Ma Jing, Sarén Tina, Jin Chuan, Kim Hyeong Su, Contreras Pineda Paola Donaji, de Bernard Marina, Amini Rose-Marie, Rondahl Veronica, Enblad Gunilla, Yu Di, Essand Magnus
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Hallym University Medical Center, Seoul, South Korea.
Cancer Immunol Immunother. 2025 Jul 12;74(8):262. doi: 10.1007/s00262-025-04112-1.
CD19 CAR-T cell therapy shows striking results in treating B cell malignancies. However, approximately two-thirds of the lymphoma patients eventually relapse, with about one-third displaying CD19-negative tumors at relapse. Our previous study showed that CAR-T cells armed with the Helicobacter pylori neutrophil-activating protein (NAP), CAR(NAP)-T cells, can trigger a bystander immune response and eliminate CAR-target-antigen-negative tumor cells. Here, we report the development of CD20-targeted CAR-T cells (CAR20-T cells), with the targeting moiety from rituximab, and the safety and efficacy of NAP-armed CAR-T cells. CAR20-T cells displayed efficient and specific cytotoxic potential against multiple human B cell lymphoma cell lines in vitro. In addition, primary mantle cell lymphoma cells, isolated from a patient who relapsed after rituximab treatment, can also be eliminated by CAR20-T cells. CAR20(NAP)-T cells delayed tumor growth and prolonged survival of mice with lymphoma. No obvious histopathological alteration in major organs were observed in mice treated with CAR(NAP)-T cells. Further, no excessive cytokine release or immune cell activation was observed when human blood from healthy volunteers was exposed to recombinant NAP protein in an ex vivo blood loop assay, suggesting a safe therapeutic profile for NAP. Taken together, these results warrant the clinical investigation of CAR20(NAP)-T cells.
CD19嵌合抗原受体T细胞（CAR-T）疗法在治疗B细胞恶性肿瘤方面显示出显著效果。然而，约三分之二的淋巴瘤患者最终会复发，其中约三分之一在复发时表现为CD19阴性肿瘤。我们之前的研究表明，携带幽门螺杆菌中性粒细胞激活蛋白（NAP）的CAR-T细胞，即CAR（NAP）-T细胞，可引发旁观者免疫反应并消除CAR靶向抗原阴性的肿瘤细胞。在此，我们报告了靶向CD20的CAR-T细胞（CAR20-T细胞）的研发情况，其靶向部分来自利妥昔单抗，以及携带NAP的CAR-T细胞的安全性和疗效。CAR20-T细胞在体外对多种人类B细胞淋巴瘤细胞系表现出高效且特异的细胞毒性潜力。此外，从一名接受利妥昔单抗治疗后复发的患者分离出的原发性套细胞淋巴瘤细胞，也能被CAR20-T细胞消除。CAR20（NAP）-T细胞延缓了淋巴瘤小鼠的肿瘤生长并延长了其生存期。在用CAR（NAP）-T细胞治疗的小鼠中，未观察到主要器官有明显的组织病理学改变。此外，在体外血循环试验中，当健康志愿者的血液暴露于重组NAP蛋白时，未观察到过度的细胞因子释放或免疫细胞激活，这表明NAP具有安全的治疗特性。综上所述，这些结果为CAR20（NAP）-T细胞的临床研究提供了依据。
