Morillon Y Maurice Ii, Smalley Rumfield Claire, Pellom Samuel T, Sabzevari Ariana, Roller Nicholas T, Horn Lucas A, Jochems Caroline, Palena Claudia, Greiner John W, Schlom Jeffrey
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Front Oncol. 2020 Apr 21;10:549. doi: 10.3389/fonc.2020.00549. eCollection 2020.
The lack of serial biopsies in patients with a range of carcinomas has been one obstacle in our understanding of the mechanism of action of immuno-oncology agents as well as the elucidation of mechanisms of resistance to these novel therapeutics. While much information can be obtained from studies conducted with syngeneic mouse models, these models have limitations, including that both tumor and immune cells being targeted are murine and that many of the immuno-oncology agents being evaluated are human proteins, and thus multiple administrations are hampered by host xenogeneic responses. Some of these limitations are being overcome by the use of humanized mouse models where human peripheral blood mononuclear cells (PBMC) are engrafted into immunosuppressed mouse strains. Bintrafusp alfa (M7824) is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII to function as a TGF-β "trap" fused to a human IgG1 antibody blocking PD-L1. A phase I clinical trial of bintrafusp alfa showed promising anti-tumor efficacy in heavily pretreated advanced solid tumors, and multiple clinical studies are currently ongoing. There is still much to learn regarding the mechanism of action of bintrafusp alfa, including its effects on both human immune cells in the periphery and in the tumor microenvironment (TME), and any temporal effects upon multiple administrations. By using the NSG-β2m mouse strain humanized with PBMC, we demonstrate here for the first time: (a) the effects of bintrafusp alfa administration on human immune cells in the periphery vs. the TME using three different human xenograft models; (b) temporal effects upon multiple administrations of bintrafusp alfa; (c) phenotypic changes induced in the TME, and (d) variations observed in the use of multiple different PBMC donors. Also discussed are the similarities and differences in the data thus far obtained employing murine syngeneic models, from clinical trials, and in the use of this humanized mouse model. The results described here may guide the future use of this agent or similar immunotherapy agents as monotherapies or in combination therapy studies.
在一系列癌症患者中缺乏连续活检，这一直是我们理解免疫肿瘤药物作用机制以及阐明对这些新型疗法耐药机制的障碍之一。虽然可以从同基因小鼠模型的研究中获得很多信息，但这些模型存在局限性，包括被靶向的肿瘤细胞和免疫细胞都是鼠源的，而且许多正在评估的免疫肿瘤药物是人类蛋白质，因此多次给药会受到宿主异种反应的阻碍。通过使用将人外周血单核细胞（PBMC）植入免疫抑制小鼠品系的人源化小鼠模型，其中一些局限性正在被克服。双特异性抗体bintrafusp alfa（M7824）是一种创新的一流双功能融合蛋白，由转化生长因子β受体II（TGF-βRII）的细胞外结构域组成，作为一种TGF-β“陷阱”，与阻断PD-L1的人IgG1抗体融合。bintrafusp alfa的I期临床试验在经过大量预处理的晚期实体瘤中显示出有前景的抗肿瘤疗效；目前多项临床研究正在进行。关于bintrafusp alfa的作用机制仍有许多需要了解的地方，包括其对外周血和肿瘤微环境（TME）中人类免疫细胞的影响，以及多次给药后的任何时间效应。通过使用用PBMC人源化的NSG-β2m小鼠品系，我们首次证明了：（a）使用三种不同的人异种移植模型，bintrafusp alfa给药对外周血与TME中人类免疫细胞的影响；（b）bintrafusp alfa多次给药后的时间效应；（c）TME中诱导的表型变化，以及（d）在使用多个不同PBMC供体时观察到的差异。还讨论了迄今为止在使用鼠同基因模型、临床试验以及使用这种人源化小鼠模型中获得的数据的异同。这里描述的结果可能会指导该药物或类似免疫治疗药物未来作为单一疗法或联合疗法研究的使用。
