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Self-regulating CAR-T cells modulate cytokine release syndrome in adoptive T-cell therapy.
Lin, Meng-Yin; Nam, Eunwoo; Shih, Ryan M; Shafer, Amanda; Bouren, Amber; Ayala Ceja, Melanie; Harris, Caitlin; Khericha, Mobina; Vo, Kenny H; Kim, Minsoo; Tseng, Chi-Hong; Chen, Yvonne Y.
Afiliação
  • Lin MY; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
  • Nam E; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
  • Shih RM; Department of Molecular Biology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Shafer A; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Bouren A; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Ayala Ceja M; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Harris C; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Khericha M; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Vo KH; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Kim M; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
  • Tseng CH; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Chen YY; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
J Exp Med ; 221(6)2024 Jun 03.
Article em En | MEDLINE | ID: mdl-38607370
ABSTRACT
Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Citocinas / Síndrome da Liberação de Citocina Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Citocinas / Síndrome da Liberação de Citocina Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article