Wunderlich Mark, Manning Nicole, Sexton Christina, O'Brien Eric, Byerly Luke, Stillwell Cody, Perentesis John P, Mulloy James C, Mizukawa Benjamin
Experimental Hematology and Cancer Biology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Oncology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Front Oncol. 2021 Apr 13;11:642466. doi: 10.3389/fonc.2021.642466. eCollection 2021.
Immune therapies such as blinatumomab, CD19-directed bispecific CD3 T-cell Engager (BiTE), have resulted in significant improvements in outcomes for relapsed B-cell acute lymphoblastic leukemia (B-ALL). However, up to half of blinatumomab treated patients do not respond completely or relapse after therapy. As a result, there is a need to identify potential strategies to improve the efficacy of BiTE therapy. The anti-PD-1 antibody pembrolizumab has been shown to successfully activate T cells against a wide range of cancer types. Here, we tested the ability of umbilical cord blood (UCB) reconstituted mice to respond to blinatumomab therapy with or without concurrent pembrolizumab treatment. Humanized mice were engrafted with patient-derived xenograft (PDX) cells derived from pediatric and adolescent/young adult (AYA) B-ALL patients who had either failed to achieve remission with negative minimum residual disease (MRD negative) or experienced a relapse. Mock-treated humanized mice engrafted with PDX cells efficiently developed overt disease within 30 days of engraftment of B-ALL. However, single agent therapy with either blinatumomab or pembrolizumab reduced disease burden in engrafted mice, with some mice observed to be MRD negative after the 28-day treatment course. Combination therapy significantly improved the percentage of MRD negative mice and improved long-term survival and cure rates as compared to mice that were given blinatumomab alone. Importantly, no benefits were observed in treated mice that lacked human immune cell reconstitution. These results indicate that UCB-humanized NRGS mice develop activatable immune function, and UCB-humanized PDX leukemia models can be used in preclinical studies to evaluate specificity, efficacy, and cooperativity of immune therapies in B-ALL.
诸如blinatumomab（一种靶向CD19的双特异性CD3 T细胞衔接器（BiTE））之类的免疫疗法已使复发的B细胞急性淋巴细胞白血病（B-ALL）患者的预后得到显著改善。然而，高达一半接受blinatumomab治疗的患者治疗后并未完全缓解或复发。因此，需要确定提高BiTE疗法疗效的潜在策略。抗PD-1抗体派姆单抗已被证明能成功激活针对多种癌症类型的T细胞。在此，我们测试了脐带血（UCB）重建小鼠在接受或不接受派姆单抗联合治疗的情况下对blinatumomab疗法产生反应的能力。将来自儿科和青少年/青年（AYA）B-ALL患者的患者来源异种移植（PDX）细胞移植到免疫人源化小鼠体内；这些患者要么未能实现微小残留病阴性（MRD阴性）的缓解，要么经历了复发。移植了PDX细胞的模拟治疗免疫人源化小鼠在移植B-ALL后30天内有效发展为明显疾病。然而，单独使用blinatumomab或派姆单抗进行单药治疗可减轻移植小鼠的疾病负担，在28天治疗疗程后观察到一些小鼠为MRD阴性。与单独给予blinatumomab 的小鼠相比，联合治疗显著提高了MRD阴性小鼠的比例，并改善了长期生存率和治愈率。重要的是，在缺乏人免疫细胞重建的治疗小鼠中未观察到任何益处。这些结果表明，UCB人源化NRGS小鼠具有可激活的免疫功能，并且UCB人源化PDX白血病模型可用于临床前研究，以评估B-ALL免疫疗法的特异性、疗效和协同性。
