Shin Seung Kak, Mishima Yuta, Lee Yoonseok, Kwon Oh Sang, Kim Ju Hyun, Kim Yun Soo, Kaneko Shin
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea.
Laboratory of Cancer Immunotherapy and Immunology, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
J Gastroenterol Hepatol. 2025 Apr;40(4):791-807. doi: 10.1111/jgh.16872. Epub 2025 Jan 26.
Adoptive cell therapy (ACT) is a type of immunotherapy in which autologous or allogeneic immune cells, such as tumor-infiltrating lymphocytes or engineered lymphocytes, are infused into patients with cancer to eliminate malignant cells. Recently, autologous T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 showed a positive response in clinical studies for hematologic malignancies and have begun to be used in clinical practice. This article discusses the current status and promise of ACT research in hepatocellular carcinoma (HCC), focusing on challenges in off-the-shelf ACT using primary cells or induced pluripotent stem cells (iPSCs) with or without genetic engineering. Early clinical trials of autologous GPC-3-, MUC1-, or CEA-targeted CAR-T cell therapies are underway for HCC. There is a growing demand for the development of off-the-shelf therapies due to the high cost and manufacturing issues associated with autologous CAR-T. The development of ACT from various cell sources, such as NK cells, NKT cells, macrophages, and γδ T cells without MHC restriction other than T cells has been proposed. Advances in genome editing, including HLA gene knockout to avoid GvHD, and strategies to enhance efficacy in overcoming the suppressive tumor microenvironment, are used to create universal 'off-the-shelf' CAR-T cells which can be used immediately as therapeutic products from healthy donors or iPSC-derived immune cells. Despite several limitations, cell-based immunotherapy is expected to become a key cancer treatment modality for both hematologic malignancies and solid tumors including HCC, thanks to technological advancements overcoming these challenges.
过继性细胞疗法（ACT）是一种免疫疗法，其中将自体或异体免疫细胞，如肿瘤浸润淋巴细胞或工程化淋巴细胞，注入癌症患者体内以消除恶性细胞。最近，经改造以表达靶向CD19的嵌合抗原受体（CAR）的自体T细胞在血液系统恶性肿瘤的临床研究中显示出阳性反应，并已开始应用于临床实践。本文讨论了ACT在肝细胞癌（HCC）研究中的现状和前景，重点关注使用原代细胞或诱导多能干细胞（iPSC）进行现货ACT（off-the-shelf ACT）的挑战，无论是否进行基因工程改造。针对HCC的自体靶向GPC-3、MUC1或CEA的CAR-T细胞疗法的早期临床试验正在进行中。由于自体CAR-T的高成本和生产问题，对现货疗法的开发需求日益增长。有人提出从各种细胞来源开发ACT，如NK细胞、NKT细胞、巨噬细胞和γδT细胞（除T细胞外无MHC限制）。基因组编辑的进展，包括敲除HLA基因以避免移植物抗宿主病（GvHD），以及在克服抑制性肿瘤微环境方面提高疗效的策略，被用于创建通用的“现货”CAR-T细胞，这些细胞可立即用作来自健康供体或iPSC衍生免疫细胞的治疗产品。尽管存在一些局限性，但由于技术进步克服了这些挑战，基于细胞的免疫疗法有望成为血液系统恶性肿瘤和包括HCC在内的实体瘤的关键癌症治疗方式。
