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靶向突变型KRAS的过继性T细胞治疗在癌症中的应用
T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer


Eric Tran ... 肿瘤 • 2016.12.08

过继性T细胞肿瘤免疫治疗已现曙光

 

任秀宝†,张鸿声‡§*

† 天津医科大学肿瘤医院生物治疗中心;‡ 同济大学医学院;§ 天津医科大学肿瘤医院

* 通讯作者

 

以CAR-T、TCR-T为代表的过继性T细胞肿瘤免疫治疗具有常规治疗无法比拟的疗效和临床前景,目前已成为全球肿瘤治疗研发和临床试验的热点。本期《新英格兰医学杂志》发表了一篇美国国立癌症研究所Rosenberg团队关于采用过继性T细胞靶向KRAS突变进行癌症治疗的文章1

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概要


在一例转移性结直肠癌患者的肿瘤浸润淋巴细胞中,我们鉴定出一种针对突变型KRAS G12D的多克隆CD8+ T细胞应答。我们将大约1.11×1011个HLA-CÖ08:02限制性肿瘤浸润淋巴细胞——由特异性靶向KRAS G12D的4种不同T细胞克隆型组成,输注给该患者,之后在所有7个肺转移灶均观察到了客观的消退。然而,在治疗后9个月的评估中,其中一个病灶出现了进展。我们将该病灶切除,发现它缺失了由6号染色体单倍体型编码的HLA-CÖ08:02一类主要组织相容性复合物(major histocompatibility complex, MHC)分子。该分子的表达缺失为肿瘤免疫逃逸提供了直接的机制。因此,对于表达突变型KRAS G12D和HLA-CÖ08:02的癌症,输注靶向突变型KRAS的CD8+细胞可以介导有效的抗肿瘤免疫治疗。

 

利用肿瘤浸润淋巴细胞离体扩增的过继细胞治疗可以使20%~25%的转移性黑色素瘤患者的肿瘤得到持久的完全缓解1,2。这种作用可能是由T细胞特异性地靶向新生体细胞突变编码的突变多肽所介导,这些突变多肽被称为新表位3-8。相关证据表明,接受免疫检查点抑制剂治疗后,癌症患者的临床反应可能也是由新表位反应性的T细胞介导9-14。研究者在一例转移性胆管癌患者中观察到了靶向新表位治疗效用的直接证据,该患者在输注了靶向其肿瘤表达的突变ERBB2IP表位的95%纯度的CD4+ T细胞之后,肿瘤消退持续了35个月15。因此,利用针对突变肿瘤抗原的T细胞应答的策略在癌症患者中可能具有临床益处。

靶向驱动突变在概念上是有吸引力的,因为它们是肿瘤特异性的,对肿瘤进展具有生物学重要性,并且可能在所有肿瘤细胞中都表达16。致癌基因KRAS中的突变较频繁,并且导致许多人类癌症的形成和进展。绝大多数的KRAS突变是在第12、13或61位密码子发生的复发性“热点”驱动突变,其中第12位密码子是突变的最常见位点。该位点的氨基酸由甘氨酸(G)转变为天冬氨酸(D)——以下称为KRAS G12D,是人类胃肠道癌症中最常见的KRAS突变,并且该突变可在约45%的胰腺癌和13%的结直肠癌中检测到17,18。尽管有几十年的研究,目前仍没有有效的针对人类KRAS G12D蛋白的药物或者疫苗。在这里,我们描述了一例转移性结直肠癌患者在接受靶向突变型KRAS G12D的细胞毒性T细胞治疗后经历肿瘤缓解的临床和生物学发现。





作者信息

Eric Tran, Ph.D., Paul F. Robbins, Ph.D., Yong-Chen Lu, Ph.D., Todd D. Prickett, Ph.D., Jared J. Gartner, M.Sc., Li Jia, M.Sc., Anna Pasetto, Ph.D., Zhili Zheng, Ph.D., Satyajit Ray, Ph.D., Eric M. Groh, M.D., Isaac R. Kriley, M.D., and Steven A. Rosenberg, M.D., Ph.D.
From the Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. Address reprint requests to Dr. Rosenberg at the Surgery Branch, National Cancer Institute, 10 Center Dr., MSC 1201, Bethesda, MD 20892, or at sar@nih.gov.

 

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