Department of Cellular Therapy, Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, 0379, Oslo, Norway.
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0379, Oslo, Norway.
Cancer Immunol Immunother. 2019 Aug;68(8):1235-1243. doi: 10.1007/s00262-019-02356-2. Epub 2019 Jun 18.
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.
由于靶向抗原在正常组织中的表达或 TCR 交叉反应，当使用 T 细胞受体 (TCR) 工程化 T 细胞治疗实体瘤时，会产生脱靶毒性，这是一个主要风险。由于 TCR 固有的交叉反应性，很难在临床前准确预测它们的靶标识别。显然，直接在人体中进行测试是评估风险的最佳方法。因此，迫切需要以比注射永久性修饰细胞产品更可控的方式来评估治疗性 TCR 的安全性。已经证明，使用瞬时修饰的 T 细胞结合剂量递增可用于嵌合抗原受体 (CAR) 工程化 T 细胞，但 TCR 方面尚无报道。我们通过 mRNA 电穿孔在 T 细胞中瞬时表达治疗性 TCR 进行了临床前评估。我们分析了该构建体在体外是否具有活性，可检测多长时间，以及这种表达形式是否适用于体内疗效评估。我们的数据表明，mRNA 工程化 T 细胞具有潜力，尽管不如永久性重定向强大，但能够诱导显著反应。因此，这些发现支持开发基于 mRNA 的 TCR 治疗策略，作为在首例人体试验中评估 TCR 安全性和疗效的可行且有效的方法。
