Myeloid-Derived Suppressor Cells in Checkpoint Protein Inhibition for Melanoma
Abstract
In this Team Science Translational proposal, we will combine for the first time an immune stimulant called nivolumab that has been shown to shrink a variety of cancers, particularly melanoma, with a novel antibody that recognizes a molecule on immune suppressive cells called TRAIL-DR5 and causes the suppressive cells to become inactive. We have shown in a prior trial that high levels of a certain type of immune suppressive cell called a myeloid derived suppressive cell, or MDSC, is associated with a poor outcome with the use of nivolumab. It was felt that eliminating or inactivating the MDSCs would benefit patients with melanoma receiving nivolumab and reverse their resistance to the drug. In this grant proposal, we suggest that addition of an antibody that binds to a molecule called TRAIL-DR5 will be well tolerated by patients and cause few additional side effects when combined with nivolumab, a drug that stimulates the human immune system and causes long-lasting shrinkage of melanoma. We feel that the TRAIL-DR5 antibody will increase the likelihood that nivolumab will shrink melanoma by decreasing the number and function of the MDSCs as well as other cells that suppress the immune system called T regulatory cells. The objective of this proposal is to find out how the TRAIL-DR5 antibody given to patients with advanced melanoma in combination with nivolumab will impact their immune system. In the first set of experiments, we will measure the effects over time of the combination of TRAIL-DR5 antibody with niviolumab on the immune system using the peripheral blood samples, serum samples, and tumor biopsies from patients on the trial. We will also test the peripheral blood samples, serum, and tumor samples from patients receiving both drugs to try and understand better the actual mechanism by which the TRAIL-DR5 antibody blocks the function of the immune suppressing cells. In the second set of experiments of the proposal, we will try to find out if there are substances we can measure using the samples of peripheral blood, serum, and tumor biopsies from patients removed before they start their treatment that will tell us how to predict who will have the best shrinkage of their tumor. In the third set of experiments, we will find out if there is a role of a biochemical pathway called the ER stress response in the control of DR5-TRAIL in MDSCs in melanoma. This will help us understand the ways that MDSCs control their expression of molecules that provide novel targets for treatment and will determine better ways to control the effect of MDSCs in cancer. We ultimately wish to use the information gathered from the experiments using the blood samples and tumors from these melanoma patients whose tumors cannot be cured with surgery and who are receiving TRAIL-DR5 antibody combined with nivolumab to improve upon the existing treatment for this deadly disease. The importance of this work is that the results of this grant proposal could significantly improve the ability of immune therapies to shrink melanoma and other cancers like lung cancer, bladder, and head and neck cancer. We will be able to use information gained from this proposal within the next 3 years to propose new trials that may further improve the results of immunotherapy for cancer, and potentially allow patients with types of cancer previously resistant to the use of immune stimulants like nivolumab to have their tumors shrink with its use. Those tumors include colon cancer, prostate cancer, and most forms of breast cancer, which afflict many members of the U.S. military. This study deals with understanding the factors that determine how patients respond to treatment with immunotherapy based on trials in melanoma to improve the treatment of members of the U.S. military that are at increasing risk of this potentially deadly disease. This is due to high levels of sunlight exposure in most areas of the world in which the U.S. military is currently engaged.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610209
Entities
People
- Chih-chi Hu
Organizations
- United States Army
- Wistar Institute