Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China.
Department of Biotherapy, Jinling Hospital of Nanjing University School of Medicine, Nanjing, 210002, China.
Cancer Immunol Immunother. 2023 Feb;72(2):409-425. doi: 10.1007/s00262-022-03238-w. Epub 2022 Aug 4.
Recently, chimeric antigen receptor T cell (CAR-T) therapy has received increasing attention as an adoptive cellular immunotherapy that targets tumors. However, numerous challenges remain for the effective use of CAR-T to treat solid tumors, including ovarian cancer, which is an aggressive and metastatic cancer with a poor therapeutic response. We screened for an effective anti-MSLN single-chain Fv antibody with comparable binding activity and non-off-target properties using human phage display library. A second-generation of anti-MSLN CAR was designed and generated. We demonstrated the efficacy of our anti-MSLN CAR-T cells for ovarian cancer treatment in an in vitro experiment to kill ovarian tumor cell lines. The anti-MSLN CAR-T cells impeded MSLN-positive tumor growth concomitant with a significant increase in cytokine levels compared with the control. Then, we demonstrated the efficacy of anti-MSLN CAR-T cells in an in vivo experiment against ovarian cancer cell-derived xenografts. Furthermore, we herein report three cases with ovarian cancer who were treated with autologous anti-MSLN CAR-T cells and evaluate the safety and effectiveness of adoptive cell therapy. In this investigator-initiated clinical trials, no patients experienced cytokine release syndrome or neurological symptoms over 2 grads. Disease stabilized in two patients, with progression-free survival times of 5.8 and 4.6 months. Transient CAR expression was detected in patient blood after infusion each time. The tumor partially subsided, and the patient's condition was relieved. In conclusion, this work proves the efficacy of the anti-MSLN CAR-T treatment strategy in ovarian cancer and provides preliminary data for the development of further clinical trials.
最近，嵌合抗原受体 T 细胞（CAR-T）疗法作为一种针对肿瘤的过继细胞免疫疗法受到了越来越多的关注。然而，CAR-T 有效治疗实体瘤（包括卵巢癌）仍存在许多挑战，卵巢癌是一种侵袭性和转移性癌症，治疗反应较差。我们使用人噬菌体展示文库筛选出具有可比结合活性和非脱靶特性的有效抗 MSLN 单链 Fv 抗体。设计并生成了第二代抗 MSLN CAR。我们在体外实验中证明了我们的抗 MSLN CAR-T 细胞对卵巢癌细胞系的杀伤效力，用于治疗卵巢癌。与对照相比，抗 MSLN CAR-T 细胞抑制了 MSLN 阳性肿瘤的生长，并伴随着细胞因子水平的显著增加。然后，我们在卵巢癌细胞衍生的异种移植的体内实验中证明了抗 MSLN CAR-T 细胞的疗效。此外，我们在此报告了三例接受自体抗 MSLN CAR-T 细胞治疗的卵巢癌患者，并评估了过继细胞疗法的安全性和有效性。在这项由研究者发起的临床试验中，没有患者出现 2 级以上的细胞因子释放综合征或神经症状。两名患者的疾病稳定，无进展生存期分别为 5.8 个月和 4.6 个月。每次输注后，患者血液中均可检测到短暂的 CAR 表达。肿瘤部分消退，患者病情缓解。总之，这项工作证明了抗 MSLN CAR-T 治疗策略在卵巢癌中的疗效，并为进一步临床试验的开展提供了初步数据。
