Impact of Obesity on Immuno-Oncology Agents in Endometrial Cancer

项目总结 肥胖与发生和死于子宫内膜癌(EC)的风险增加有关，约60% 欧共体患者肥胖的比例。自从程序性死亡蛋白-1(PD-1)及其配体，程序性死亡配体 1(PD-L1)，在内皮细胞中高表达，针对这两个靶点的免疫肿瘤抑制药前景广阔 对于肥胖导致的EC的治疗，特别是当~25%的EC具有微卫星不稳定性时，一种已知的 PD-1/PD-L1抑制剂反应的生物标志物。阿替唑珠单抗就是这样一种抗PD-L1的单抗。 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，最终 在增强对阿达唑单抗的敏感性方面。通过ONC201可以增强阿替唑单抗在EC中的疗效， 上调肿瘤坏死因子相关的小分子选择性多巴胺受体2拮抗剂 凋亡诱导配体，激活T细胞和自然杀伤(NK)细胞。因此，ONC201是一种合乎逻辑的治疗方法 泰唑珠单抗的合作伙伴。 然而，在EC中使用阿替唑单抗+ONC201会因肥胖而复杂化。与小分子相比 在药物中，单抗是通过单核吞噬细胞系统(MPS；单核细胞)的细胞清除的，MPS是MPS的一部分 先天免疫系统。MPS细胞是一种天然的单抗摄取和清除机制，通过其Fc- γ受体(Fc、ɣ、Rs)。我们的研究表明，MPS介质、Fc、ɣ受体的数量和血液中的功能都很高 可变的，与高的和临床相关的变异性有关 单抗的药代动力学/药效学(PK/Pd)。肥胖患者的MPS更高、更具变异性 介体、Fcɣ受体和功能，导致mAbs暴露较低。因此，评估肥胖对健康的影响 阿替唑单抗和ONC201在EC患者中的PK/PD具有临床相关性和重要意义。我们的假设 阿替唑单抗+ONC201在EC中是安全的；然而，尽管肥胖的EC患者有更高的表达 PD-L1和促炎肿瘤环境中，他们的阿替唑单抗血浆水平将低于非 相同剂量的肥胖者由于吞噬清除增加，需要在肥胖者中使用更高的剂量来 达到与非肥胖患者相当的血清水平。 我们建议对阿替唑单抗+ONC201的新组合进行一期临床试验，使用的是一种创新的 肥胖者和非肥胖者转移性和复发性食管癌患者的平行队列设计。我们的初选 目的评价阿替唑单抗和ONC201双重方案治疗肥胖症的安全性和耐受性。 非肥胖EC患者寻找最大耐受剂量组合，然后在 未来的第二阶段研究。为了全面描述肥胖对健康的影响 Atezolizumab+ONC201，我们将比较肥胖和非肥胖EC组两者的PK/PD 药物，反映免疫肿瘤学和两种药物MPS清除的生物标志物，以及他们的 炎症性代谢征兆。

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.