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.

项目摘要 肥胖与子宫内膜癌（EC）的发展和屈服的风险增加有关，约60％ EC患者肥胖。由于编程的死亡蛋白-1（PD-1）及其配体，编程的死亡配体 1（PD-L1）在EC中高度表达，这两个目标的免疫肿瘤抑制剂具有很大的前景 为了治疗肥胖驱动的EC，尤其是〜25％的EC具有微卫星不稳定性， PD-1/PD-L1抑制剂反应的生物标志物。 atezolizumab是一种这样的抗PD-L1单克隆抗体（MAB）。 我们的研究表明，肥胖触发的促炎子宫肿瘤环境增加了PD-L1/2，高潮 为了增强对阿托唑珠单抗的敏感性。 Atezolizumab在EC中的效率可以通过ONC201提高 小分子选择性多巴胺接收器2拮抗剂，该拮抗剂上调肿瘤坏死因子相关 凋亡诱导配体并激活T和天然杀手（NK）细胞。那是ONC201是一种逻辑疗法 Atezolizumab的合作伙伴。 然而，肥胖症在EC中使用了Atezolizumab + ONC201。与小分子相比 药物，mAb通过单核吞噬细胞系统（MPS;单核细胞）的细胞清除，该细胞是该细胞的一部分 先天免疫系统。 MPS细胞是通过其FC-的自然摄取和清除率的自然机制 伽马受体（FCɣRS）。我们的研究表明，MPS介体，FCɣRS的数量和血液功能高度高 可变且与高和临床相关的可变性相关 MAB的药代动力学/药效学（PK/PD）。肥胖患者的MPS较高和更可变 介体，FCɣRS和功能，导致mAb的暴露较低。这是评估肥胖对 EC患者的Atezolizumab和Onc201的PK/PD在临床上相关且至关重要。我们的假设 是Atezolizumab + ONC201在EC中是安全的；但是，多皮特肥胖EC患者表达较高 PD-L1和促炎性肿瘤环境，它们将比非非 - 肥胖是由于吞噬细胞清除率增加而导致的，肥胖需要更高的剂量 达到与非肥胖患者相当的血清水平。 我们提出了使用创新的Atezolizumab + ONC201的新型组合的1期临床试验 肥胖和非肥胖患者转移和经常性EC的平行人群的设计。我们的主要 目的是评估Atezolizumab和Onc201双重方案的安全性和耐受性 非肥胖EC患者以找到最大耐受剂量组合，然后在A 未来的第二阶段研究。为了全面描述肥胖对组合的影响 Atezolizumab + Onc201，我们将在肥胖和非肥胖EC组之间进行比较两者的PK/PD 代理，生物标志物反映了两种药物的免疫肿瘤学和国会议员清除率 炎症代谢特征。