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

IF 4.3 3区 生物学 Human Cell Pub Date : 2024-05-01 DOI:10.1007/s13577-024-01066-x
Xiaoyan Wang, Guodong Liu, Xianggang Shi, Yuxing Wang, Bo Jiang, Wei Liu, Anran Dai, Xiangzhi Zhang, Feng Yu
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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.

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过表达 Bcl-2 可增强小鼠嵌合抗原受体 T 细胞治疗实体瘤的效果
嵌合抗原受体 T(CART)细胞疗法在治疗血液系统恶性肿瘤方面具有广阔的前景。然而,由于肿瘤微环境的限制性,它在实体瘤中的应用受到了限制,导致 CART 细胞功能失效且存活率低。研究发现,在人 CART 细胞(hCART)中过表达 Bcl-2 可显著增强其在体外和体内的抗凋亡作用。然而,在临床前研究中对 hCART 细胞的评估主要依赖于免疫缺陷小鼠异种移植肿瘤模型,这使得评估 hCART 细胞对正常组织和免疫系统的影响具有挑战性。我们建立了一种过度表达 Bcl-2、靶向表皮生长因子受体变体 III(EGFRvIII)的小鼠 CART(mCART),命名为 EGFRvIII-mCART-Bcl2。它在体外表现出卓越的增殖、细胞毒性和抗凋亡能力。在免疫功能正常的结直肠癌腹腔转移小鼠模型中,EGFRvIII-mCART-Bcl2 改善了腹腔内 CART 的存活率,提高了肿瘤清除率,并显著延长了小鼠的总存活率。总之,我们的研究提供了证据,证明在 mCART 细胞中引入 Bcl-2 可提高其对实体瘤的疗效,同时确保安全性。
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来源期刊
Human Cell
Human Cell 生物-细胞生物学
CiteScore
6.60
自引率
2.30%
发文量
176
期刊介绍: Human Cell is the official English-language journal of the Japan Human Cell Society. The journal serves as a forum for international research on all aspects of the human cell, encompassing not only cell biology but also pathology, cytology, and oncology, including clinical oncology. Embryonic stem cells derived from animals, regenerative medicine using animal cells, and experimental animal models with implications for human diseases are covered as well. Submissions in any of the following categories will be considered: Research Articles, Cell Lines, Rapid Communications, Reviews, and Letters to the Editor. A brief clinical case report focusing on cellular responses to pathological insults in human studies may also be submitted as a Letter to the Editor in a concise and short format. Not only basic scientists but also gynecologists, oncologists, and other clinical scientists are welcome to submit work expressing new ideas or research using human cells.
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