CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors.
CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors.
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DOI：
10.1158/1078-0432.ccr-18-0432
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发表时间：
2019-04-15
期刊：
影响因子：
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通讯作者：
Mackall CL
中科院分区：
文献类型：
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作者：
Majzner RG;Theruvath JL;Nellan A;Heitzeneder S;Cui Y;Mount CW;Rietberg SP;Linde MH;Xu P;Rota C;Sotillo E;Labanieh L;Lee DW;Orentas RJ;Dimitrov DS;Zhu Z;Croix BS;Delaidelli A;Sekunova A;Bonvini E;Mitra SS;Quezado MM;Majeti R;Monje M;Sorensen PHB;Maris JM;Mackall CL
复发性儿科实体瘤和中枢神经系统恶性肿瘤患者的治疗选择很少，并且经常死于疾病。嵌合抗原受体（CAR）T细胞在治疗复发性小儿急性淋巴细胞白血病方面取得了巨大成功，但这尚未转化为治疗实体瘤。这部分是由于缺乏差异表达的细胞表面分子的实体瘤，可以安全地靶向。在这里，我们将B7-H3（CD 276）作为儿童实体瘤（包括中枢神经系统中出现的实体瘤）的CAR T细胞治疗的假定靶点。我们开发了一种新的B7-H3 CAR，其结合剂来源于mAb，该mAb已被证明优先结合肿瘤组织，并已在早期临床试验中安全地用于人类。我们在各种儿科癌症模型中测试了B7-H3 CAR T细胞。B7-H3 CAR T细胞在体内介导显著的抗肿瘤活性，导致异种移植模型中建立的实体瘤消退，包括骨肉瘤、成神经管细胞瘤和尤文肉瘤。我们证明，B7-H3 CAR T细胞的功效在很大程度上取决于肿瘤组织上的高表面靶抗原密度，并且针对表达低水平抗原的靶细胞的活性大大降低，因此尽管B7-H3的正常组织表达水平低，但仍提供了可能的治疗窗口。B7-H3 CAR T细胞可能是某些致命复发性或难治性儿科恶性肿瘤患者的一种令人兴奋的治疗选择，应该在精心设计的临床试验中进行测试。我们进行了迄今为止最大的儿童实体瘤和CNS恶性肿瘤B7-H3表达的筛查。使用先前描述的优先结合肿瘤B7-H3的结合剂（MGA 271，enoblituzumab），我们产生了新的第二代嵌合抗原受体（CAR）。B7-H3 CAR T细胞对致死性儿童癌症的一系列异种移植模型显示出显著的体内活性，包括骨肉瘤、尤文肉瘤和髓母细胞瘤的原位模型。B7-H3 CAR T细胞优先靶向具有高B7-H3表达的肿瘤细胞，证明了这种新型药物的可能治疗窗口。这项工作值得转化为临床，其中患有复发性儿科肿瘤的患者几乎没有治疗选择，但需要精心设计的研究来减轻潜在的毒性。
Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system. We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models. B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3. B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials. We have undertaken the largest screen to date of B7-H3 expression on pediatric solid tumors and CNS malignancies. Using a previously described binder that preferentially binds tumor B7-H3 with restricted recognition on normal human tissues (MGA271, enoblituzumab), we generated a novel second-generation chimeric antigen receptor (CAR). B7-H3 CAR T cells show significant in vivo activity against a range of xenograft models of lethal childhood cancers, including orthotopic models of osteosarcoma, Ewing sarcoma, and medulloblastoma. B7-H3 CAR T cells preferentially target tumor cells with high B7-H3 expression, demonstrating a possible therapeutic window for this novel agent. This work merits translation to the clinic where patients who have relapsed pediatric tumors have few therapeutic options, but will require carefully designed studies to mitigate potential toxicity.