Stransky Nicolai, Ji Ranran, Prause Lukas, Ganser Katrin, Wels Winfried S, Ruth Peter, Huber Stephan M, Eckert Franziska
Department of Radiation Oncology, University Hospital Tübingen, 72076 Tübingen, Germany.
Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tübingen, 72076 Tübingen, Germany.
iScience. 2025 Apr 23;28(5):112523. doi: 10.1016/j.isci.2025.112523. eCollection 2025 May 16.
Chimeric antigen receptors - natural killer (CAR-NK) cells are a promising new cancer treatment approach. They possess distinct benefits over CAR-T cells, including an intrinsic ability to differentiate between malignant and non-malignant cells, and a lower risk of graft-versus-host disease. Here, we evaluated two CAR-NK-92 cell lines, targeting either CD276 or HER2, and their potential on-target/off-tumor effects . CD276-directed CAR-NK-92 cells showed little dependence on target antigen density, while HER2-directed CAR-NK-92 displayed a pronounced dependence on target antigen density, mostly sparing target cells with low amounts of HER2. The activity of both cell lines was modulated by the expression of HLA-I on target cells, ultimately reducing their activity against non-malignant cells. Lower modulation of activity of HER2-directed CAR-NK-92 can be explained by the lower surface expression of inhibitory NK receptors, such as NKG2A and ILT-2. These results underscore the importance of thoroughly testing new cell products to fine-tune anti-cancer activity, while limiting potential on-target/off-tumor toxicity.
嵌合抗原受体 - 自然杀伤（CAR-NK）细胞是一种很有前景的新型癌症治疗方法。与CAR-T细胞相比，它们具有明显的优势，包括能够在恶性细胞和非恶性细胞之间进行区分的内在能力，以及较低的移植物抗宿主病风险。在此，我们评估了两种靶向CD276或HER2的CAR-NK-92细胞系，以及它们潜在的靶向肿瘤外效应。靶向CD276的CAR-NK-92细胞对靶抗原密度的依赖性较小，而靶向HER2的CAR-NK-92细胞对靶抗原密度有明显的依赖性，大多放过HER2含量低的靶细胞。两种细胞系的活性均受靶细胞上HLA-I表达的调节，最终降低了它们对非恶性细胞的活性。靶向HER2的CAR-NK-92细胞活性的较低调节可通过抑制性NK受体（如NKG2A和ILT-2）较低的表面表达来解释。这些结果强调了全面测试新细胞产品以微调抗癌活性、同时限制潜在的靶向肿瘤外毒性的重要性。
