T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer.
T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer.
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DOI：
10.1056/nejmoa1609279
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发表时间：
2016-12-08
期刊：
影响因子：
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通讯作者：
Rosenberg SA
中科院分区：
文献类型：
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作者：
Tran E;Robbins PF;Lu YC;Prickett TD;Gartner JJ;Jia L;Pasetto A;Zheng Z;Ray S;Groh EM;Kriley IR;Rosenberg SA
我们鉴定了从转移性结直肠癌患者获得的肿瘤浸润淋巴细胞中针对突变型KRAS G12 D的多克隆CD 8 + T细胞应答。在输注约1.11×1011 HLA-C*08：02限制性肿瘤浸润淋巴细胞后，我们观察到所有7个肺转移瘤的客观消退，这些淋巴细胞由特异性靶向KRAS G12 D的4种不同T细胞克隆型组成。然而，其中一个病变在治疗后9个月进行评估时进展。切除病变，发现已丢失编码HLA-C*08：02 I类主要组织相容性复合体（MHC）分子的6号染色体单倍型。该分子表达的缺失提供了肿瘤免疫逃避的直接机制。因此，靶向突变型KRAS的CD 8+细胞的输注介导针对表达突变型KRAS G12 D和HLA-C*08：02的癌症的有效抗肿瘤免疫疗法。
We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×1011 HLA-C*08:02–restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.