4.6 Article

Design and Validation of Inducible TurboCARs with Tunable Induction and Combinatorial Cytokine Signaling

Journal

CANCER IMMUNOLOGY RESEARCH
Volume 10, Issue 9, Pages 1069-1083

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-21-0253

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Funding

  1. Allogene Therapeutics

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Engineering iTurboCAR T cells allows for flexible control of cellular phenotype and function, leading to improved antitumor efficacy while minimizing viral cargo footprint.
Although cytokine support can enhance CAR T-cell function, coadministering cytokines or engineering CAR T cells to secrete cytokines can result in toxicities. To mitigate these safety risks, we engineered iTurboCAR T cells that co-express a novel inducible Turbo (iTurbo) cytokine signaling domain. iTurbo domains consist of modular components that are customizable to a variety of activating inputs, as well as cytokine signaling outputs multiplexable for combinatorial signaling outcomes. Unlike most canonical cytokine receptors that are heterodimeric, iTurbo domains leverage a compact, homodimeric design that minimizes viral vector cargo. Using an iTurbo domain activated by the clinically validated dimerizer, AP1903, homodimeric iTurbo domains instigated signaling that mimicked the endogenous heterodimeric cytokine receptor. Different iTurbo domains programmed iTurboCAR T cells toward divergent phenotypes and resulted in improved antitumor efficacy. iTurbo domains, therefore, offer the flexibility for user-programmable signaling outputs, permitting control over cellular phenotype and function while minimizing viral cargo footprint.

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