Targeting myeloid-derived suppressor cells in lung cancer

2021

Dwight Owen, MD

The Ohio State University Comprehensive Cancer Center

Columbus

Immunotherapy has become a standard treatment regimen for advanced-stage non-small cell lung cancer. However, most patients do not respond. One significant barrier to immunotherapy efficacy is the tumor microenvironment (TME), which contains immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs). MDSCs represent an important tumor immune escape mechanism and play a role in the development and progression of lung cancer. Dr. Owen will be studying how this group of cells can be targeted to improve the effect of immunotherapy.

Research Summary

Lung cancer is the leading cause of cancer-related death in the United States and worldwide, and the typical survival for patients with advanced lung cancer is approximately one year. Treatments that specifically target the immune system have been shown to improve survival in some patients, yet most patients eventually need supplementary treatments to manage their disease. Even with advances in treatment, the optimal treatment for patients after other therapies fail is still unknown. We need to understand why current treatment options either do not work from the beginning, or stop working over time, in order to develop new strategies to improve outcomes for patients with lung cancer. In this study, we will study the combination of an approved immune targeting treatment (atezolizumab) with a vitamin A derivative called all-trans retinoic acid (ATRA). ATRA, an oral, non-chemotherapy medication commonly used to treat a form of leukemia, may be help to in promote an immune response when taken along with immunotherapy. Our studies focus on a specific cell of the immune system that can interfere with available immune treatments, myeloid-derived suppressor cells (MDSCs). We will study changes in MDSCs in the blood during treatment to see if these changes can predict whether the treatment is working, or if it is likely to stop working soon. We hope that our immune cell studies will lead to improved treatment options for patients with lung cancer, and that the new drug combination described in this proposal will lead to better outcomes in patients with lung cancer when current treatment options fail to control the cancer.

Technical Abstract

Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Immune checkpoint inhibitors (ICIs) have shown durable responses and improved survival in some patients with advanced non-small cell lung cancer (NSCLC). However, nearly all patients eventually progress on these therapies, and the median survival for patients with metastatic NSCLC remains around one year. Combining immunotherapy with cytotoxic chemotherapy has shown an incremental benefit but at the cost of increased toxicity. Patients who progress on currently available immunotherapies have few effective treatment options. One significant barrier to ICI therapy efficacy is the tumor microenvironment (TME), which contains immunosuppressive cells including myeloid-derived suppressor cells (MDSCs). MDSCs represent an important tumor immune escape mechanism and play a role in the development and progression of lung cancer. Higher levels of MDSCs in the blood are associated with shorter overall survival in patients with NSCLC, and MDSCs are associated with resistance to immune checkpoint inhibitor (ICI) therapy. However, there is significant variation in methods of measurement of MDSCs including 1) the classification of the most common phenotypes, namely CD15+ polymorphonuclear MDSC (PMN-MDSC) and CD14+ monocytic MDSC (M-MDSC), and 2) the functional assessment of MDSCs. There are also significant differences in MDSC function and phenotype in animal models and in patients with cancer. We propose to investigate the role of MDSCs in tumor immune escape, and to target the immunosuppressive impact of MDSCs to improve outcomes of patients with NSCLC treated with ICI. Utilizing mass cytometry and in vitro co-culture assays, we will evaluate MDSC levels and function as well as immune cell subset changes in patients receiving standard of care immunotherapy to identify the cell populations that drive immune responses and resistance. We will then conduct a phase 1b clinical trial of all-trans retinoic acid (ATRA) combined with atezolizumab to test whether this treatment can improve responses and overcome ICI resistance in patients with NSCLC who have progressed on standard therapies. We hypothesize that a decrease in the frequency and immunosuppressive function of circulating MDSCs will be associated with increased clinical benefit in patients with NSCLC, and that modulation of MDSCs through the use of ATRA given in combination with ICIs will be safe, tolerable, and exhibit preliminary efficacy in overcoming resistance to available ICIs. The proposed studies include the first trial of this novel treatment in patients with lung cancer and will examine the potential for targeting MDSCs to overcome resistance and enhance the efficacy of immunotherapy. If successful, these studies may lead to an increased number of patients with advanced NSCLC experiencing durable responses and improved survival.

Targeting myeloid-derived suppressor cells in lung cancer

LUNGevity Foundation

CHICAGO OFFICE

BETHESDA OFFICE

MAILING ADDRESS