Sensitive bispecific chimeric T cell receptors for cancer therapy

Sensitive bispecific chimeric T cell receptors for cancer therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Sensitive bispecific chimeric T cell receptors for cancer therapy Stanley Riddell, Sylvain Simon, Grace Bugos, Rachel Prins, Anusha Rajan, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4253777/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Mar, 2025 Read the published version in Nature Cancer → Version 1 posted You are reading this latest preprint version 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. Health sciences/Medical research/Translational research Biological sciences/Biotechnology/Biologics/Cell therapies Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy Biological sciences/Cancer/Haematological cancer Biological sciences/Biological techniques/Genetic engineering Full Text Additional Declarations Yes there is potential Competing Interest. 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 Therapeutics; S.R.R is a founder of and holds equity in Lyell Immunopharma and has served on the advisory boards for Adaptive Biotechnologies, Outpace Bio and Nohla. Supplementary Files TableS1Simon2024.xlsx Supplementary table 1 ExtendedDataSimon2024.pdf Extended Data 1 to 9 Cite Share Download PDF Status: Published Journal Publication published 17 Mar, 2025 Read the published version in Nature Cancer → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4253777","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":291996599,"identity":"4742c0af-6b36-4e9a-b567-bae78fca17a1","order_by":0,"name":"Stanley 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