin et al. used alpha-fold to design a similarly sized antagonistic peptide (VIPRa) for this immunosuppressive axis, and expressed it with a CAR. During manufacturing, VIPRa-expressing CAR T cells were less activated, but highly activatable, less exhausted, and had a memory phenotype, translating to improved tumor infiltration and in vivo efficacy. CAR/VIPRa T cells were metabolically superior, and more effectively engaged endogenous immunity.
Contributed by Ute Burkhardt
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.
Author Info:
(1) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (2) Department of Hematology and Medical Oncology, Emory University School
of Medicine, Atlanta, GA, USA. (3) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (4) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (5) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (6) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (7) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. (8) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (9) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. (10) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. (11) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (12) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (13) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (14) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (15) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (16) Biostatistics Shared Resource, Emory University School of Medicine, Atlanta, GA, USA. (17) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (18) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (19) Cambium Oncology, Atlanta, GA, USA. (20) Achieve Clinics, Los Angeles, CA, USA. (21) Achieve Clinics, Los Angeles, CA, USA. Eldred Advisors, Los Angeles, CA, USA. (22) Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. (23) Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA. (24) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (25) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (26) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (27) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (28) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. (29) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (30) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Citation: Sci Transl Med 2026 Jul 22 18:eadt9565 Epub07/22/2026
