美国国立卫生研究院Christian S. Hinrichs研究组取得最新进展。他们将靶向E7的TCR工程改造T细胞，用于转移性HPV相关上皮癌患者。这一研究成果发表在2021年2月8日出版的国际学术期刊《自然-医学》上。
他们对靶向T细胞受体的HPV-16 E7工程改造的T细胞，进行了人体1期临床试验，该疗法可用于治疗转移性人乳头瘤病毒相关的上皮癌（NCT02858310）。主要终点是最大耐受剂量。细胞剂量不受毒性限制，最大剂量为1×1011工程化T细胞。使用RECIST（实体瘤中的反应评估标准）指南评估治疗后的肿瘤反应。
在12例患者中有6例观察到了具有客观临床反应的明显肿瘤消退，包括8例抗PD-1难治性疾病中的4例。反应包括在某些患者中大体积肿瘤的广泛消退和大多数肿瘤的完全消退。基因组研究包括具有二分治疗反应的住院患者肿瘤，揭示了抗原呈递关键成分和干扰素反应途径中的缺陷引起的耐药机制。
这些发现表明，工程改造的T细胞可以介导常见癌的消退，并且它们揭示了免疫编辑是对晚期上皮癌中细胞疗法和其他免疫疗法治愈潜力的限制。
据了解，基因工程T细胞疗法可在血液系统恶性肿瘤中诱导显著的肿瘤反应。但是，尚不知道这种疗法是否可以有效地应用于上皮癌，上皮癌占人类恶性肿瘤的80-90％。
附：英文原文
Title: TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers
Author: Nisha B. Nagarsheth, Scott M. Norberg, Andrew L. Sinkoe, Sabina Adhikary, Thomas J. Meyer, Justin B. Lack, Andrew C. Warner, Colleen Schweitzer, Stacey L. Doran, Soumya Korrapati, Sanja Stevanovi, Cornelia L. Trimble, Jennifer A. Kanakry, Mohammad Hadi Bagheri, Erin Ferraro, Stephanie H. Astrow, Adrian Bot, William C. Faquin, David Stroncek, Nikolaos Gkitsas, Steven Highfill, Christian S. Hinrichs
Issue&Volume: 2021-02-08
Abstract: Genetically engineered T cell therapy can induce remarkable tumor responses in hematologic malignancies. However, it is not known if this type of therapy can be applied effectively to epithelial cancers, which account for 80–90% of human malignancies. We have conducted a first-in-human, phase 1 clinical trial of T cells engineered with a T cell receptor targeting HPV-16 E7 for the treatment of metastatic human papilloma virus-associated epithelial cancers (NCT02858310). The primary endpoint was maximum tolerated dose. Cell dose was not limited by toxicity with a maximum dose of 1×1011 engineered T cells administered. Tumor responses following treatment were evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. Robust tumor regression was observed with objective clinical responses in 6 of 12 patients, including 4 of 8 patients with anti-PD-1 refractory disease. Responses included extensive regression of bulky tumors and complete regression of most tumors in some patients. Genomic studies, which included intra-patient tumors with dichotomous treatment responses, revealed resistance mechanisms from defects in critical components of the antigen presentation and interferon response pathways. These findings demonstrate that engineered T cells can mediate regression of common carcinomas, and they reveal immune editing as a constraint on the curative potential of cellular therapy and possibly other immunotherapies in advanced epithelial cancer.
DOI: 10.1038/s41591-020-01225-1
Source: https://www.nature.com/articles/s41591-020-01225-1
Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex
本期文章：《自然—医学》：Online/在线发表
