Impact of Obesity on Immuno-Oncology Agents in Endometrial Cancer

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.

Grant Number: 5R21CA267584-02
NIH Institute/Center: NIH
Principal Investigator: Victoria Bae-Jump