肿瘤细胞治疗研究
英文原题：RapaCaspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells.
即使过继性细胞转移（ACT）已在癌症等不同类型疾病中展现出显著的临床疗效，一些不良事件仍持续发生，而自杀基因是管理这些事件的一个有趣系统。
即使过继性细胞转移（ACT）已在癌症等不同类型疾病中展现出良好的临床疗效，一些不良事件仍持续发生，而自杀基因是管理这些事件的一个有前景的系统。我们的团队开发了一种新的候选药物，即靶向白细胞介素-1受体辅助蛋白（IL-1RAP）的嵌合抗原受体（CAR），需要在临床试验中结合临床可用的自杀基因系统对其进行评估。为预防副作用并确保我们候选药物的安全性，我们设计了两种携带可诱导自杀基因的构建体，RapaCasp9-G或RapaCasp9-A，其中包含一个影响内源性caspase 9效率的单核苷酸多态性（rs1052576）。这些自杀基因由雷帕霉素激活，基于人caspase 9与修饰的人FK结合蛋白的融合，从而实现条件性二聚化。表达RapaCasp9-G和RapaCasp9-A的基因修饰T细胞（GMTCs）由健康供者（HDs）和急性髓系白血病（AML）供者产生。RapaCasp9-G自杀基因表现出更好的效率，我们展示了其在不同临床相关培养条件下的体外功能性。此外，由于雷帕霉素并非药理学惰性，我们还证明了其作为我们治疗方案一部分的安全使用。
Even if adoptive cell transfer (ACT) has already shown great clinical efficiency in different types of disease, such as cancer, some adverse events consistently occur, and suicide genes are an interesting system to manage these events. Our team developed a new medical drug candidate, a chimeric antigen receptor (CAR) targeting interleukin-1 receptor accessory protein (IL-1RAP), which needs to be evaluated in clinical trials with a clinically applicable suicide gene system. To prevent side effects and ensure the safety of our candidate, we devised two constructs carrying an inducible suicide gene, RapaCasp9-G or RapaCasp9-A, containing a single-nucleotide polymorphism (rs1052576) affecting the efficiency of endogenous caspase 9. These suicide genes are activated by rapamycin and based on the fusion of human caspase 9 with a modified human FK-binding protein, allowing conditional dimerization. RapaCasp9-G- and RapaCasp9-A-expressing gene-modified T cells (GMTCs) were produced from healthy donors (HDs) and acute myeloid leukemia (AML) donors. The RapaCasp9-G suicide gene demonstrated better efficiency, and we showed its in vitro functionality in different clinically relevant culture conditions. Moreover, as rapamycin is not pharmacologically inert, we also demonstrated its safe use as part of our therapy.
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