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Rather than rally T cells against cancer, scientists have used different human immune cells called natural killer (NK) cells as a novel means to fight cancer, according to a study.
The team of scientists at Albert Einstein College of Medicine described findings that could boost the impact of immune-checkpoint therapy, the study said. Findings have been published in The Journal of Clinical Investigation (JCI).
Immune checkpoint inhibitors such as Keytruda and Opdivo work by unleashing the immune system’s T cells to attack tumour cells. Their introduction a decade ago marked a major advance in cancer therapy, but only 10 per cent to 30 per cent of treated patients experience long-term improvement, the study said.
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The surfaces of immune cells are studded with receptors known as ‘checkpoint’ proteins, which prevent immune cells from straying beyond their usual targets, which are pathogen-infected cells and cancer cells. When checkpoint receptors on immune cells bind with proteins expressed by the body’s own normal cells, the interaction puts the brakes on a possible immune-cell attack, the study explained.
Diabolically, most types of cancer cells express proteins that bind with checkpoint proteins, tricking immune cells into standing down and not attacking the tumour, the study said.
Immune checkpoint inhibitors are monoclonal antibodies designed to short-circuit immune-cell/cancer-cell interactions by blocking either the tumour proteins or the immune-cell receptors that bind with tumour proteins. With no brakes to impede them, immune cells can attack and destroy cancer cells, the study said.
The limited effectiveness of checkpoint inhibitors prompted Zang and other scientists to look at checkpoint pathways involving NK cells, which – like T cells – play major roles in eliminating unwanted cells, the study said.
A cancer-cell protein called PVR soon captured their attention.
”We realized that PVR may be a very important protein that human cancers use to hobble the immune system’s attack,” said Zang.
PVR protein is usually absent or very scarce in normal tissues but is found in abundance in many types of tumours including colorectal, ovarian, lung, esophageal, head and neck, stomach, and pancreatic cancer as well as myeloid leukemia and melanoma, the study said.
Moreover, PVRs appeared to inhibit T cell and NK cell activity by binding to a checkpoint protein called TIGIT, prompting efforts to interrupt the TIGIT/PVR pathway by using monoclonal antibodies made against TIGIT. More than 100 clinical trials targeting TIGIT are now in progress worldwide. However, several clinical studies including two large phase 3 clinical trials have recently failed to improve cancer outcomes.
Meanwhile, according to the study, the cancer-cell protein PVR was found to have another ‘binding partner’ on NK cells – KIR2DL5.
”We hypothesized that PVR suppresses NK cell activity not by binding with TIGIT but by binding with the recently recognized KIR2DL5,” said Zang. To find out, he and his colleagues synthesized a monoclonal antibody targeting KIR2DL5 and carried out in vitro and in vivo experiments using the antibody, the study said.
Zang and colleagues demonstrated that KIR2DL5 is a commonly occurring checkpoint receptor on the surface of human NK cells, which PVR cancer proteins use to suppress immune attack, the study said.
In studies involving humanized animal models of several types of human cancers, the researchers showed that their monoclonal antibody against KIR2DL5 – by blocking the KIR2DL5/PVR pathway – allowed NK cells to vigorously attack and shrink human tumours and prolong animal survival.
”These preclinical findings raise our hopes that targeting the KIR2DL5/PVR pathway was a good idea and that the monoclonal antibody we have developed may be an effective immunotherapy,” said Zang.
The research team has filed a patent application for KIR2DL5/PVR immune checkpoint including antibody drugs and is interested in a partnership to further develop and commercialize the technology.