New York [US], November 16 (ANI): Immune checkpoint inhibitors like Opdivo and Keytruda function by releasing the T cells of the immune system to attack tumour cells. Although its release ten years ago signalled a significant advancement in cancer treatment, only 10 per cent to 30 per cent of those who receive them experience long-term benefits.
The Albert Einstein College of Medicine researchers discuss their findings in a paper made available online in The Journal of Clinical Investigation (JCI). This finding may increase the efficacy of immune-checkpoint therapy.
The Einstein study team used various human immune cells known as natural killer (NK) cells instead of mobilising T cells to fight cancer, with remarkable results. Xingxing Zang, M.D., PhD, the Louis Goldstein Swan Chair in Cancer Research, professor of microbiology & immunology, oncology, urology, and medicine at Einstein, and a member of the Cancer Therapeutics Program of the Montefiore Einstein Cancer Center, said, “We believe the novel immunotherapy we’ve developed has great potential to move into clinical trials involving various types of cancer.”
Distinguishing a friend from a foe
Immune cells have “checkpoint” protein receptors on their surfaces that keep them from deviating from their intended targets (pathogen-infected cells and cancer cells). A potential immune-cell onslaught is stopped when checkpoint receptors on immune cells engage with proteins expressed by the body’s own normal cells. In a cunning move, the majority of cancer cells say proteins that interact with checkpoint proteins, deceiving the immune system into halting its tumour-attacking activity.
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.
New Focus on Natural Killer Cells
Dr Zang and other researchers began investigating the checkpoint pathways involving NK cells, which, like T cells, are crucial in the elimination of cancerous cells, as a result of the checkpoint inhibitors’ poor efficacy. Their focus immediately turned to a protein called PVR that is found in cancer cells. We came to the conclusion that PVR might be a crucial protein that human malignancies employ to thwart an immune system onslaught, according to Dr Zang.
Normal tissues often lack or have very little PVR protein, but many tumour forms, including colorectal, ovarian, lung, oesophagal, head and neck, stomach, and pancreatic cancers, as well as myeloid leukaemia and melanoma, have high levels of PVR protein.
Additionally, PVRs appeared to suppress T cell and NK cell activity by attaching to the checkpoint protein TIGIT, which prompted studies to block the TIGIT/PVR pathway by utilising monoclonal antibodies raised against TIGIT. There are now more than 100 clinical trials globally that target TIGIT. However, a number of recent clinical investigations, including two sizable phases 3 clinical trials, have not succeeded in enhancing cancer outcomes.
Recognizing the Role of a New Receptor
Meanwhile, 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 Dr 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.
KIR2DL5 is a frequently found checkpoint receptor on the surface of human NK cells, which PVR cancer proteins employ to thwart the immune attack, according to Dr Zang and colleagues’ research published in JCI. The researchers demonstrated that their monoclonal antibody against KIR2DL5, by blocking the KIR2DL5/PVR pathway, allowed NK cells to vigorously attack and reduce human tumours and prolong animal survival in tests using humanised animal models of various types of human cancers (see an accompanying illustration). The monoclonal antibody we have developed may be a successful immunotherapy, according to Dr Zang, who added that the preclinical results “raise our hopes that targeting the KIR2DL5/PVR pathway was a good idea.”
For KIR2DL5/PVR immune checkpoint containing antibody medicines, Einstein has submitted a patent application, and the company is looking for a collaboration to advance and market the invention.
More than ten immune checkpoint inhibitors have already been created and patented by Dr Zang.
Several hundred patients with advanced solid cancers (melanoma, lymphoma, non-small cell lung cancer, nasopharyngeal cancer, head and neck cancer, small cell lung cancer, and lymphoma) or recurrent/refractory blood cancers are currently participating in phase 2 clinical trials in China testing one of those inhibitors (acute myeloid leukaemia, myelodysplastic syndromes). Beginning in the next year, a different immune checkpoint inhibitor developed by Dr Zang will be tested in cancer clinical trials in the US. (ANI)
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