B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity.
B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity.
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DOI：
10.1038/gt.2015.29
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发表时间：
2015-08
期刊：
影响因子：
5.1
通讯作者：
Sentman CL
中科院分区：
文献类型：
--
作者：
Wu MR;Zhang T;DeMars LR;Sentman CL
嵌合抗原受体（CAR）T细胞疗法已在临床试验中证明了针对B细胞白血病的持久且潜在的治愈性治疗功效。CAR策略可以靶向任何肿瘤表面抗原，只要可以产生抗原结合受体。需要靶向实体瘤并具有靶向多种肿瘤类型的潜力的新汽车。在这项研究中，B7 H6是NK细胞活化受体NKp 30的配体，被靶向以产生靶向多种肿瘤类型的CAR。B7 H6在各种原发性人类肿瘤上表达，包括白血病、淋巴瘤和胃肠道间质瘤（GIST），但其在正常组织上不组成性表达。当与B7 H6+肿瘤细胞共培养时，B7 H6特异性CAR T细胞具有稳健的细胞毒性和IFN-γ分泌，并且它们对未成熟树突状细胞（iDC）或促炎单核细胞表现出很少的自身反应性。在体内，B7 H6特异性CAR T细胞大大提高了携带RMA/B7 H6淋巴瘤的小鼠的存活率。长期存活小鼠受到保护，免受B7 H6缺陷型肿瘤再攻击。这种CAR疗法还降低了鼠卵巢癌模型中的肿瘤负荷。总之，B7 H6特异性汽车具有治疗B7 H6+血液肿瘤和实体肿瘤的潜力。
Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable and potentially curative therapeutic efficacy against B cell leukemia in clinical trials. A CAR strategy can target any tumor surface antigens as long as an antigen-binding receptor can be generated. New CARs which target solid tumors and have the potential to target multiple tumor types are needed. In this study, B7H6, a ligand for the NK cell activating receptor NKp30, was targeted to create a CAR which targets multiple tumor types. B7H6 is expressed on various primary human tumors, including leukemia, lymphoma, and gastrointestinal stromal tumors (GISTs), but it is not constitutively expressed on normal tissues. B7H6-specific CAR T cells have robust cellular cytotoxicity and IFN-γ secretion when co-cultured with B7H6+ tumor cells, and they exhibit little self-reactivity to immature dendritic cells (iDCs) or pro-inflammatory monocytes. In vivo, B7H6-specific CAR T cells greatly enhanced the survival of RMA/B7H6 lymphoma bearing mice. The long-term survivor mice were protected against a B7H6-deficient tumor re-challenge. This CAR therapy also decreased tumor burden in a murine ovarian cancer model. In conclusion, B7H6-specific CARs have the potential to treat B7H6+ hematologic and solid tumors.