دورية أكاديمية
أعرض في EDS

Safety switch optimization enhances antibody-mediated elimination of CAR T cells.

التفاصيل البيبلوغرافية
العنوان: Safety switch optimization enhances antibody-mediated elimination of CAR T cells.
المؤلفون: Shabaneh TB; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, United States., Moffett HF; Outpace Bio, Inc., Seattle, WA, United States., Stull SM; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, United States., Derezes T; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, United States., Tait LJ; Outpace Bio, Inc., Seattle, WA, United States., Park S; Lyell Immunopharma, Inc., Seattle, WA, United States., Riddell SR; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, United States., Lajoie MJ; Outpace Bio, Inc., Seattle, WA, United States.
المصدر: Frontiers in molecular medicine [Front Mol Med] 2022 Oct 11; Vol. 2, pp. 1026474. Date of Electronic Publication: 2022 Oct 11 (Print Publication: 2022).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Frontiers Media S.A Country of Publication: Switzerland NLM ID: 9918402378306676 Publication Model: eCollection Cited Medium: Internet ISSN: 2674-0095 (Electronic) Linking ISSN: 26740095 NLM ISO Abbreviation: Front Mol Med Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [Lausanne, Switzerland] : Frontiers Media S.A., [2021]-
مستخلص: Activation of a conditional safety switch has the potential to reverse serious toxicities arising from the administration of engineered cellular therapies, including chimeric antigen receptor (CAR) T cells. The functionally inert, non-immunogenic cell surface marker derived from human epidermal growth factor receptor (EGFRt) is a promising safety switch that has been used in multiple clinical constructs and can be targeted by cetuximab, a clinically available monoclonal antibody. However, this approach requires high and persistent cell surface expression of EGFRt to ensure that antibody-mediated depletion of engineered cells is rapid and complete. Here we show that incorporating a short juxtamembrane sequence into the EGFRt polypeptide enhances its expression on the surface of T cells and their susceptibility to antibody-dependent cellular cytotoxicity (ADCC). Incorporating this optimized variant (EGFRopt) into bicistronic and tricistronic CAR designs results in more rapid in vivo elimination of CAR T cells and robust termination of their effector activity compared to EGFRt. These studies establish EGFRopt as a superior safety switch for the development of next-generation cell-based therapeutics.
Competing Interests: SR is a co-founder of Lyell Immunopharma, Inc. and has received grant funding from Lyell Immunopharma,Inc. SR was a cofounder Juno Therapeutics, a Bristol Myers Squibb company and has served as a scientific advisor to Juno Therapeutics and Adaptive Biotechnologies. SP is an employee of Lyell Immunopharma, Inc. ML is a co-founder of Lyell Immunopharma, Inc., and Outpace Bio. HM andML are listed as inventors on patent applications related to this work.HM, LT, andMLare employees of Outpace Bio, a licensee of patent rights owned by Lyell Immunopharma, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Shabaneh, Moffett, Stull, Derezes, Tait, Park, Riddell and Lajoie.)
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فهرسة مساهمة: Keywords: CAR T cell therapy; EGFRopt; antibody-dependent cellular cytotoxicity; safety switch; truncated EGFR-derived polypeptide
تواريخ الأحداث: Date Created: 20240801 Latest Revision: 20240802
رمز التحديث: 20240802
مُعرف محوري في PubMed: PMC11285702
DOI: 10.3389/fmmed.2022.1026474
PMID: 39086975
قاعدة البيانات: MEDLINE
الوصف
تدمد:2674-0095
DOI:10.3389/fmmed.2022.1026474