Related Experiment Video
Updated: Jan 23, 2026
Electrochemotherapy of Tumours
Published on: December 15, 2008
Preclinical assessment of transiently TCR redirected T cells for solid tumour immunotherapy
Nadia Mensali1, Marit Renée Myhre1, Pierre Dillard1
1Department of Cellular Therapy, Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, 0379, Oslo, Norway.
Abstract:
Off-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks. There is, therefore, a clear unmet need for assessing the safety of a therapeutic TCR in a more controllable manner than by the injection of permanently modified cellular products. Using transiently modified T cells combined with dose escalation has already been shown feasible for chimeric antigen receptor (CAR)-engineered T cells, but nothing is yet reported for TCR. We performed a preclinical evaluation of a therapeutic TCR transiently expressed in T cells by mRNA electroporation. We analyzed if the construct was active in vitro, how long it was detectable for and if this expression format was adapted to in vivo efficacy assessment. Our data demonstrate the potential of mRNA engineered T cells, although less powerful than permanent redirection, to induce a significant response. Thus, these findings support the development of mRNA based TCR-therapy strategies as a feasible and efficacious method for evaluating TCR safety and efficacy in first-in-man testing.
Insights
Transiently engineered T cells expressing therapeutic T cell receptors (TCRs) via mRNA electroporation offer a safer method for evaluating TCR efficacy and safety in initial human trials.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- T cell receptor (TCR)-engineered T cells show promise for solid tumour treatment but carry risks like off-target toxicity and cross-reactivity.
- Predicting TCR target recognition pre-clinically is challenging, highlighting the need for safer evaluation methods.
- Current methods for assessing therapeutic TCRs in humans are limited, especially compared to chimeric antigen receptor (CAR)-engineered T cells.
Purpose of the Study:
- To evaluate the preclinical safety and efficacy of transiently expressed therapeutic TCRs using mRNA electroporation in T cells.
- To assess the in vitro activity, duration of expression, and suitability for in vivo assessment of mRNA-engineered T cells.
- To establish a feasible and effective strategy for evaluating TCR safety and efficacy in first-in-human testing.
Main Methods:
- Preclinical evaluation of a therapeutic TCR transiently expressed in T cells via mRNA electroporation.
- Analysis of in vitro activity and detectability of the mRNA-engineered TCR construct.
- Assessment of the suitability of transient expression for in vivo efficacy evaluation.
Main Results:
- mRNA-engineered T cells demonstrated significant in vitro and in vivo responses, though less potent than permanently modified cells.
- Transient expression of TCRs via mRNA electroporation proved feasible for preclinical assessment.
- The study confirmed the potential of mRNA-based TCR-therapy for evaluating safety and efficacy.
Conclusions:
- Transiently modified T cells using mRNA electroporation provide a viable platform for assessing TCR safety and efficacy in early clinical trials.
- This approach addresses the unmet need for controllable evaluation of therapeutic TCRs, mitigating risks associated with permanent modification.
- mRNA-based TCR-therapy strategies are supported as feasible and efficacious for first-in-man testing of novel TCRs.
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