Important Target For Novel NK Immune Checkpoint Inhibitor Identified!

In the last decade, the introduction of immune checkpoint inhibitors such as CTLA-4/PD-1/PD-L1, and immune drugs such as Keytruda and Opdivo have marked a major advance in cancer treatment by "liberating" immune T cells and giving them back their ability to attack cancer cells. However, previous data has shown that only 10-30% of patients have a good outcome with these immunotherapies. However, a paper recently published in the Journal of Clinical Investigation (JCI) shows that scientists may have found another new path to immunotherapy.
Rather than continuing the T-cell idea of fighting cancer, scientists from the Albert Einstein College of Medicine, this time, took a different route and used another type of immune cell known as natural killer cells, or NK cells, for their research, with remarkable results.

"We believe that the novel immunotherapies we are developing, which have great potential, hold promise for entering clinical trials in all types of cancer," describes the study's leader, Dr Xingxing Zang, Louis Goldstein Swan Chair in Cancer Research and Professor of Microbiology and Immunology, who is also a member of the Montefiore Einstein Cancer Center's cancer treatment programme.

Distinguishing friend from foe

The surface of immune cells is covered with receptors called 'checkpoints', which prevent immune cells from going off course and 'braking' instead of attacking pathogen-infected cells or cancer cells. When the immune cells' checkpoint receptors bind to proteins expressed by the body's own normal cells, they interact to stop the immune cells from attacking. Unfortunately, in many types of cancer, cancer cells express proteins that, by binding to checkpoint receptors, induce immune cells to stop attacking the tumour.

When this 'braking' device is removed, the immune cells can often attack and destroy the cancer cells.

A new focus on natural killer cells


Because of the limited effectiveness of previous T-cell immune checkpoint inhibitors, Dr Zang and other scientists have investigated the checkpoint pathway of NK cells, a powerful immune cell that, like T cells, plays an important role in eliminating unwanted bad cells.
A cancer cell protein called PVR soon caught the attention of scientists. "We realised that PVR could be a very important protein that cancer uses to block NK cell attacks," said Dr Zang.

PVR proteins are usually absent or rare in normal tissues, but are abundant in many types of cancer, such as colorectal, ovarian, lung, oesophageal, head and neck, gastric and pancreatic cancers, as well as myeloid leukaemia and malignant melanoma, among others.

In addition, the PVR protein appears to inhibit the activity of NK and T cells by binding to another checkpoint protein called TIGHT. As a result more than 100 clinical trials related to immune checkpoint inhibitors targeting TIGHT are currently underway worldwide. However, a number of studies, including two large phase III clinical trials, have failed to show improved prognosis in the treatment of cancer patients.

Recognising the role of new receptors

cancer cells, the PVR protein was found to have another binding site on NK cells: KIR2DL5. "We hypothesised that the pathway by which PVR inhibits NK cell activity is not the TIGHT checkpoint protein, but the newly discovered KIR2DL5," said Dr Zang. To test the answer, he and his colleagues synthesised a monoclonal antibody specifically targeting KIR2DL5 and performed in vivo and in vitro experiments.

Monoclonal antibodies make tumour cell/NK cell interactions impossible, allowing NK cells to attack and destroy tumour cells

In their JCI paper, Dr Zang and colleagues demonstrate that KIR2DL5 is a common checkpoint receptor on the surface of human NK cells and that the PVR cancer protein inhibits immune cell attack through it.

Using several humanised animal models, the researchers showed that by blocking the KIR2DL5/PVR pathway, they could free NK cells to attack cancer cells, shrink tumours and prolong animal survival. "These preclinical findings lead us to believe that blocking the pathway of KIR2DL5/PVR is a good idea and that the monoclonal antibody we have developed could be an effective immunotherapy."