Duong MyLinh T, Collinson-Pautz Matthew R, Morschl Eva, Lu An, Szymanski Slawomir P, Zhang Ming, Brandt Mary E, Chang Wei-Chun, Sharp Kelly L, Toler Steven M, Slawin Kevin M, Foster Aaron E, Spencer David M, Bayle J Henri
Bellicum Pharmaceuticals, 2130 W. Holcombe Blvd., Suite 800, Houston, TX 77030, USA.
Mol Ther Oncolytics. 2018 Dec 20;12:124-137. doi: 10.1016/j.omto.2018.12.009. eCollection 2019 Mar 29.
Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow elimination of CAR-T cells. iMC costimulation induced by systemic rimiducid administration enhanced CAR-T cell proliferation, cytokine secretion, and antitumor efficacy in both assays and xenograft tumor models. Conversely, rapamycin-mediated iRC9 dimerization rapidly induced apoptosis in a dose-dependent fashion as an approach to mitigate therapy-related toxicity. This novel, regulatable dual-switch system may promote greater CAR-T cell expansion and prolonged persistence in a drug-dependent manner while providing a safety switch to mitigate toxicity concerns.
使用嵌合抗原受体（CAR）作为靶向过继性T细胞疗法的基础，已在对抗多种血液系统恶性肿瘤方面展现出显著疗效，但对体积较大的实体瘤的效力仍显滞后，这可能是由于CAR-T细胞的扩增和持久性不足所致。为提高CAR-T细胞的疗效，我们利用了基于瑞咪朵辛诱导型髓样分化因子88（MyD88）和CD40（iMC）信号元件的强效激活开关。为抵消这种增强型CAR可能带来的毒性风险，我们开发了一种正交调控、雷帕霉素诱导、基于半胱天冬酶-9的安全开关（iRC9），以实现对CAR-T细胞的清除。在实验和异种移植肿瘤模型中，全身给予瑞咪朵辛诱导的iMC共刺激均增强了CAR-T细胞的增殖、细胞因子分泌及抗肿瘤疗效。相反，雷帕霉素介导的iRC9二聚化以剂量依赖的方式迅速诱导细胞凋亡，以此作为减轻治疗相关毒性的一种手段。这种新型的、可调控的双开关系统可能以药物依赖的方式促进CAR-T细胞的更大程度扩增和延长其持久性，同时提供一个安全开关以减轻对毒性的担忧。
