TY - JOUR
T1 - Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities
AU - Mog, Brian J.
AU - Marcou, Nikita
AU - DiNapoli, Sarah R.
AU - Pearlman, Alexander H.
AU - Nichakawade, Tushar D.
AU - Hwang, Michael S.
AU - Douglass, Jacqueline
AU - Hsiue, Emily Han Chung
AU - Glavaris, Stephanie
AU - Wright, Katharine M.
AU - Konig, Maximilian F.
AU - Paul, Suman
AU - Wyhs, Nicolas
AU - Ge, Jiaxin
AU - Miller, Michelle S.
AU - Azurmendi, P. Aitana
AU - Watson, Evangeline
AU - Pardoll, Drew M.
AU - Gabelli, Sandra B.
AU - Bettegowda, Chetan
AU - Papadopoulos, Nickolas
AU - Kinzler, Kenneth W.
AU - Vogelstein, Bert
AU - Zhou, Shibin
N1 - Publisher Copyright:
Copyright © 2024 The Authors, some rights reserved
PY - 2024/7/10
Y1 - 2024/7/10
N2 - Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen–binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.
AB - Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen–binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.
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UR - http://www.scopus.com/inward/citedby.url?scp=85198440791&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adg7123
DO - 10.1126/scitranslmed.adg7123
M3 - Article
C2 - 38985855
AN - SCOPUS:85198440791
SN - 1946-6234
VL - 16
JO - Science translational medicine
JF - Science translational medicine
IS - 755
M1 - eadg7123
ER -