T-Cell Receptor Gene Therapy for Human Papillomavirus-Associated Epithelial Cancers: A First-in-Human, Phase I/II Study
T-Cell Receptor Gene Therapy for Human Papillomavirus-Associated Epithelial Cancers: A First-in-Human, Phase I/II Study
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DOI：
10.1200/jco.18.02424
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发表时间：
2019-10-20
影响因子：
45.3
通讯作者：
Hinrichs, Christian S.
中科院分区：
文献类型：
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作者：
Doran, Stacey L.;Stevanovic, Sanja;Hinrichs, Christian S.
目的基因工程T细胞治疗是一种新兴的血液肿瘤治疗方法，在上皮性肿瘤中具有潜在的应用价值。我们研究了T细胞治疗转移性人乳头瘤病毒（HPV）相关的上皮cancer.METHODS的治疗，这一阶段I/II，单中心试验招募转移性HPV 16阳性癌症患者从任何原发肿瘤部位谁接受了铂类药物为基础的治疗。治疗包括自体基因工程T细胞表达的T细胞受体针对HPV 16 E6（E6 T细胞受体T细胞），预处理方案，和全身阿地白介素。在I期部分未观察到剂量限制性毒性。最高剂量队列中的2例患者出现了客观肿瘤缓解。一名患有三个肺转移瘤的患者经历了一个肿瘤的完全消退和两个肿瘤的部分消退，随后被切除;她在治疗后3年没有疾病的证据。所有患者在治疗后1个月表现出高水平的外周血E6 T细胞受体T细胞植入（中位数，30%;范围，4%至53%）。一名患者的耐药肿瘤表现出干扰素γ受体1的移码缺失，干扰素γ受体1介导对干扰素γ的应答，干扰素γ是T细胞介导的抗肿瘤活性的必需分子。另一名患者的耐药肿瘤表现出HLA-A*02：01的损失，这种治疗所需的抗原呈递分子。一个病人的肿瘤谁回应治疗没有表现出遗传缺陷的干扰素γ反应或抗原presentation.CONCLUSION工程化的T细胞可以诱导上皮癌的消退。在T细胞程序性死亡-1表达和干扰素γ和抗原呈递途径组分缺陷的背景下观察到肿瘤抗性。这些发现对上皮癌细胞治疗的发展具有重要意义。(C)2019年美国临床肿瘤学会
PURPOSE Genetically engineered T-cell therapy is an emerging treatment of hematologic cancers with potential utility in epithelial cancers. We investigated T-cell therapy for the treatment of metastatic human papillomavirus (HPV)-associated epithelial cancers.METHODS This phase I/II, single-center trial enrolled patients with metastatic HPV16-positive cancer from any primary tumor site who had received prior platinum-based therapy. Treatment consisted of autologous genetically engineered T cells expressing a T-cell receptor directed against HPV16 E6 (E6 T-cell receptor T cells), a conditioning regimen, and systemic aldesleukin.RESULTS Twelve patients were treated in the study. No dose-limiting toxicities were observed in the phase I portion. Two patients, both in the highest-dose cohort, experienced objective tumor responses. A patient with three lung metastases experienced complete regression of one tumor and partial regression of two tumors, which were subsequently resected; she has no evidence of disease 3 years after treatment. All patients demonstrated high levels of peripheral blood engraftment with E6 T-cell receptor T cells 1 month after treatment (median, 30%; range, 4% to 53%). One patient's resistant tumor demonstrated a frameshift deletion in interferon gamma receptor 1, which mediates response to interferon gamma, an essential molecule for T-cell-mediated antitumor activity. Another patient's resistant tumor demonstrated loss of HLA-A*02:01, the antigen presentation molecule required for this therapy. A tumor from a patient who responded to treatment did not demonstrate genetic defects in interferon gamma response or antigen presentation.CONCLUSION Engineered T cells can induce regression of epithelial cancer. Tumor resistance was observed in the context of T-cell programmed death-1 expression and defects in interferon gamma and antigen presentation pathway components. These findings have important implications for development of cellular therapy in epithelial cancers. (C) 2019 by American Society of Clinical Oncology