Schindler-Wnek Katharina, Stahringer Anika, Heimer Nadine, Koehl Ulrike, Fricke Stephan, Schmiedel Dominik
Department for Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.
Department for Internal Medicine III, Klinikum Chemnitz gGmbH, Chemnitz, Germany.
Oncoimmunology. 2025 Dec;14(1):2546443. doi: 10.1080/2162402X.2025.2546443. Epub 2025 Sep 5.
CAR-based cell therapies have shown clinical success in treating various cancers, with CAR T cell therapies entering the clinical route and CAR NK cell therapies being evaluated in early-stage clinical trials. A key challenge is the presence of tumor-associated antigens on healthy cells, risking on-target off-tumor toxicities. Our comparative analysis of CAR T and CAR NK cells targeting the multiple myeloma-associated antigens BCMA, SLAMF7, and CD38 revealed that antigen density on target cells significantly modulates CAR NK cell activation and cytotoxicity. The cytotoxic potential of CAR NK cells was comparable to that of CAR T cells when targeting BCMA and CD38, but notable differences were observed in SLAMF7-directed CAR cells. While CAR sensitivity was similar in both cell types, CAR NK cell activity was balanced by inhibitory receptors like KIRs and NKG2A. This balance allows effective tumor control while potentially reducing on-target off-tumor effects on healthy cells with low antigen expression. Consequently, CAR NK cells offer greater flexibility in target antigen selection, potentially expanding the range of targetable antigens for cancer immunotherapy.
基于嵌合抗原受体（CAR）的细胞疗法在治疗多种癌症方面已取得临床成功，CAR T细胞疗法已进入临床应用阶段，CAR NK细胞疗法正在早期临床试验中接受评估。一个关键挑战是健康细胞上存在肿瘤相关抗原，存在脱靶肿瘤毒性的风险。我们对靶向多发性骨髓瘤相关抗原BCMA、信号淋巴细胞激活分子家族7（SLAMF7）和CD38的CAR T细胞和CAR NK细胞进行的比较分析表明，靶细胞上的抗原密度显著调节CAR NK细胞的激活和细胞毒性。当靶向BCMA和CD38时，CAR NK细胞的细胞毒性潜力与CAR T细胞相当，但在靶向SLAMF7的CAR细胞中观察到显著差异。虽然两种细胞类型对CAR的敏感性相似，但CAR NK细胞的活性受到抑制性受体（如杀伤细胞免疫球蛋白样受体（KIRs）和NKG2A）的平衡。这种平衡允许有效控制肿瘤，同时可能减少对低抗原表达的健康细胞的脱靶肿瘤效应。因此，CAR NK细胞在靶抗原选择上具有更大的灵活性，有可能扩大癌症免疫治疗的可靶向抗原范围。
