Stern Lawrence A, Jonsson Vanessa D, Priceman Saul J
Department of Hematology and Hematopoietic Cell Transplantation, Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
Cancer Treat Res. 2020;180:297-326. doi: 10.1007/978-3-030-38862-1_11.
The past two decades have marked the beginning of an unprecedented success story for cancer therapy through redirecting antitumor immunity [1]. While the mechanisms that control the initial and ongoing immune responses against tumors remain a strong research focus, the clinical development of technologies that engage the immune system to target and kill cancer cells has become a translational research priority. Early attempts documented in the late 1800s aimed at sparking immunity with cancer vaccines were difficult to interpret but demonstrated an opportunity that more than 100 years later has blossomed into the current field of cancer immunotherapy. Perhaps the most recent and greatest illustration of this is the widespread appreciation that tumors actively shut down antitumor immunity, which has led to the emergence of checkpoint pathway inhibitors that re-invigorate the body's own immune system to target cancer [2, 3]. This class of drugs, with first FDA approvals in 2011, has demonstrated impressive durable clinical responses in several cancer types, including melanoma, lung cancer, Hodgkin's lymphoma, and renal cell carcinoma, with the ongoing investigation in others. The biology and ultimate therapeutic successes of these drugs led to the 2018 Nobel Prize in Physiology or Medicine, awarded to Dr. James Allison and Dr. Tasuku Honjo for their contributions to cancer therapy [4]. In parallel to the emerging science that aided in unleashing the body's own antitumor immunity with checkpoint pathway inhibitors, researchers were also identifying ways to re-engineer antitumor immunity through adoptive cellular immunotherapy approaches. Chimeric antigen receptor (CAR)-based T cell therapy has achieved an early head start in the field, with two recent FDA approvals in 2017 for the treatment of B-cell malignancies [5]. There is an explosion of preclinical and clinical efforts to expand the therapeutic indications for CAR T cell therapies, with a specific focus on improving their clinical utility, particularly for the treatment of solid tumors. In this chapter, we will highlight the recent progress, challenges, and future perspectives surrounding the development of CAR T cell therapies for solid tumors.
在过去二十年里，通过重定向抗肿瘤免疫开启了癌症治疗前所未有的成功篇章[1]。虽然控制针对肿瘤的初始和持续免疫反应的机制仍是研究重点，但利用免疫系统靶向并杀死癌细胞的技术的临床开发已成为转化研究的优先事项。19世纪后期记录的早期尝试旨在通过癌症疫苗激发免疫，但难以解读，不过显示出一个机会，100多年后这个机会已发展成为当前的癌症免疫治疗领域。或许对此最新、最有力的例证是，人们普遍认识到肿瘤会主动关闭抗肿瘤免疫，这导致了检查点通路抑制剂的出现，这些抑制剂可重振人体自身免疫系统以靶向癌症[2,3]。这类药物于2011年首次获得美国食品药品监督管理局（FDA）批准，已在多种癌症类型中展现出令人印象深刻的持久临床反应，包括黑色素瘤、肺癌、霍奇金淋巴瘤和肾细胞癌，其他癌症类型的研究也在进行中。这些药物的生物学特性和最终治疗成功促使2018年诺贝尔生理学或医学奖授予詹姆斯·艾利森博士和本庶佑博士，以表彰他们对癌症治疗的贡献[4]。与借助检查点通路抑制剂释放人体自身抗肿瘤免疫的新兴科学并行，研究人员也在通过过继性细胞免疫治疗方法寻找重新设计抗肿瘤免疫的途径。基于嵌合抗原受体（CAR）的T细胞疗法已在该领域率先起步，2017年FDA最近批准了两种用于治疗B细胞恶性肿瘤的疗法[5]。为扩大CAR T细胞疗法的治疗适应症，开展了大量临床前和临床研究工作，特别关注提高其临床效用，尤其是用于治疗实体瘤。在本章中，我们将重点介绍实体瘤CAR T细胞疗法开发的最新进展、挑战及未来前景。
