小柯机器人

美国斯坦福大学医学院的Crystal L. Mackall研究组近期取得新进展。他们发现局部给药的靶向B7-H3的CAR T细胞可用于治疗非典型的类畸胎/横纹肌瘤（ATRT）。相关论文于2020年4月27日发表于《自然-医学》杂志上。

他们表示，ATRTs高表达B7-H3 / CD276，这不是由SMARCB1的失活突变引起的，该突变驱动ATRT中的肿瘤发生，但需要BRG1 / SMARCA4介导的残留的SWItch /不可发酵蔗糖（SWI / SNF）活性。与ATRT的胚胎起源一致，B7-H3在产前大脑中高表达，但在产后大脑中却不高。与静脉注射CAR T细胞相比，在脑室内或肿瘤内施用的B7-H3.BB.z-嵌合抗原受体（CAR）T细胞介导对小鼠脑ATRT异种移植物的有效抗肿瘤作用，具有更快的动力学，更大的效力和降低炎性细胞因子全身水平。

施用ICV的CAR T细胞也从中枢神经系统（CNS）转运到周围。在清除ATRT异种移植物后，脑室内或静脉内施用的B7-H3.BB.z-CAR T细胞介导了抗原特异性保护，使其免受大脑和周围区域的肿瘤攻击。这些结果表明，B7-H3是这种无法治愈的小儿肿瘤的引人注目的治疗靶标，与局部输注CAR T细胞用于中枢神经系统恶性肿瘤的全身递送相比，局部区域具有重要优势。

据了解，ATRT通常出现在3岁以下儿童的CNS中。尽管进行了密集的多式联运疗法（外科手术、化学疗法以及在年龄允许的情况下进行放射治疗），中位生存期仍仅为17个月。

附：英文原文

Title: Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors

Author: Johanna Theruvath, Elena Sotillo, Christopher W. Mount, Claus Moritz Graef, Alberto Delaidelli, Sabine Heitzeneder, Louai Labanieh, Shaurya Dhingra, Amaury Leruste, Robbie G. Majzner, Peng Xu, Sabine Mueller, Derek W. Yecies, Martina A. Finetti, Daniel Williamson, Pascal D. Johann, Marcel Kool, Stefan Pfister, Martin Hasselblatt, Michael C. Frhwald, Olivier Delattre, Didier Surdez, Franck Bourdeaut, Stephanie Puget, Sakina Zaidi, Siddhartha S. Mitra, Samuel Cheshier, Poul H. Sorensen, Michelle Monje, Crystal L. Mackall

Issue&Volume: 2020-04-27

Abstract: Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.

DOI: 10.1038/s41591-020-0821-8

Source: https://www.nature.com/articles/s41591-020-0821-8

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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