Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China.
Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan Er Road, Guangzhou, 510280, Guangdong, China.
J Hematol Oncol. 2024 Nov 5;17(1):105. doi: 10.1186/s13045-024-01625-7.
Chimeric antigen receptor (CAR)-T cell therapy demonstrates substantial efficacy in various hematological malignancies. However, its application in solid tumors is still limited. Clinical studies report suboptimal outcomes such as reduced cytotoxicity of CAR-T cells and tumor evasion, underscoring the need to address the challenges of sliding cytotoxicity in CAR-T cells. Despite improvements from fourth and next-generation CAR-T cells, new challenges include systemic toxicity from continuously secreted proteins, low productivity, and elevated costs. Recent research targets genetic modifications to boost killing potential, metabolic interventions to hinder tumor progression, and diverse combination strategies to enhance CAR-T cell therapy. Efforts to reduce the duration and cost of CAR-T cell therapy include developing allogenic and in-vivo approaches, promising significant future advancements. Concurrently, innovative technologies and platforms enhance the potential of CAR-T cell therapy to overcome limitations in treating solid tumors. This review explores strategies to optimize CAR-T cell therapies for solid tumors, focusing on enhancing cytotoxicity and overcoming application restrictions. We summarize recent advances in T cell subset selection, CAR-T structural modifications, infiltration enhancement, genetic and metabolic interventions, production optimization, and the integration of novel technologies, presenting therapeutic approaches that could improve CAR-T cell therapy's efficacy and applicability in solid tumors.
嵌合抗原受体 (CAR)-T 细胞疗法在各种血液恶性肿瘤中显示出显著的疗效。然而,其在实体瘤中的应用仍然有限。临床研究报告了不理想的结果,例如 CAR-T 细胞的细胞毒性降低和肿瘤逃逸,这凸显了需要解决 CAR-T 细胞滑动细胞毒性的挑战。尽管第四代和下一代 CAR-T 细胞有所改进,但新的挑战包括连续分泌蛋白的全身毒性、低生产率和成本升高。最近的研究目标是通过基因修饰来提高杀伤潜力、代谢干预来阻碍肿瘤进展以及采用多种组合策略来增强 CAR-T 细胞疗法。减少 CAR-T 细胞疗法的持续时间和成本的努力包括开发同种异体和体内方法,有望取得重大的未来进展。同时,创新技术和平台增强了 CAR-T 细胞疗法治疗实体瘤的潜力,克服了其在治疗实体瘤方面的限制。本综述探讨了优化 CAR-T 细胞疗法治疗实体瘤的策略,重点是增强细胞毒性和克服应用限制。我们总结了 T 细胞亚群选择、CAR-T 结构修饰、浸润增强、遗传和代谢干预、生产优化以及新型技术整合方面的最新进展,提出了可能提高 CAR-T 细胞疗法在实体瘤中的疗效和适用性的治疗方法。
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