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- Title
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.
- Authors
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, Aitana; Watson, Evangeline; Pardoll, Drew M.; Gabelli, Sandra B.; Bettegowda, Chetan
- 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. Editor's summary: Commonly used T cell therapies such as engineered T cell receptors (TCRs) and chimeric antigen receptors (CARs) have greatly improved outcomes for many patients; however, both still have their associated drawbacks. To overcome some of these limitations, Mog et al. have developed high-affinity antibody–expressing T cells that use a receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. They further show in vivo that these Co-STARs induce T cell expansion and induce long-term regression in mouse models with low densities of antigen, representing a promising strategy that requires further evaluation. —Dorothy Hallberg
- Subjects
CHIMERIC antigen receptors; TUMOR antigens; TUMOR treatment; T cell receptors; HLA histocompatibility antigens
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 755, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adg7123