美国加州大学Lili Yang团队近期取得重要工作进展，他们研究利用临床指导的培养方法从造血干细胞和祖细胞中生成异体CAR-NKT细胞。相关研究成果2024年5月14日在线发表于《自然—生物技术》杂志上。

据介绍，使用自体嵌合抗原受体（CAR）T细胞的癌症免疫疗法在制造和患者选择方面面临挑战，可以通过使用“现成”产品（如同种异体CAR自然杀伤T（^AlloCAR-NKT）细胞）来避免这些挑战。

此前，研究人员报道了一种将人造血干细胞和祖细胞分化为^AlloCAR NKT细胞的系统，但三维培养和异种饲养器的使用阻碍了其临床应用。研究人员描述了一种临床指导的方法，以高产率和高纯度分化和扩增IL-15增强的^AlloCAR NKT细胞。研究人员生成了靶向七种癌症的^AlloCAR NKT细胞，并在多发性骨髓瘤模型中证明了它们的抗肿瘤功效、扩展性和持久性。

这些细胞还选择性地耗尽肿瘤微环境中的免疫抑制细胞，并通过CAR、TCR和NK受体的三重靶向拮抗肿瘤免疫逃避。它们表现出与表观遗传学和信号调节相关的稳定的低免疫原性表型，并且没有诱导可检测的移植物抗宿主疾病或细胞因子释放综合征。

总之，^AlloCAR NKT细胞的这些特性支持其在临床转化中的潜力。

附：英文原文

Title: Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method

Author: Li, Yan-Ruide, Zhou, Yang, Yu, Jiaji, Kim, Yu Jeong, Li, Miao, Lee, Derek, Zhou, Kuangyi, Chen, Yuning, Zhu, Yichen, Wang, Yu-Chen, Li, Zhe, Yu, Yanqi, Dunn, Zachary Spencer, Guo, Wenbin, Cen, Xinjian, Husman, Tiffany, Bajpai, Aarushi, Kramer, Adam, Wilson, Matthew, Fang, Ying, Huang, Jie, Li, Shuo, Zhou, Yonggang, Zhang, Yuchong, Hahn, Zoe, Zhu, Enbo, Ma, Feiyang, Pan, Calvin, Lusis, Aldons J., Zhou, Jin J., Seet, Christopher S., Kohn, Donald B., Wang, Pin, Zhou, Xianghong Jasmine, Pellegrini, Matteo, Puliafito, Benjamin R., Larson, Sarah M., Yang, Lili

Issue&Volume: 2024-05-14

Abstract: Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using ‘off-the-shelf’ products, such as allogeneic CAR natural killer T (AlloCAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem and progenitor cells into AlloCAR-NKT cells, but the use of three-dimensional culture and xenogeneic feeders precluded its clinical application. Here we describe a clinically guided method to differentiate and expand IL-15-enhanced AlloCAR-NKT cells with high yield and purity. We generated AlloCAR-NKT cells targeting seven cancers and, in a multiple myeloma model, demonstrated their antitumor efficacy, expansion and persistence. The cells also selectively depleted immunosuppressive cells in the tumor microenviroment and antagonized tumor immune evasion via triple targeting of CAR, TCR and NK receptors. They exhibited a stable hypoimmunogenic phenotype associated with epigenetic and signaling regulation and did not induce detectable graft versus host disease or cytokine release syndrome. These properties of AlloCAR-NKT cells support their potential for clinical translation.

DOI: 10.1038/s41587-024-02226-y

Source: https://www.nature.com/articles/s41587-024-02226-y