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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.
Mog, Brian J; Marcou, Nikita; DiNapoli, Sarah R; Pearlman, Alexander H; Nichakawade, Tushar D; Hwang, Michael S; Douglass, Jacqueline; Hsiue, Emily Han-Chung; Glavaris, Stephanie; Wright, Katharine M; Konig, Maximilian F; Paul, Suman; Wyhs, Nicolas; Ge, Jiaxin; Miller, Michelle S; Azurmendi, P; Watson, Evangeline; Pardoll, Drew M; Gabelli, Sandra B; Bettegowda, Chetan; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin.
Affiliation
  • Mog BJ; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Marcou N; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • DiNapoli SR; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Pearlman AH; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Nichakawade TD; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Hwang MS; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • Douglass J; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Hsiue EH; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Glavaris S; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • Wright KM; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Konig MF; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Paul S; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • Wyhs N; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Ge J; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Miller MS; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • Azurmendi P; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Watson E; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Pardoll DM; Institute for NanoBioTechnology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
  • Gabelli SB; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Bettegowda C; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • Papadopoulos N; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Kinzler KW; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Vogelstein B; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • Zhou S; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Sci Transl Med ; 16(755): eadg7123, 2024 Jul 10.
Article in En | MEDLINE | ID: mdl-38985855
ABSTRACT
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Antigen, T-Cell / Receptors, Chimeric Antigen / Neoplasms Limits: Animals / Humans Language: En Journal: Sci Transl Med Journal subject: CIENCIA / MEDICINA Year: 2024 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Antigen, T-Cell / Receptors, Chimeric Antigen / Neoplasms Limits: Animals / Humans Language: En Journal: Sci Transl Med Journal subject: CIENCIA / MEDICINA Year: 2024 Document type: Article Affiliation country: Country of publication: