Koh Seung Kwon, Kim Hyojin, Han Bohwa, Jo Hantae, Doh Junsang, Park Jeehun, Nguyen Minh Ha, Kim Hyun-Young, Kim Haneul, Lee Seung-Hwan, Kim Chan Hyuk, Cho Duck
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Blood. 2025 Feb 27;145(9):956-969. doi: 10.1182/blood.2024025673.
Anti-CD19 chimeric antigen receptor (CAR)-engineered T and natural killer (NK) cell therapies have revolutionized the treatment of B-cell malignancies, but challenges including CD19 antigen loss greatly hinder their full therapeutic potential. Here, we revealed that cotreatment with anti-CD19 monoclonal antibody enhances antitumor activity of anti-CD19 CAR-T and -NK cells. Even though the treated antibody interferes with CD19 antigen binding of CAR, it significantly induces rapid detachment of anti-CD19 CAR effector cells from target cells, facilitating improved serial killing. This reduced interaction between CAR effector cells and target cells also leads to the alleviation of CAR-mediated trogocytosis. Interestingly, cotreatment with anti-CD19 antibody reveals time-dependent effects on the antitumor activity of anti-CD19 CAR-T cells, characterized by a reduction in early T cell activation followed by sustained high activity during prolonged exposure to target cells. This temporal modulation ultimately results in enhanced antitumor potency in vivo. These findings underscore the improved therapeutic efficacy achieved by combining anti-CD19 antibody with anti-CD19 CAR-T or -NK cells against B-cell malignancies.
抗CD19嵌合抗原受体（CAR）工程化T细胞和自然杀伤（NK）细胞疗法彻底改变了B细胞恶性肿瘤的治疗方式，但包括CD19抗原丢失在内的挑战极大地阻碍了它们的全部治疗潜力。在此，我们发现抗CD19单克隆抗体联合治疗可增强抗CD19 CAR-T细胞和NK细胞的抗肿瘤活性。尽管所使用的抗体干扰了CAR与CD19抗原的结合，但它能显著诱导抗CD19 CAR效应细胞从靶细胞上快速脱离，从而促进连续杀伤作用的改善。CAR效应细胞与靶细胞之间这种减少的相互作用也导致CAR介导的胞啃作用减轻。有趣的是，抗CD19抗体联合治疗对抗CD19 CAR-T细胞的抗肿瘤活性呈现出时间依赖性效应，其特征是早期T细胞活化减少，随后在长时间接触靶细胞期间保持高活性。这种时间上的调节最终导致体内抗肿瘤效力增强。这些发现强调了将抗CD19抗体与抗CD19 CAR-T细胞或NK细胞联合用于治疗B细胞恶性肿瘤可提高治疗效果。
