1. Academic Validation
  2. CRASH-IT Switch Enables Reversible and Dose-Dependent Control of TCR and CAR T-cell Function

CRASH-IT Switch Enables Reversible and Dose-Dependent Control of TCR and CAR T-cell Function

  • Cancer Immunol Res. 2021 Sep;9(9):999-1007. doi: 10.1158/2326-6066.CIR-21-0095.
Ali Can Sahillioglu 1 Mireille Toebes 1 Georgi Apriamashvili 1 Raquel Gomez 1 Ton N Schumacher 2
Affiliations

Affiliations

  • 1 Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 2 Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. t.schumacher@nki.nl.
Abstract

Adoptive transfer of genetically modified or donor-derived T cells can efficiently eradicate human tumors but is also frequently associated with major toxicity. There are several switches that can be used to kill the infused cell pool in the case of major toxicity, but the irreversible nature of these suicide switches means that the therapeutic effect is lost when they are used. To address this issue, we engineered a small-molecule responsive genetic safety switch that in the absence of drug robustly blocked cytotoxicity and cytokine expression of primary human T cells. Upon administration of drug, T-cell functions were restored in a reversible and titratable manner. We showed that this T-cell switch was universal, as it could be combined with endogenous or transduced T-cell receptors (TCR), as well as chimeric antigen receptors. The modular nature of the Chemically Regulated - SH2-delivered Inhibitory Tail (CRASH-IT) switch concept, in which inhibitory domains are brought to activating immune receptors in a controlled manner, makes it a versatile platform to regulate the activity of cell products that signal through immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors.

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