Time to evolve: predicting engineered T cell-associated toxicity with next-generation models
Emmanuel Donnadieu1, Maik Luu2, Miriam Alb2
1Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France.
Abstract:
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.
Insights
Engineered T-cell therapies show promise but cause severe toxicities. New preclinical models are being developed to better predict and prevent these adverse events in cancer patients.
Area of Science:
- Oncology
- Immunotherapy
- Preclinical Research
Background:
- Engineered T-cell therapies, like CAR and TCR T cells, offer clinical benefits for certain cancers but are linked to severe adverse events such as cytokine release syndrome and neurotoxicity.
- These toxicities limit the widespread application of these advanced cancer treatments.
- Current preclinical models have historically failed to accurately predict severe toxicities observed in human clinical trials.
Purpose of the Study:
- To review existing preclinical models for assessing engineered T-cell therapy safety.
- To highlight the limitations of current models in predicting clinical toxicities.
- To propose improvements for developing more predictive preclinical models.
Main Methods:
- Review of existing literature on preclinical models for engineered T-cell therapy safety assessment.
- Analysis of limitations in current models regarding prediction of cytokine release syndrome and neurotoxicity.
- Discussion of ongoing efforts, including humanized mouse models, to improve predictive value.
Main Results:
- Existing preclinical models have shown inadequacy in predicting severe adverse events associated with engineered T-cell therapies.
- Recent advancements include the development of humanized mouse models aiming for better recapitulation of patient toxicities.
- The T2EVOLVE consortium is focused on creating higher-predictive preclinical models and tools.
Conclusions:
- There is a critical need for improved preclinical models to accurately assess the safety of engineered T-cell therapies.
- Enhanced models are essential for accelerating the clinical translation of promising T-cell products.
- Future research should focus on developing and validating novel models that better predict clinical safety and efficacy.
