肿瘤细胞治疗研究
英文原题：Closed-loop sonothermogenetic control of CAR T cells for metronomic brain cancer therapy.
实现针对原发性脑肿瘤和转移灶的持久CAR T细胞应答，需要能够实现颅内治疗控制、克服实体瘤治疗障碍且不损害安全性的策略。
实现对原发性脑肿瘤和转移灶的持久CAR T细胞应答，需要能够实现颅内治疗控制、克服实体瘤治疗屏障且不损害安全性的策略。在此，我们展示闭环声热遗传学能够通过完整颅骨对CAR T细胞治疗活性进行远程调控。利用MR引导的聚焦超声结合闭环温度反馈，我们调控经基因编码热生物开关改造的CAR T细胞，在大脑中实现节律性激活，且对健康脑组织无持久不良影响。在脑癌小鼠模型中，瘤内CAR T细胞节律性产生NKG2D T细胞衔接器，克服了乳腺癌脑转移中的抗原异质性和胶质母细胞瘤中的髓源性免疫抑制，从而驱动抗肿瘤应答。我们的发现支持使用闭环声热遗传学对靶向实体脑肿瘤的CAR T细胞疗法进行空间和时间控制。
Achieving durable CAR T cell responses against primary brain tumors and metastases requires strategies that enable intracranial control of therapy to overcome the barriers of solid tumor treatment without compromising safety. Here, we show that closed-loop sonothermogenetics enables remote regulation of CAR T cell therapeutic activity through the intact skull. Using MR-guided focused ultrasound with closed-loop temperature feedback, we modulate CAR T cells engineered with a genetically encoded thermal bioswitch to achieve metronomic activation in the brain without lasting adverse effects on healthy brain tissue. In murine models of brain cancer, metronomic production of NKG2D T cell engagers by intratumoral CAR T cells overcomes antigen heterogeneity in breast cancer brain metastasis and myeloid-derived immunosuppression in glioblastoma to drive antitumor responses. Our findings support the use of closed-loop sonothermogenetics for spatial and temporal control of CAR T cell therapies targeting solid brain tumors.
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