Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas.
Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas.
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DOI：
10.1038/s41591-018-0006-x
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发表时间：
2018-05
期刊：
影响因子：
82.9
通讯作者：
Mackall CL
中科院分区：
文献类型：
--
作者：
Mount CW;Majzner RG;Sundaresh S;Arnold EP;Kadapakkam M;Haile S;Labanieh L;Hulleman E;Woo PJ;Rietberg SP;Vogel H;Monje M;Mackall CL
弥漫性内在脑桥胶质瘤（DIPG）和其他弥漫性中线胶质瘤（DMG）与突变的组蛋白H3 K27 M（H3-K27 M），，，，-是侵略性和普遍致命的儿科脑癌。表达嵌合抗原受体（CAR）的T细胞在B细胞恶性肿瘤中介导了令人印象深刻的临床活性，最近的结果表明在中枢神经系统恶性肿瘤中的益处。在这里，我们报告说，患者来源的H3-K27 M突变胶质瘤细胞培养物表现出均匀的，高表达的二唾液酸神经节苷脂GD 2。掺入4-1BBz共刺激结构域的抗GD 2 CAR T细胞在体外表现出稳健的抗原依赖性细胞因子产生和对DMG细胞的杀伤。在五个独立的患者来源的H3-K27 M +DMG原位异种移植模型中，全身施用靶向GD 2的CAR T细胞清除了移植的肿瘤，除了少量残留的GD 2胶质瘤细胞。迄今为止，靶向GD 2的CAR T细胞在临床试验中耐受良好。尽管GD 2靶向CAR T细胞给药在大多数携带原位异种移植物的小鼠中是耐受的，但在抗肿瘤活性的急性期期间的瘤周神经炎症导致脑积水，这在一部分动物中是致命的。鉴于中线胶质瘤的神经解剖位置不稳定，人工翻译需要仔细监测和积极的神经重症监护管理。通过谨慎的多学科临床方法，GD 2靶向CAR T细胞治疗脑桥，丘脑和脊髓的H3-K27 M+弥漫性胶质瘤可能会对这些致命的儿童癌症产生变革性影响。
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M), , , –are aggressive and universally fatal pediatric brain cancers. Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies, , –, and recent results suggest benefit in central nervous system malignancies, –. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2loglioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials, –. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.
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通讯作者：
Cheung NV
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82.9
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Long, Adrienne H.;Haso, Waleed M.;Shern, Jack F.;Wanhainen, Kelsey M.;Murgai, Meera;Ingaramo, Maria;Smith, Jillian P.;Walker, Alec J.;Kohler, M. Eric;Venkateshwara, Vikas R.;Kaplan, Rosandra N.;Patterson, George H.;Fry, Terry J.;Orentas, Rimas J.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.