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Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo.
Rafiq, Sarwish; Yeku, Oladapo O; Jackson, Hollie J; Purdon, Terence J; van Leeuwen, Dayenne G; Drakes, Dylan J; Song, Mei; Miele, Matthew M; Li, Zhuoning; Wang, Pei; Yan, Su; Xiang, Jingyi; Ma, Xiaojing; Seshan, Venkatraman E; Hendrickson, Ronald C; Liu, Cheng; Brentjens, Renier J.
Afiliação
  • Rafiq S; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Yeku OO; Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Jackson HJ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Purdon TJ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • van Leeuwen DG; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Drakes DJ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Song M; Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
  • Miele MM; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.
  • Li Z; Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Wang P; Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Yan S; Eureka Therapeutics Inc., Emeryville, California, USA.
  • Xiang J; Eureka Therapeutics Inc., Emeryville, California, USA.
  • Ma X; Eureka Therapeutics Inc., Emeryville, California, USA.
  • Seshan VE; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.
  • Hendrickson RC; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Liu C; Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Brentjens RJ; Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Nat Biotechnol ; 36(9): 847-856, 2018 10.
Article em En | MEDLINE | ID: mdl-30102295
The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1+ hematologic and solid tumors. The efficacy was similar to or better than that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach may improve safety, as the secreted scFvs remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Linfócitos T / Anticorpos de Cadeia Única / Receptor de Morte Celular Programada 1 / Receptores de Antígenos Quiméricos Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Linfócitos T / Anticorpos de Cadeia Única / Receptor de Morte Celular Programada 1 / Receptores de Antígenos Quiméricos Idioma: En Ano de publicação: 2018 Tipo de documento: Article