# Targeted MEK inhibition to enhance immunotherapy in cholangiocarcinoma

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $424,213

## Abstract

Cholangiocarcinoma (CC) is an aggressive cancer that has been refractory to most chemotherapeutic or targeted
agents. Our goal is to extend success of immunotherapy to CC, and identify relevant biomarkers for this
approach. This proposal will translate pre-clinical findings showing that MEK inhibitors (MEKi) enhance infiltration
of CD8+ T effector cells, prevent their exhaustive apoptotic cell death, and enhance efficacy of anti-PD-L1 Ab in
tumor models. We hypothesize that MEKi will synergize with PD-L1 blockade to elicit anti-tumor responses via
altering cytokine and chemokine signatures that promote CD8+ T cell infiltration and survival and decreased
immunosuppressive cells in the tumor microenvironment (TME). We will conduct an innovative randomized
phase 2 clinical trial to examine safety and efficacy of a MEKi (cobimetinib) in combination with an inhibitor of
PD-L1 (atezolizumab) and atezolizumab monotherapy in patients with unresectable CC. This trial will be
performed in the context of our approved NCI-sponsored UM1 clinical trials grant. Concurrent studies will
elucidate the mechanism by which MEKi acts on T and myeloid cells, and augments efficacy of PD-L1 blockade.
The trial will provide paired biopsies from patients with accessible tumor in which we can validate our mechanistic
findings using innovative multi-spectral imaging. This will be the largest clinical study of CC in the second line.
We will pursue three Specific Aims: 1) To conduct a randomized phase 2 clinical trial of the PD-L1 inhibitor
atezolizumab in combination with the MEKi cobimetinib versus atezolizumab monotherapy in participants with
unresectable CC. We have completed approval through the NCI Cancer Therapy Evaluation Program (CTEP)
to conduct this randomized, multicenter clinical trial in 76 evaluable subjects who have received at least one prior
chemotherapy. If successful, this regimen has potential to become the standard of care for CC in the second
line. This trial will provide samples to evaluate the effect of MEKi on key biomarkers in the TME. 2) To determine
how MEKi alter the TME to improve the response to anti-PD-L1 therapy. A unique panel of human CC cell lines
will be used study how MEKi modulates tumor-derived chemokines that regulate T cell migration. Using clinical
trial biopsies, we will evaluate CD8+ T cell infiltration and PD-L1 expression as integrated biomarkers. Multi-
spectral IHC will characterize the impact of treatment on immune subsets and markers of exhaustive T cell death
(i.e. Nur77) in the TME as well as the impact on immunosuppressive T regulatory cells and myeloid-derived
suppressor cells. 3) To determine the role of systemic cytokines and immune cell populations in the response to
MEKi and PD-L1 blockade. In vivo models will test if the efficacy of MEKi + anti-PD-L1 therapy is dependent on
IFN-, a key cytokine regulator of T cell function and chemokine-mediated trafficking. In vitro studies will define
if MEKi alters the impact of ...

## Key facts

- **NIH application ID:** 10004585
- **Project number:** 5R01CA228414-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Nilofer S. Azad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,213
- **Award type:** 5
- **Project period:** 2018-07-03 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004585

## Citation

> US National Institutes of Health, RePORTER application 10004585, Targeted MEK inhibition to enhance immunotherapy in cholangiocarcinoma (5R01CA228414-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004585. Licensed CC0.

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