Impact of Obesity on Immuno-Oncology Agents in Endometrial Cancer

肥胖对子宫内膜癌免疫肿瘤药物的影响

• 批准号: 10357423
• 负责人: Victoria Lin Bae-Jump
• 金额: $ 21.81万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357423
• 关键词: Antigen-Presenting Cells; Apoptosis; Biological Markers; Blood; CCL2 gene; CD32 Antigens; Cancer Patient; Cells; Cessation of life; Clinical; Clinical Trials; DRD2 gene; Dopamine Receptor; Dose; Drug Kinetics; Endocrine system; Endometrial Carcinoma; Enrollment; Environment; Exposure to; FCGR3B gene; Fatty Acids; Funding; Future; Generations; Goals; Hormonal; Hormones; IgG Receptors; Immune; Immunooncology; Inflammatory; Innate Immune System; Ligands; Link; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Mediator of activation protein; Metabolic; Metastatic/Recurrent; Microsatellite Instability; Molecular; Monoclonal Antibodies; Mononuclear; Mus; Natural Killer Cells; Non obese; Obesity; Pathway interactions; Patients; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology Study; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; Predisposition; Progression-Free Survivals; Proteins; RANTES; Reactive Oxygen Species; Regimen; Risk; Safety; Serum; System; TNF gene; TNFSF10 gene; Testing; Therapeutic; Thinness; Treatment Efficacy; Up-Regulation; Uterine Neoplasms; Woman; antagonist; antitumor effect; cancer cell; cancer type; chemokine; clinically relevant; cohort; cytokine; design; dosage; expectation; immune checkpoint; individualized medicine; inhibitor; innovation; lipid metabolism; monocyte; mouse model; novel; obese patients; obesity treatment; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 designs; phase 2 study; phase I trial; programmed cell death ligand 1; programmed cell death protein 1; receptor function; response; small molecule; tumor; tumor microenvironment; uptake

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.

项目概要 肥胖与患子宫内膜癌 (EC) 的风险增加相关，约 60% 由于程序性死亡蛋白-1 (PD-1) 及其配体、程序性死亡配体，EC 患者的肥胖率增加。 1 (PD-L1) 在 EC 中高表达，针对这两个靶点的免疫肿瘤抑制剂前景广阔 用于治疗肥胖驱动的 EC，特别是约 25% 的 EC 具有微卫星不稳定性，这是已知的 PD-1/PD-L1 抑制剂反应的生物标志物 Atezolizumab 就是这样一种抗 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会增加 PD-L1/2，最终 增强对 atezolizumab 的敏感性 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的 凋亡诱导配体并激活 T 细胞和自然杀伤 (NK) 细胞因此，ONC201 是一种合理的治疗方法。 阿特珠单抗的合作伙伴。 然而，与小分子相比，在 EC 中使用 atezolizumab + ONC201 会使肥胖变得复杂。 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，该系统是吞噬细胞的一部分 MPS 细胞是通过其 Fc- 摄取和清除 mAb 的天然机制。 我们的研究表明 MPS 介质、FcɣR 的数量和血液中的功能高度相关。 变量并与临床相关的高变异性相关 mAb 的药代动力学/药效学 (PK/PD) 肥胖患者的 MPS 更高且变化更大。 介体、FcɣR 和功能，导致 mAb 暴露量降低，因此，评估肥胖对 Atezolizumab 和 ONC201 在 EC 患者中的 PK/PD 具有临床相关性并且至关重要。 然而，尽管肥胖 EC 患者的表达较高，但 atezolizumab + ONC201 在 EC 中是安全的； PD-L1 和促炎性肿瘤环境，它们的阿替利珠单抗血浆水平比非 由于吞噬细胞清除增加，在相同剂量下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。 我们建议使用创新的方法对 atezolizumab + ONC201 的新型组合进行 1 期临床试验 患有转移性和复发性 EC 的肥胖和非肥胖患者的平行队列的设计。 目的是评估 atezolizumab 和 ONC201 双方案在肥胖和肥胖人群中的安全性和耐受性 非肥胖 EC 患者找到最大耐受剂量组合，然后在两个队列中推进 未来的2期研究旨在全面描绘肥胖对组合的影响。 atezolizumab + ONC201，我们将比较肥胖和非肥胖 EC 组之间的 PK/PD 药剂、反映免疫肿瘤学和两种药剂的 MPS 清除率的生物标志物及其 炎症代谢特征。