Lin Haolong, Zhang Lingfeng, Ge Tong, An Ning, Yang Yongkun, Zhang Yicheng, Mu Wei
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, P. R. China.
Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, 430030, Hubei, China.
J Transl Med. 2025 Apr 8;23(1):409. doi: 10.1186/s12967-025-06432-3.
The therapeutic application of chimeric antigen receptor (CAR) T cells in T-cell malignancies faces substantial limitations owing to fratricide and potential T cell aplasia, primarily attributed to the shared expression of target antigens, such as CD5, between normal and malignant T cells. Although natural killer (NK) cell-based immunotherapy is a promising alternative approach, its efficacy in treating hematologic malignancies remains to be fully elucidated.
CD5-targeted CAR-modified primary NK cells, T cells and NK92 cell lines were generated and comprehensively evaluated for their anti-tumor efficacy through in vitro cytotoxicity assays and xenograft mouse models. Furthermore, preliminary investigation of the herpes simplex virus-1 thymidine kinase (HSV-TK) suicide switch system in CAR-NK cells were conducted using ganciclovir (GCV) as the activating agent.
CAR-NK cells exhibited significantly increased cytotoxic activity against CD5-positive cell lines and primary tumor cells, compared to NK, CAR-NK92, and CAR-T cells. Moreover, CAR-NK cells effectively decreased the leukemic burden and extended survival in murine model. Additionally, an off-switch utilizing the HSV-TK switch system successfully eradicated CAR-NK cells for safety considerations.
This study developed a controllable CD5 CAR-NK cells that exhibit high efficacy against T-cell malignancies, although further validation is necessary to assess their clinical potential.
嵌合抗原受体（CAR）T细胞在T细胞恶性肿瘤中的治疗应用面临诸多重大限制，原因在于细胞间杀伤作用以及潜在的T细胞发育不全，这主要归因于正常T细胞和恶性T细胞之间存在共同表达的靶抗原，如CD5。尽管基于自然杀伤（NK）细胞的免疫疗法是一种很有前景的替代方法，但其在治疗血液系统恶性肿瘤方面的疗效仍有待充分阐明。
构建了靶向CD5的CAR修饰的原代NK细胞、T细胞和NK92细胞系，并通过体外细胞毒性试验和异种移植小鼠模型全面评估了它们的抗肿瘤疗效。此外，以更昔洛韦（GCV）作为激活剂，对CAR-NK细胞中的单纯疱疹病毒1型胸苷激酶（HSV-TK）自杀开关系统进行了初步研究。
与NK细胞、CAR-NK92细胞和CAR-T细胞相比，CAR-NK细胞对CD5阳性细胞系和原发性肿瘤细胞表现出显著增强的细胞毒性活性。此外，CAR-NK细胞在小鼠模型中有效降低了白血病负担并延长了生存期。另外，出于安全考虑，利用HSV-TK开关系统的关闭开关成功清除了CAR-NK细胞。
本研究开发了一种可控的CD5 CAR-NK细胞，其对T细胞恶性肿瘤具有高效性，不过仍需进一步验证以评估其临床潜力。
