Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Naval Medical University, Shanghai, China.
FASEB J. 2022 Apr;36(4):e22244. doi: 10.1096/fj.202101548RR.
Cancer immunotherapy has achieved impressive therapeutic effects in many cancers, while only a small subset of patients benefit from it and some patients even have experienced severe toxicity. It is urgent to develop a feasible large-cohort humanized mouse model to evaluate the pre-clinical efficacy and safety of cancer immunotherapy. Furthermore, developing potentially effective combination therapy between cancer immunotherapy and other therapies also needs humanized mouse model to adequately mimic clinical actual setting. Herein, we established a humanized mouse model engrafted with less human CD34 HSCs than ever before and then evaluated reconstitution efficiency and the profiles of human immune cells in this humanized mouse model. Also, this humanized mouse model was used to evaluate the preclinical efficacy and safety of cancer immunotherapy. For each batch of CD34 HSCs humanized mouse model, a relatively-large cohort with over 25% human CD45 cells in peripheral blood was established. This humanized mouse model could efficiently reconstitute human innate and adaptive immune cells. This humanized mouse model supported patient-derived xenograft tumor growth and tumor infiltration of PD-1 human T cells. Furthermore, therapeutic efficacy, re-activation of tumor-infiltrated T cells, and side effects of checkpoint blockade therapy could be monitored in this humanized mouse model. Human T cells from this humanized mouse model were successfully engineered with CD19-CAR. CD19 CAR-T cells could effectively deplete B cells and suppress tumor growth of acute lymphoblastic leukemia in vivo in this humanized mouse model. This humanized mouse model also could be used to demonstrate the efficacy of bispecific antibodies, such as anti-CD19/CD3. Overall, our work provides a feasible large-cohort humanized mouse model for evaluating a variety of cancer immunotherapy approaches including checkpoint inhibitors, adoptive cell therapy, and bispecific antibody therapy, and demonstrates that human T cells from this humanized mouse model possess anti-tumor activities in vitro and in vivo.
癌症免疫疗法在许多癌症中取得了令人瞩目的治疗效果，但只有一小部分患者从中受益，有些患者甚至经历了严重的毒性反应。因此，迫切需要开发一种可行的大群体人源化小鼠模型，以评估癌症免疫疗法的临床前疗效和安全性。此外，开发癌症免疫疗法与其他疗法之间的潜在有效联合治疗也需要人源化小鼠模型来充分模拟临床实际情况。在此，我们建立了一种人源化小鼠模型，其中植入的人类 CD34 HSCs 数量少于以往任何时候，然后评估了该人源化小鼠模型中的重建效率和人类免疫细胞的特征。此外，还使用该人源化小鼠模型来评估癌症免疫疗法的临床前疗效和安全性。对于每一批 CD34 HSCs 人源化小鼠模型，均建立了一个外周血中人类 CD45 细胞超过 25%的相对较大的队列。该人源化小鼠模型能够有效地重建人类固有和适应性免疫细胞。该人源化小鼠模型支持患者来源的异种移植肿瘤生长和 PD-1 人类 T 细胞浸润肿瘤。此外，在该人源化小鼠模型中可以监测检查点阻断治疗的疗效、肿瘤浸润 T 细胞的再激活以及副作用。从该人源化小鼠模型中分离出的人类 T 细胞成功地构建了 CD19-CAR。在该人源化小鼠模型中，CD19 CAR-T 细胞能够有效地耗竭 B 细胞并抑制体内急性淋巴细胞白血病的肿瘤生长。该人源化小鼠模型还可用于证明双特异性抗体（如抗 CD19/CD3）的疗效。总之，我们的工作提供了一种可行的大群体人源化小鼠模型，可用于评估包括检查点抑制剂、过继细胞疗法和双特异性抗体疗法在内的多种癌症免疫疗法方法，并表明该人源化小鼠模型中的人类 T 细胞具有体外和体内的抗肿瘤活性。
