The use of immune checkpoint inhibitors to improve outcomes of patients with myeloid malignancies

Amer Zeidan

MBBS

Yale University

Project Term: July 1, 2018 - June 30, 2023

Project Summary

Cancers survive in part through their ability to resist being killed by the immune system. To evade the immune system, cancer cells use the immune checkpoint pathway, which is comprised of proteins that prevent an overactive immune system from attacking normal cells. Many cancers co-opt this mechanism to avoid attack by the immune system. Immune checkpoint inhibitors (ICBI) are drugs that remove this brake on the immune system leading to activation of the immune cells and killing of cancer cells. These ICBIs have significantly improved outcomes in multiple solid tumors, but their impact in myeloid blood cancers remains poorly understood. Myelodysplastic syndromes (MDS) are malignancies of the bone marrow, the patients of which have a poor survival rate, particularly in advanced cases. The most often used therapies have limited efficacy, and in cases where conventional therapy is ineffective, patients have poor survival. ICBIs also have limited success in MDS, in part because of the action of a group of suppressive immune cells. In laboratory models, a drug called entinostat reduces the number and activity of the immune suppressive cells, thereby making the cancer cells susceptible to the killing effect of the ICBI. Drawing on these observations, we are conducting a clinical trial in which we are combining entinostat with an ICBI called pembrolizumab in patients with MDS in whom conventional therapy has not been effective. The hope is that this approach will block the inhibitory aspects of the immune system and produce a more durable response in MDS patients with no current FDA-approved options. Chronic myeloid leukemia (CML) is another malignancy of the bone marrow. Most CML patients have a normal life expectancy by taking a targeted therapy called a tyrosine kinase inhibitor (TKI). However, these patients are not cured and most patients will remain on the TKI indefinitely. Some CML patients who have a very small number of CML cells can stop TKIs, and some of these patients who stopped treatment remain disease free. Research suggests that patient relapse may be due to the inability of their immune system to control the remaining CML cells in the body, and this is possibly through the immune checkpoint pathway. We have used this information to open a clinical trial to test the ability of ICPIs to augment TKIs. CML patients who are taking TKIs and have detectable CML will be treated with the ICBI pembrolizumab in addition to the TKI. The goal is to decrease the disease level to a degree that would allow stopping both drugs, possibly leading to durable control of the disease without any ongoing therapy.