Nakayama Izuma, Shitara Kohei
Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Am Soc Clin Oncol Educ Book. 2025 Jan;45(1):e471716. doi: 10.1200/EDBK-25-471716. Epub 2025 Jan 22.
Cell-based therapies have become integral to the routine clinical management of hematologic malignancies. Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated efficacy in immunogenic solid tumors, such as melanoma. However, in the GI field, evidence supporting the clinical success of cell-based therapies is still awaited. CLDN18.2, a key tight junction molecule in stomach epithelium, has emerged as a promising target for gastric cancer (GC) treatment. Because of its lineage-specific expression, significant efforts have been made to develop chimeric antigen receptor T-cell (CAR-T) therapies targeting CLDN18.2. These therapies have shown encouraging tumor shrinkage in patients with heavily pretreated GC. However, durable responses remain uncommon. CAR-T exhaustion driven by immune-suppressive cells in the tumor microenvironment, along with the heterogeneous expression of target molecules, poses significant challenges. In addition, managing on-target, off-tumor toxicities remains a critical issue in therapies targeting tissue-associated antigens. Next-generation CARs are expected to address these resistance mechanisms. Furthermore, adoptive macrophage and natural killer cell therapies hold promise for not only their efficacy but also for the ease off-the-shelf production. Advanced neoantigen prediction and identification of optimal T-cell activation targets could facilitate the clinical application of TIL and T-cell receptor-T therapies in GI cancers. Cell-based therapies might have the potential to transform the treatment landscape for GI cancers.
基于细胞的疗法已成为血液系统恶性肿瘤常规临床管理的重要组成部分。肿瘤浸润淋巴细胞（TIL）疗法已在免疫原性实体瘤（如黑色素瘤）中显示出疗效。然而，在胃肠领域，支持基于细胞疗法临床成功的证据仍有待证实。CLDN18.2是胃上皮细胞中的一种关键紧密连接分子，已成为胃癌（GC）治疗的一个有前景的靶点。由于其谱系特异性表达，人们已做出重大努力来开发靶向CLDN18.2的嵌合抗原受体T细胞（CAR-T）疗法。这些疗法在经过大量预处理的GC患者中显示出令人鼓舞的肿瘤缩小情况。然而，持久反应仍然不常见。肿瘤微环境中免疫抑制细胞驱动的CAR-T耗竭，以及靶分子的异质性表达，带来了重大挑战。此外，管理靶向非肿瘤毒性仍然是针对组织相关抗原的疗法中的一个关键问题。预计下一代CARs将解决这些耐药机制。此外，过继性巨噬细胞和自然杀伤细胞疗法不仅因其疗效，而且因其易于现货生产而具有前景。先进的新抗原预测和最佳T细胞激活靶点的鉴定可能会促进TIL和T细胞受体-T疗法在胃肠道癌症中的临床应用。基于细胞的疗法可能有潜力改变胃肠道癌症的治疗格局。
