Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia; Université de Paris, Inserm, U976 HIPI Unit, Institut de Recherche Saint-Louis, Paris, France; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia; School of Women's and Children's Health, UNSW Sydney, Sydney, Australia.
Ann Oncol. 2021 Nov;32(11):1366-1380. doi: 10.1016/j.annonc.2021.07.018. Epub 2021 Aug 8.
Chimeric antigen receptor (CAR)-T-cell therapy is a promising approach for the treatment of childhood cancers, particularly high-risk tumors that fail to respond to standard therapies. CAR-T cells have been highly successful in treating some types of hematological malignancies. However, CAR-T cells targeting solid cancers have had limited success so far for multiple reasons, including their poor long-term persistence and proliferation. Evidence is emerging to show that maintaining CAR-T cells in an early, less-differentiated state in vitro results in superior persistence, proliferation, and antitumor effects in vivo. Children are ideal candidates for receiving less-differentiated CAR-T cells, because their peripheral T-cell pool primarily comprises naïve cells that could readily be harvested in large numbers to generate early-phenotype CAR-T cells. Although several studies have reported different approaches to successfully generate early CAR-T cells, there are only a few clinical trials testing these in adult patients. No trials are currently testing early CAR-T cells in children. Here, we summarize the different strategies used to maintain CAR-T cells in an early phenotypic stage and present evidence suggesting that this approach may be particularly relevant to treating childhood cancers.
嵌合抗原受体 (CAR)-T 细胞疗法是治疗儿童癌症的一种很有前途的方法，特别是对那些对标准疗法没有反应的高危肿瘤。CAR-T 细胞在治疗某些类型的血液恶性肿瘤方面非常成功。然而，到目前为止，针对实体瘤的 CAR-T 细胞的疗效有限，原因有多种，包括其长期持久性和增殖性差。有证据表明，在体外将 CAR-T 细胞保持在早期、低分化状态可导致体内更好的持久性、增殖性和抗肿瘤效果。儿童是接受低分化 CAR-T 细胞的理想人选，因为他们的外周 T 细胞池主要由幼稚细胞组成，可以大量采集这些细胞来产生早期表型 CAR-T 细胞。尽管有几项研究报告了成功生成早期 CAR-T 细胞的不同方法，但只有少数临床试验在成人患者中测试了这些方法。目前没有临床试验在儿童中测试早期 CAR-T 细胞。在这里，我们总结了用于将 CAR-T 细胞维持在早期表型阶段的不同策略，并提出了证据表明，这种方法可能特别适用于治疗儿童癌症。
