小柯机器人

加拿大多伦多大学Cynthia Hawkins研究团队经过不懈努力而取得新进展。他们发现嵌合抗原受体T细胞（CAR-T）在脑脊髓液的局部转运，可用于治疗转移性髓母细胞瘤和室管膜瘤。相关论文于2020年4月27日发表于《自然-医学》杂志上。

他们鉴定了三个细胞表面靶点：EPHA、HER2和白介素13受体α2，在髓母细胞瘤和室管膜瘤上表达，但在正常发育的大脑中不表达。他们证明EPHA2、HER2和白介素13受体α2嵌合抗原受体T细胞的鞘内传递，是对小鼠模型中原发性、转移性和复发性第3组髓母细胞瘤和后颅窝A组（PFA）室管膜异种移植的有效治疗途径。

最后，他们证明了将这些CAR-T细胞单独或与氮杂胞苷组合施用到脑脊液中，是治疗第3组髓母细胞瘤和PFA室膜瘤的多种转移性小鼠模型的高效疗法，从而为这些方法在人类临床试验的应用提供了依据。

据介绍，复发性髓母细胞瘤和室管膜瘤普遍致死，尚无被批准的靶向疗法，目前尚缺乏临床评估的候选药物。几乎所有复发性髓母细胞瘤和PFA室管膜瘤都位于脑脊液附近，并浸润在脑脊液，因此绕过了血脑屏障，这为局部治疗提供了机会。

附：英文原文

Title: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author: Laura K. Donovan, Alberto Delaidelli, Sujith K. Joseph, Kevin Bielamowicz, Kristen Fousek, Borja L. Holgado, Alex Manno, Dilakshan Srikanthan, Ahmed Z. Gad, Randy Van Ommeren, David Przelicki, Cory Richman, Vijay Ramaswamy, Craig Daniels, Jonelle G. Pallota, Tajana Douglas, Alyssa C. M. Joynt, Joonas Haapasalo, Carolina Nor, Maria C. Vladoiu, Claudia M. Kuzan-Fischer, Livia Garzia, Stephen C. Mack, Srinidhi Varadharajan, Matthew L. Baker, Liam Hendrikse, Michelle Ly, Kaitlin Kharas, Polina Balin, Xiaochong Wu, Lei Qin, Ning Huang, Ana Guerreiro Stucklin, A. Sorana Morrissy, Florence M. G. Cavalli, Betty Luu, Raul Suarez, Pasqualino De Antonellis, Antony Michealraj, Avesta Rastan, Meenakshi Hegde, Martin Komosa, Olga Sirbu, Sachin A. Kumar, Zied Abdullaev, Claudia C. Faria, Stephen Yip, Juliette Hukin, Uri Tabori, Cynthia Hawkins

Issue&Volume: 2020-04-27

Abstract: Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood–brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.

DOI: 10.1038/s41591-020-0827-2

Source: https://www.nature.com/articles/s41591-020-0827-2

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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