التفاصيل البيبلوغرافية
| العنوان: |
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. |
| المؤلفون: |
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 |
| المصدر: |
Science Translational Medicine; 7/10/2024, Vol. 16 Issue 755, p1-17, 17p |
| مصطلحات موضوعية: |
CHIMERIC antigen receptors, TUMOR antigens, TUMOR treatment, T cell receptors, HLA histocompatibility antigens |
| مستخلص: |
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 [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
