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.
Highlights
T cell therapy has demonstrated impressive clinical results and is attracting considerable interest in the treatment of both haematological and solid cancers
We have recently shown that a T cell receptor (TCR) named Radium-1 targeting a neoantigen frequently expressed in microsatellite instable (MSI) colon cancer can be expressed transiently by mRNA electroporation and permanently using retroviral transduction [18]
We first tested the expression of the TCR in mRNA electroporated T cells using a Vβ3-FITC antibody as multimers binding the Radium-1 TCR were not available (Fig. 1a)
Summary
T cell therapy has demonstrated impressive clinical results and is attracting considerable interest in the treatment of both haematological and solid cancers. CAR T cell treatment against haematological malignancies is so far the most widely used as demonstrated by the recent FDA approval of CD19 CAR T cells for the treatment of B-cell acute lymphoblastic leukaemia (ALL) Both CAR and TCR expression and functionality upon mRNA transfection has been previously shown in vitro [2, 3], in murine hematological xenograft models for CARs [4,5,6,7,8] and recently in models of solid tumour [9] and clinically [10, 11]. We have recently shown that a TCR named Radium-1 targeting a neoantigen frequently expressed in microsatellite instable (MSI) colon cancer can be expressed transiently by mRNA electroporation and permanently using retroviral transduction [18]. Together our data show the first preclinical assessment of transiently TCR redirected T cells
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