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The risk of reactivity against healthy tissues: Novel CARs demand testing for overlooked binding properties
Astrid Holzinger1, Florian Weber2, Hinrich Abken1
1Leibniz Institute for Immunotherapy (LIT), Division of Genetic Immunotherapy, Regensburg, Germany.
Abstract:
A rapidly growing number of chimeric antigen receptors (CARs) is being translated into cell therapy for malignant and autoimmune diseases. While cancer cell-selective CAR targeting is undergoing continuous refinement, specific testing for overlooked recognition of healthy tissues is commonly not performed, which potentially results in underestimating of the risk of severe tissue damage upon CAR T cell application. Using the FcμR/IgM receptor/FAIM3/TOSO-specific CAR, designed to target chronic lymphocytic leukemia cells, we exemplarily outline a screen to uncover reactivities to healthy tissues and discuss the value of such pre-clinical testing to improve safety in CAR T cell application.
Insights
Chimeric antigen receptor (CAR) T cell therapy shows promise, but testing for healthy tissue reactivity is crucial. This study introduces a preclinical screen to identify potential off-target effects, enhancing CAR T cell therapy safety.
Area of Science:
- Immunotherapy
- Cell Therapy
- Oncology
Background:
- Chimeric antigen receptor (CAR) T cell therapies are increasingly used for malignant and autoimmune diseases.
- Current CAR T cell development often lacks thorough testing for healthy tissue recognition, risking severe adverse events.
Purpose of the Study:
- To develop and exemplify a preclinical screening method for identifying healthy tissue reactivity of CARs.
- To highlight the importance of pre-clinical safety testing in CAR T cell therapy development.
Main Methods:
- Utilized a FcmicroR/IgM receptor/FAIM3/TOSO-specific CAR, designed for chronic lymphocytic leukemia.
- Developed and applied a screening approach to detect unintended reactivity against healthy tissues.
Main Results:
- The study successfully demonstrated a method for uncovering healthy tissue reactivities in CARs.
- Identified potential off-target interactions that could lead to tissue damage.
Conclusions:
- Pre-clinical screening for healthy tissue reactivity is essential for improving the safety profile of CAR T cell therapies.
- Implementing such screens can mitigate the risk of severe tissue damage associated with CAR T cell application.
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