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CAR T Cells Targeting MISIIR for the Treatment of Ovarian Cancer and Other Gynecologic Malignancies.
Molecular Therapy ( IF 12.1 ) Pub Date : 2019-12-06 , DOI: 10.1016/j.ymthe.2019.11.028
Alba Rodriguez-Garcia 1 , Prannda Sharma 1 , Mathilde Poussin 1 , Alina C Boesteanu 2 , Nicholas G Minutolo 1 , Sarah B Gitto 1 , Dalia K Omran 3 , Matthew K Robinson 4 , Gregory P Adams 4 , Fiona Simpkins 5 , Daniel J Powell 1
Affiliation  

The prognosis of patients diagnosed with advanced ovarian or endometrial cancer remains poor, and effective therapeutic strategies are limited. The Müllerian inhibiting substance type 2 receptor (MISIIR) is a transforming growth factor β (TGF-β) receptor family member, overexpressed by most ovarian and endometrial cancers while absent in most normal tissues. Restricted tissue expression, coupled with an understanding that MISIIR ligation transmits apoptotic signals to cancer cells, makes MISIIR an attractive target for tumor-directed therapeutics. However, the development of clinical MISIIR-targeted agents has been challenging. Prompted by the responses achieved in patients with blood malignancies using chimeric antigen receptor (CAR) T cell therapy, we hypothesized that MISIIR targeting may be achieved using a CAR T cell approach. Herein, we describe the development and evaluation of a CAR that targets MISIIR. T cells expressing the MISIIR-specific CAR demonstrated antigen-specific reactivity in vitro and eliminated MISIIR-overexpressing tumors in vivo. MISIIR CAR T cells also recognized a panel of human ovarian and endometrial cancer cell lines, and they lysed a battery of patient-derived tumor specimens in vitro, without mediating cytotoxicity of a panel of normal primary human cells. In conclusion, these results indicate that MISIIR targeting for the treatment of ovarian cancer and other gynecologic malignancies is achievable using CAR technology.

中文翻译:

靶向 MISIIR 的 CAR T 细胞用于治疗卵巢癌和其他妇科恶性肿瘤。

诊断为晚期卵巢癌或子宫内膜癌的患者预后仍然很差,有效的治疗策略有限。苗勒管抑制物质 2 型受体 (MISIIR) 是一种转化生长因子 β (TGF-β) 受体家族成员,在大多数卵巢癌和子宫内膜癌中过度表达,而在大多数正常组织中不存在。受限的组织表达,加上对 MISIIR 连接将凋亡信号传递给癌细胞的理解,使 MISIIR 成为肿瘤定向治疗的有吸引力的靶标。然而,临床 MISIIR 靶向药物的开发一直具有挑战性。受使用嵌合抗原受体 (CAR) T 细胞疗法在血液恶性肿瘤患者中取得的反应的提示,我们假设可以使用 CAR T 细胞方法实现 MISIIR 靶向。在此处,我们描述了针对 MISIIR 的 CAR 的开发和评估。表达 MISIIR 特异性 CAR 的 T 细胞在体外表现出抗原特异性反应性,并在体内消除了 MISIIR 过表达肿瘤。MISIIR CAR T 细胞还识别一组人类卵巢和子宫内膜癌细胞系,并且它们在体外裂解了一组患者来源的肿瘤标本,而不介导一组正常原代人类细胞的细胞毒性。总之,这些结果表明使用 CAR 技术可以实现 MISIIR 靶向治疗卵巢癌和其他妇科恶性肿瘤。MISIIR CAR T 细胞还识别一组人类卵巢和子宫内膜癌细胞系,并且它们在体外裂解了一组患者来源的肿瘤标本,而不介导一组正常原代人类细胞的细胞毒性。总之,这些结果表明使用 CAR 技术可以实现 MISIIR 靶向治疗卵巢癌和其他妇科恶性肿瘤。MISIIR CAR T 细胞还识别一组人类卵巢和子宫内膜癌细胞系,并且它们在体外裂解了一组患者来源的肿瘤标本,而不介导一组正常原代人类细胞的细胞毒性。总之,这些结果表明使用 CAR 技术可以实现 MISIIR 靶向治疗卵巢癌和其他妇科恶性肿瘤。
更新日期:2019-12-06
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