Chimeric antigen receptor T-cell(CAR T) therapy is a kind of effective cancer immunotherapy. However,designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shar...Chimeric antigen receptor T-cell(CAR T) therapy is a kind of effective cancer immunotherapy. However,designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches(e.g.,daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing(fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies(clone MM12 T or clone MM27) or proteins(H02 H or H08 H) were used to block CD38 or the CAR single-chain variable fragment(scFv) domain, respectively, on the T cell surface.The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38+ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-a, IFN-g and IL-2 were significantly upregulated in the supernatants of A549CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.展开更多
CD38在多发性骨髓瘤、急性髓细胞性白血病、急性淋巴细胞白血病及淋巴瘤等多种血液系统恶性肿瘤中广泛表达,已成为嵌合抗原受体T细胞(chimeric antigen receptor T cell,CAR-T)疗法中备受关注的潜在治疗靶点。本文系统综述了CD38靶向CA...CD38在多发性骨髓瘤、急性髓细胞性白血病、急性淋巴细胞白血病及淋巴瘤等多种血液系统恶性肿瘤中广泛表达,已成为嵌合抗原受体T细胞(chimeric antigen receptor T cell,CAR-T)疗法中备受关注的潜在治疗靶点。本文系统综述了CD38靶向CAR-T疗法在血液系统恶性肿瘤中的研究进展。近年来的研究主要集中于通过结构或功能优化CAR-T细胞,以降低治疗相关不良反应、增强细胞体内持久性并提高整体治疗效果。此外,研究还探索了通过全反式维甲酸上调肿瘤细胞表面CD38表达,或采用双靶点CAR-T疗法以增强抗肿瘤效应。然而,仍需开展更多前瞻性临床研究,以进一步优化CD38-CAR-T疗法在复发/难治性血液系统恶性肿瘤患者中的适用人群与剂量方案,并评估其长期疗效与安全性。展开更多
肾移植是目前治疗终末期肾病的最佳治疗方案,随着免疫抑制药物的发展,急性排斥反应发生率显著下降,但远期存活仍不理想。慢性活动性抗体介导的排斥反应(chronic active antibody-mediated rejection,CaAMR)是影响移植肾远期存活的关键因...肾移植是目前治疗终末期肾病的最佳治疗方案,随着免疫抑制药物的发展,急性排斥反应发生率显著下降,但远期存活仍不理想。慢性活动性抗体介导的排斥反应(chronic active antibody-mediated rejection,CaAMR)是影响移植肾远期存活的关键因素,但是传统的治疗方案和新型生物制剂均未获得确切疗效。慢性活动性抗体介导的排斥反应与抗体尤其是供体特异性抗体(donor specific antibody,DSA)密切相关,因此针对B细胞及浆细胞的治疗,有望获得良好疗效。CD38单抗作为靶向浆细胞的一种新型生物制剂,在多发性骨髓瘤的挽救性治疗中获得较好疗效。目前也有研究探索其对CaAMR的治疗作用及潜力。本文就CD38单抗治疗CaAMR的疗效及安全性的现状予以综述。展开更多
基金supported by the grants from the National Natural Science Foundation of China (Nos. 81830002 and 31870873 to W.D.H.)the National Key Research and Development Program of China (Nos. 2016YFC1303501 and 2016YFC1303504 to WDH, and No. 2017YFC0909803 to W.Y.)
文摘Chimeric antigen receptor T-cell(CAR T) therapy is a kind of effective cancer immunotherapy. However,designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches(e.g.,daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing(fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies(clone MM12 T or clone MM27) or proteins(H02 H or H08 H) were used to block CD38 or the CAR single-chain variable fragment(scFv) domain, respectively, on the T cell surface.The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38+ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-a, IFN-g and IL-2 were significantly upregulated in the supernatants of A549CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.
文摘CD38在多发性骨髓瘤、急性髓细胞性白血病、急性淋巴细胞白血病及淋巴瘤等多种血液系统恶性肿瘤中广泛表达,已成为嵌合抗原受体T细胞(chimeric antigen receptor T cell,CAR-T)疗法中备受关注的潜在治疗靶点。本文系统综述了CD38靶向CAR-T疗法在血液系统恶性肿瘤中的研究进展。近年来的研究主要集中于通过结构或功能优化CAR-T细胞,以降低治疗相关不良反应、增强细胞体内持久性并提高整体治疗效果。此外,研究还探索了通过全反式维甲酸上调肿瘤细胞表面CD38表达,或采用双靶点CAR-T疗法以增强抗肿瘤效应。然而,仍需开展更多前瞻性临床研究,以进一步优化CD38-CAR-T疗法在复发/难治性血液系统恶性肿瘤患者中的适用人群与剂量方案,并评估其长期疗效与安全性。
文摘肾移植是目前治疗终末期肾病的最佳治疗方案,随着免疫抑制药物的发展,急性排斥反应发生率显著下降,但远期存活仍不理想。慢性活动性抗体介导的排斥反应(chronic active antibody-mediated rejection,CaAMR)是影响移植肾远期存活的关键因素,但是传统的治疗方案和新型生物制剂均未获得确切疗效。慢性活动性抗体介导的排斥反应与抗体尤其是供体特异性抗体(donor specific antibody,DSA)密切相关,因此针对B细胞及浆细胞的治疗,有望获得良好疗效。CD38单抗作为靶向浆细胞的一种新型生物制剂,在多发性骨髓瘤的挽救性治疗中获得较好疗效。目前也有研究探索其对CaAMR的治疗作用及潜力。本文就CD38单抗治疗CaAMR的疗效及安全性的现状予以综述。
