CD28
医学
癌症研究
CD8型
淋巴瘤
人口
T细胞
弥漫性大B细胞淋巴瘤
抗体
化学免疫疗法
免疫学
免疫系统
CD22
美罗华
B细胞
环境卫生
作者
Joyce Wei,Welby Montalvo-Ortiz,Lola Yu,Amanda Krasco,Kara Olson,Sahar Rizvi,Nathalie Fiaschi,Sandra Coetzee,Fang Wang,Erica Ullman,Hassan Ahmed,Evan Herlihy,Ken-Wing Lee,Lauren S. Havel,Terra Potocky,Sarah Ebstein,Davor Frleta,Aditi Patel,Stephen Godin,Sara Hamon
标识
DOI:10.1126/scitranslmed.abn1082
摘要
Although many patients with diffuse large B cell lymphoma (DLBCL) may achieve a complete response to frontline chemoimmunotherapy, patients with relapsed/refractory disease typically have poor outcomes. Odronextamab, a CD20xCD3 bispecific antibody that provides “signal 1” through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. However, not all patients achieve complete responses, and many relapse, thus representing a high unmet medical need. Here, we investigated whether adding a costimulatory “signal 2” by engaging CD28 receptors on T cells could augment odronextamab activity. We demonstrate that REGN5837, a bispecific antibody that cross-links CD22-expressing tumor cells with CD28-expressing T cells, enhances odronextamab by potentiating T cell activation and cytolytic function. In preclinical DLBCL studies using human immune system–reconstituted animals, REGN5837 promotes the antitumor activity of odronextamab and induces intratumoral expansion of reprogrammable T cells while skewing away from a dysfunctional state. Although REGN5837 monotherapy shows limited activity and no toxicity in primate studies, it augments T cell activation when dosed in combination with odronextamab. In addition, analysis of non-Hodgkin lymphoma clinical samples reveals an increase in CD28 + CD8 + T cells after odronextamab treatment, demonstrating the presence of a population that could potentially be targeted by REGN5837. Collectively, our data demonstrate that REGN5837 can markedly enhance the antitumor activity of odronextamab in preclinical NHL models, and the combination of these two bispecific antibodies may provide a chemotherapy-free approach for the treatment of DLBCL.
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