Time to evolve: predicting engineered T cell-associated toxicity with next-generation models

J Immunother Cancer. 2022 May;10(5):e003486. doi: 10.1136/jitc-2021-003486.


Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, including humanized mouse models, which can better recapitulate toxicities observed in patients. The Accelerating Development and Improving Access to CAR and TCR-engineered T cell therapy (T2EVOLVE) consortium is a public-private partnership directed at accelerating the preclinical development and increasing access to engineered T-cell therapy for patients with cancer. A key ambition in T2EVOLVE is to design new models and tools with higher predictive value for clinical safety and efficacy, in order to improve and accelerate the selection of lead T-cell products for clinical translation. Herein, we review existing preclinical models that are used to test the safety of engineered T cells. We will also highlight limitations of these models and propose potential measures to improve them.

Keywords: immunotherapy.

Publication types

  • Review

MeSH terms

  • Animals
  • Cytokine Release Syndrome
  • Humans
  • Immunotherapy, Adoptive* / adverse effects
  • Mice
  • Neoplasms* / therapy
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / therapeutic use
  • T-Lymphocytes


  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen