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人表皮生长因子受体2(HER2)特异性嵌合抗原受体修饰T细胞的免疫治疗HER2阳性乳腺...

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发表于 2016-1-26 20:42:36 | 显示全部楼层 |阅读模式
Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma.
PURPOSE:
The 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 METHODS:
We 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 × 10(4)/m(2) to 1 × 10(8)/m(2)) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells).
RESULTS:
We 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 × 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 × 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).
CONCLUSION:
This 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.
人表皮生长因子受体2HER2)特异性嵌合抗原受体修饰T细胞的免疫治疗HER2阳性乳腺癌肉瘤。
目的:
转移性或复发性肉瘤患者的预后仍然很差。肿瘤靶向细胞治疗是一个很有吸引力的治疗选择,但从来没有被评估肉瘤。
途径和方法:
我们进行的I / II期临床研究中,复发/难治性人类表皮生长因子受体2HER2)阳性肿瘤的患者接受高剂量(1×104/m2 1~×108/ m2)带的表达HER2特异性嵌合抗原受体修饰的T细胞,该受体结合了CD28ζ号域,即HER2 -CAR T细胞。
结果:
我们收纳了19HER2阳性肿瘤(骨肉瘤16例,尤文肉瘤1,原始神经外胚层肿瘤一例,结缔组织增生性小圆细胞肿瘤1)。HER2-CAR T细胞输注耐受性良好,无剂量限制性毒性。剂量水平31×105/m2)及以上,我们发现16位病人中有14位在输注HER2-CAR T细胞三小时之后会出现荧光定量聚合酶链反应。9位评估的病人中,有7位能够在6周内持续监测到HER2-CAR T细胞的存在。2位检查的病人中有2位发现在肿瘤部位存在HER2-CAR T细胞。17位病人中,有4位从12周持续到14个月,病情稳定。有3位病人的肿瘤消除,其中一个显示了≥90%坏死。所有19例患者的中位总生存期为10.3个月(范围5.129.1个月)。
结论:
HER2-CAR T细胞这一评估的安全性和疗效显示,细胞可以在癌症患者中持续6周无明显毒性,我们需要搭建一个平台,结合HER2-CAR T细胞与其他免疫调节的办法来提高他们的扩张和持续作用能力。
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