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过表达 Bcl-2 增强了针对实体瘤的嵌合抗原受体 T 细胞治疗。

Overexpressing Bcl-2 enhances murine chimeric antigen receptor T cell therapy against solid tumor.

机构信息

Department of Gastroenterology, Suqian First People's Hospital, Suqian, 223800, Jiangsu, China.

Department of General Surgery, Suqian First People's Hospital, Suqian, 223800, Jiangsu, China.

出版信息

Hum Cell. 2024 Jul;37(4):1107-1119. doi: 10.1007/s13577-024-01066-x. Epub 2024 May 1.

Abstract

Chimeric antigen receptor T (CART) cell therapy has demonstrated promising potential in the treatment of hematologic malignancies. However, its application to solid tumors is limited due to the restrictive nature of the tumor microenvironment, resulting in functional failure and poor persistence of CART cells. Overexpression of Bcl-2 in human CART cells (hCART) has been found to significantly enhance their anti-apoptotic effects both in vitro and in vivo. Nevertheless, the evaluation of hCART cells in preclinical studies has predominantly relied on immunodeficient mice xenograft tumor models, making it challenging to assess the impact of hCART cells on normal tissues and the immune system. We established a murine CART (mCART) that overexpresses Bcl-2 and targets the epidermal growth factor receptor variant III (EGFRvIII), named EGFRvIII·mCART-Bcl2. It demonstrated superior proliferation, cytotoxicity, and anti-apoptotic capabilities in vitro. In an immunocompetent mouse model of abdominal metastasis of colorectal cancer, EGFRvIII·mCART-Bcl2 exhibited improved survival of CART in the abdomen, increased tumor clearance, and significantly prolonged overall mouse survival. In summary, our study provides evidence that the introduction of Bcl-2 into mCART cells can enhance their therapeutic efficacy against solid tumors while ensuring safety.

摘要

嵌合抗原受体 T(CART)细胞疗法在治疗血液恶性肿瘤方面显示出了巨大的潜力。然而,由于肿瘤微环境的限制,其在实体瘤中的应用受到限制,导致 CART 细胞功能衰竭和持久性差。在体外和体内实验中,人 CART 细胞(hCART)中 Bcl-2 的过表达已被证实能显著增强其抗凋亡作用。尽管如此,hCART 细胞在临床前研究中的评估主要依赖于免疫缺陷小鼠异种移植肿瘤模型,因此难以评估 hCART 细胞对正常组织和免疫系统的影响。我们构建了一种过表达 Bcl-2 并靶向表皮生长因子受体变异体 III(EGFRvIII)的小鼠 CART(mCART),命名为 EGFRvIII·mCART-Bcl2。它在体外表现出优越的增殖、细胞毒性和抗凋亡能力。在结直肠癌腹腔转移的免疫功能正常的小鼠模型中,EGFRvIII·mCART-Bcl2 提高了 CART 在腹部的存活率,增加了肿瘤清除率,并显著延长了小鼠的总生存期。综上所述,我们的研究表明,将 Bcl-2 导入 mCART 细胞可以增强其对实体瘤的治疗效果,同时保证安全性。

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