Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma
Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma
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DOI：
10.1200/jco.2014.58.0225
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发表时间：
2015-05-20
影响因子：
45.3
通讯作者：
Gottschalk, Stephen
中科院分区：
文献类型：
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作者：
Ahmed, Nabil;Brawley, Vita S.;Gottschalk, Stephen
目的转移性或复发性肉瘤患者的预后仍然较差。肿瘤导向T细胞的过继治疗是一种有吸引力的治疗选择，但从未在肉瘤中进行过评估。患者和方法我们进行了一项I/II期临床研究，在该研究中，复发/难治性人表皮生长因子受体2(HER2)阳性肉瘤患者接受了递增剂量(1×10(4)/m(2)至1×10(8)/m(2))的表达HER2特异性嵌合抗原受体和CD28的T细胞。结果纳入19例HER2阳性肿瘤患者(骨肉瘤16例，尤文肉瘤1例，原始神经外胚层瘤1例，促结缔组织增生性小圆细胞瘤1例)。HER2-CAR T细胞输注耐受性良好，没有剂量限制性毒性。在剂量水平3(1×10(5)/m(2))及以上时，我们用定量聚合酶链式反应检测了16例患者中14例输注后3h的HER2-CAR T细胞。在接受HER2-CAR T细胞超过1×10(6)/m(2)的9名可评估患者中，有7名患者的HER2-CAR T细胞持续了至少6周(P=0.005)。在两名接受检查的患者中，有两名患者的肿瘤部位检测到HER2-CAR T细胞。在17名可评估的患者中，4名患者的病情稳定了12周至14个月。其中三名患者的肿瘤被切除，其中一名患者出现90%的坏死。所有19名输血患者的中位总生存期为10.3个月(5.1~29.1个月)。结论首次对HER2-CAR T细胞在癌症患者中的安全性和有效性进行了评估，结果显示该细胞可以存活6周而没有明显的毒性，为将HER2-CAR T细胞与其他免疫调节方法相结合以增强其扩增和持久性的研究奠定了基础。(C)2015年度美国临床肿瘤学会
PurposeThe outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma.Patients and MethodsWe conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) -positive sarcoma received escalating doses (1 x 10(4)/m(2) to 1 x 10(8)/m(2)) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28. signaling domain (HER2-CAR T cells).ResultsWe enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 x 10(5)/m(2)) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 x 10(6)/m(2) HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months).ConclusionThis first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence. (C) 2015 by American Society of Clinical Oncology