T Cell Engineering, Mayo Clinic, Rochester, MN.
Division of Hematology, Mayo Clinic, Rochester, MN.
Blood. 2024 Jan 18;143(3):258-271. doi: 10.1182/blood.2022018905.
In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.
在开发用于治疗 B 细胞恶性肿瘤的各种抗 CD19 免疫疗法策略的过程中，CD19 单克隆抗体治疗是否会损害随后的 CD19 靶向嵌合抗原受体 T 细胞（CART19）治疗仍不清楚。我们在临床前模型中评估了靶向 CD19 的单克隆抗体 tafasitamab 与 CART19 治疗之间的潜在干扰。tafasilumab 与 CART19 同时治疗显示出主要的 CD19 结合竞争，从而导致 CART19 功能受损。然而，当 CD19+细胞系用 tafasitamab 预处理过夜并从培养物中去除未结合的抗体时，CART19 功能不受影响。在临床前体内模型中，与单独使用 CART19 相比，tafasilamab 预处理可降低细胞因子释放综合征的发生率和严重程度，并表现出更好的抗肿瘤作用和总生存。这与 tafasitamab 短暂的 CD19 占据有关，这反过来又抑制了 CART19 的过度激活，导致 CAR T 细胞凋亡和肿瘤细胞的细胞焦亡减少。
