New immunotherapy approach promises to improve cancer outcomes

CANCER DIGEST – Nov. 19, 2022 – Researchers at Albert Einstein College of Medicine have identified an additional protein cancer cells use to blunt immune system attacks on tumors. The study results were published in The Journal of Clinical Investigation (JCI). 

Over the past 10 years the introduction of immunotherapy medicines such as Keytruda and Opdivo have extended survival for patients with a number of cancers, including colorectal, lung and melanoma and bladder cancers, among others. These drugs work by blocking what are called checkpoint inhibitors, which cancer cells use to trick the immune system into ignoring them and not attacking.

These current checkpoint inhibitor drugs are very effective in allowing immune system T cells to attack tumors and shrink or eliminate cancers. Unfortunately, they only work in 10 percent to 30 percent of patients.

Looking to increase the effectiveness of checkpoint inhibitor drugs, the researchers led by Xingxing Zang, identified another protein cancer cells use to trick the immune system into ignoring them. Called PVR, this protein is usually absent or very rare in normal tissues, but is produced in abundance by many types of cancer cells. PVR has been shown to inhibit both T cells and another immune system cell, called Natural Killer or NK cells. PVR does this by binding to a pair of checkpoint proteins called TIGIT and KIR2DL5.

There are more than 100 clinical trials under way using drugs that target TIGIT, but recent results have failed to improve cancer outcomes. That led Dr. Zang’s team to hypothesize that PVR blunts NK cells attack on cancers not by binding the TIGIT but by binding to KIR2DL5. 

In the JCI paper the team demonstrated that KIR2DL5 is a commonly occurring checkpoint receptor on the surface of NK cells, which PVR proteins produced by cancer calls use to suppress the NK attack on the tumor. They then showed in humanized animal models that blocking PVR from binding to KIR2DL5 allowed the NK cells to vigorously attack and shrink human tumors. 

The researchers have filed a patent application for their PVR/KIR2DL5 antibody and are actively pursuing approval for human clinical trials. If proven successful in patients, the addition of NK immunotherapy could increase the number of patients who experience long-term improvement from immunotherapies.

Source: Albert Einstein College of Medicine press release