Zhang Jianxiang, Wang Lingyu
1 The High School Affiliated to Renmin University, Beijing, People's Republic of China.
2 Department of Biology, Duke University, Durham, NC, USA.
Technol Cancer Res Treat. 2019 Jan 1;18:1533033819831068. doi: 10.1177/1533033819831068.
T-cell receptor-engineered T-cell therapy and chimeric antigen receptor T-cell therapy are 2 types of adoptive T-cell therapy that genetically modify natural T cells to treat cancers. Although chimeric antigen receptor T-cell therapy has yielded remarkable efficacy for hematological malignancies of the B-cell lineages, most solid tumors fail to respond significantly to chimeric antigen receptor T cells. T-cell receptor-engineered T-cell therapy, on the other hand, has shown unprecedented promise in treating solid tumors and has attracted growing interest. In order to create an unbiased, comprehensive, and scientific report for this fast-moving field, we carefully analyzed all 84 clinical trials using T-cell receptor-engineered T-cell therapy and downloaded from ClinicalTrials.gov updated by June 11, 2018. Informative features and trends were observed in these clinical trials. The number of trials initiated each year is increasing as expected, but an interesting pattern is observed. NY-ESO-1, as the most targeted antigen type, is the target of 31 clinical trials; melanoma is the most targeted cancer type and is the target of 33 clinical trials. Novel antigens and underrepresented cancers remain to be targeted in future studies and clinical trials. Unlike chimeric antigen receptor T-cell therapy, only about 16% of the 84 clinical trials target against hematological malignancies, consistent with T-cell receptor-engineered T-cell therapy's high potential for solid tumors. Six pharma/biotech companies with novel T-cell receptor-engineered T-cell ideas and products were examined in this review. Multiple approaches have been utilized in these companies to increase the T-cell receptor's affinity and efficiency and to minimize cross-reactivity. The major challenges in the development of the T-cell receptor-engineered T-cell therapy due to tumor microenvironment were also discussed here.
T细胞受体工程化T细胞疗法和嵌合抗原受体T细胞疗法是两种过继性T细胞疗法,它们通过对天然T细胞进行基因改造来治疗癌症。尽管嵌合抗原受体T细胞疗法已在B细胞系血液恶性肿瘤中取得显著疗效,但大多数实体瘤对嵌合抗原受体T细胞的反应并不明显。另一方面,T细胞受体工程化T细胞疗法在治疗实体瘤方面显示出前所未有的前景,并引起了越来越多的关注。为了为这个快速发展的领域撰写一份客观、全面且科学的报告,我们仔细分析了从ClinicalTrials.gov下载的、截至2018年6月11日更新的所有84项使用T细胞受体工程化T细胞疗法的临床试验。在这些临床试验中观察到了丰富的特征和趋势。每年启动的试验数量正如预期那样在增加,但也观察到了一个有趣的模式。NY-ESO-1作为最常被靶向的抗原类型,是31项临床试验的靶点;黑色素瘤是最常被靶向的癌症类型,是33项临床试验的靶点。新型抗原和研究及临床试验中较少涉及的癌症仍有待作为靶点。与嵌合抗原受体T细胞疗法不同,在这84项临床试验中,只有约16%的试验针对血液恶性肿瘤,这与T细胞受体工程化T细胞疗法在实体瘤方面的巨大潜力相符。本综述考察了六家拥有新型T细胞受体工程化T细胞理念和产品的制药/生物技术公司。这些公司采用了多种方法来提高T细胞受体的亲和力和效率,并尽量减少交叉反应性。本文还讨论了由于肿瘤微环境导致的T细胞受体工程化T细胞疗法开发中的主要挑战。