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Sensitive bispecific chimeric T cell receptors for cancer therapy.
Simon, Sylvain; Bugos, Grace; Prins, Rachel; Rajan, Anusha; Palani, Arulmozhi; Heyer, Kersten; Stevens, Andrew; Zeng, Longhui; Thompson, Kirsten; Price, Jason P; Kluesner, Mitchell K; Jaeger-Ruckstuhl, Carla; Shabaneh, Tamer B; Olson, James M; Su, Xiaolei; Riddell, Stanley R.
Afiliação
  • Simon S; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Bugos G; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Prins R; Department of Immunology, University of Washington, Seattle, WA 98195, USA.
  • Rajan A; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Palani A; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Heyer K; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Stevens A; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Zeng L; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Thompson K; Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.
  • Price JP; Yale Cancer Center, Yale University, New Haven, CT 06520, USA.
  • Kluesner MK; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Jaeger-Ruckstuhl C; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Shabaneh TB; Seattle Children's Research Institute, Ben Towne Center For Childhood Cancer Research, Seattle, WA 98105, USA.
  • Olson JM; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Su X; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
  • Riddell SR; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Res Sq ; 2024 Apr 22.
Article em En | MEDLINE | ID: mdl-38746248
ABSTRACT
The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article