Impact of Obesity on Immuno-Oncology Agents in Endometrial Cancer

项目摘要 肥胖与发展和死于子宫内膜癌（EC）的风险增加有关，约60% 食管癌患者的肥胖率由于程序性死亡蛋白-1（PD-1）及其配体，程序性死亡配体 1（PD-L1）在EC中高度表达，针对这两个靶点的免疫肿瘤抑制剂具有很大的前景 对于治疗肥胖驱动的EC，特别是因为约25%的EC具有微卫星不稳定性，这是已知的 PD-1/PD-L1抑制剂应答的生物标志物。Atezolizumab是一种这样的抗PD-L1单克隆抗体（mAb）。 我们的研究表明，肥胖引发的促炎性子宫肿瘤环境增加了PD-L1/2， 对atezolizumab的敏感性增强。atezolizumab在EC中的疗效可通过ONC201增强， 一种小分子选择性多巴胺受体2拮抗剂，可上调肿瘤坏死因子相关 凋亡诱导配体和激活T和自然杀伤（NK）细胞。因此，ONC201是一种合理的治疗药物， atezolizumab的合作伙伴。 然而，atezolizumab + ONC201在EC中的使用因肥胖而复杂化。与小分子相比 药物，单克隆抗体通过单核吞噬细胞系统（MPS;单核细胞）的细胞清除，单核吞噬细胞系统是药物的一部分。 先天免疫系统MPS细胞作为mAb通过其Fc-γ的摄取和清除的天然机制。 γ-受体（Fc γ R）。我们的研究表明，MPS介质，Fc受体的数量和血液中的功能是高度相关的。 变量，并与高和临床相关的变异性， 在一些实施方案中，本发明提供了mAb的药代动力学/药效学（PK/PD）。肥胖患者的MPS更高，变化更大 介质、Fc受体和功能，导致mAb的暴露量降低。因此，评估肥胖对 atezolizumab和ONC201在EC患者中的PK/PD具有临床相关性且至关重要。我们的假设 阿特珠单抗+ONC201在EC中是安全的;然而，尽管肥胖EC患者具有更高的表达， PD-L1和促炎性肿瘤环境的患者，其atezolizumab血浆水平将低于非PD-L1和促炎性肿瘤环境的患者。 由于吞噬细胞清除率增加，肥胖者需要更高的剂量， 达到与非肥胖患者相当的血清水平。 我们提出了一项1期临床试验的新组合atezolizumab + ONC201使用创新的 转移性和复发性EC的肥胖和非肥胖患者的平行队列设计。我们的首要 目的是评估atezolizumab和ONC201双重方案治疗肥胖和 非肥胖EC患者，以找到最大耐受剂量组合，然后推进两个队列， 未来的第二阶段研究。为了全面地描述肥胖对以下因素组合的影响， atezolizumab + ONC201，我们将比较肥胖和非肥胖EC组之间的PK/PD， 试剂、反映免疫肿瘤学和两种试剂的MPS清除的生物标志物，及其 炎症代谢特征

PROJECT SUMMARY Obesity is associated with increased risk of developing and succumbing to endometrial cancer (EC), with ~60% of EC patients being obese. Since programmed death protein-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), are highly expressed in ECs, immuno-oncologic inhibitors for these two targets hold great promise for the treatment of obesity-driven EC, especially as ~25% of ECs have microsatellite instability, a known biomarker for PD-1/PD-L1 inhibitor response. Atezolizumab is one such anti-PD-L1 monoclonal antibody (mAb). Our studies suggest the obesity-triggered pro-inflammatory uterine tumor milieu increases PD-L1/2, culminating in enhanced susceptibility to atezolizumab. The efficacy of atezolizumab in EC may be enhanced via ONC201, a small molecular selective dopamine receptor 2 antagonist that upregulates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and activates T and natural killer (NK) cells. Thus, ONC201 is a logical therapeutic partner for atezolizumab. However, the use of atezolizumab + ONC201 in EC is complicated by obesity. Compared to small molecule drugs, mAbs are cleared via cells of the mononuclear phagocyte system (MPS; monocytes) which is part of the innate immune system. MPS cells serve as a natural mechanism of uptake and clearance for mAbs via their Fc- gamma-receptors (FcɣRs). Our studies show MPS mediators, number of FcɣRs and function in blood are highly variable and associated with the high and clinically relevant variability in the pharmacokinetics/pharmacodynamics (PK/PD) of mAbs. Obese patients have higher and more variable MPS mediators, FcɣRs and function, resulting in lower exposures of mAbs. Thus, evaluating effects of obesity on the PK/PD of atezolizumab and ONC201 in EC patients is clinically relevant and critically important. Our hypothesis is that atezolizumab + ONC201 will be safe in EC; however, despite obese EC patients having higher expression of PD-L1 and a pro-inflammatory tumor milieu, they will have lower atezolizumab plasma levels, than the non- obese at the same dose due to increased phagocytic clearance, necessitating higher dosing in the obese to achieve serum levels comparable to those of the non-obese patients. We propose a phase 1 clinical trial of the novel combination of atezolizumab + ONC201 using an innovative design of parallel cohorts of obese and non-obese patients with metastatic and recurrent EC. Our primary objective is to evaluate the safety and tolerability of the dual regimen of atezolizumab and ONC201 in obese and non-obese EC patients to find the maximal tolerable dose combination to then advance for both cohorts in a future phase 2 study. In order to comprehensively delineate the impact of obesity on the combination of atezolizumab + ONC201, we will compare between the obese and non-obese EC groups the PK/PD of both agents, biomarkers reflective of the immune-oncology and of the MPS clearance of both agents, and their inflammatory metabolic signatures.