Sensitive bispecific chimeric T cell receptors for cancer therapy.

Autor:	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.; Department of Immunology, University of Washington, Seattle, WA 98195, USA., Prins R; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, 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; Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Center, Yale University, New Haven, CT 06520, USA., Thompson K; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Price JP; Seattle Children's Research Institute, Ben Towne Center For Childhood Cancer Research, Seattle, WA 98105, USA., Kluesner MK; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Jaeger-Ruckstuhl C; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Shabaneh TB; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Olson JM; Seattle Children's Research Institute, Ben Towne Center For Childhood Cancer Research, Seattle, WA 98105, USA., Su X; Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA.; Yale Cancer Center, Yale University, New Haven, CT 06520, USA., Riddell SR; Translational Sciences and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.; Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Apr 22. Date of Electronic Publication: 2024 Apr 22.
DOI:	10.21203/rs.3.rs-4253777/v1
Abstrakt:	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. Competing Interests: Competing Interests: S.S., G.B. and S.R.R. are inventors on a patent (FHCC: 21–126-WO-PCT | App No. PCT/US2023/066466| COMPOSITIONS AND METHODS FOR CELLULAR IMMUNOTHERAPY) filed by Fred Hutchinson Cancer Center and related to this work. S.R.R. was a founder, has served as an advisor, and has patents licensed to Juno Therapeuwcs; S.R.R is a founder of and holds equity in Lyell Immunopharma and has served on the advisory boards for Adapwve Biotechnologies, Outpace Bio and Nohla.
Databáze:	MEDLINE
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