Impact of Obesity on Immuno-Oncology Agents in Endometrial Cancer

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

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.