Research results could strengthen the effectiveness of immune checkpoint therapy

Research results could strengthen the effectiveness of immune checkpoint therapy

Immune checkpoint inhibitors like Keytruda and Opdivo work by unleashing the immune system's T cells to attack tumor cells. Their introduction a decade ago marked a major advance in cancer therapy, but only 10% to 30% of treated patients experience long-term improvement. In a paper published online today in the Journal of Clinical Investigation (JCI), scientists at the Albert Einstein College of Medicine describe findings that could strengthen the effectiveness of immune checkpoint therapy.

Instead of collecting T cells to fight cancer, the Einstein research team used various human immune cells known as natural killer (NK) cells - with dramatic results.

We believe that the novel immunotherapy we have developed has great potential to enter clinical trials in various types of cancer.”

Xingxing Zang, M.Med., Ph.D., principal investigator

Xingxing Zang is the Louis Goldstein Swan Chair in Cancer Research and Professor of Microbiology and Immunology, Oncology, Urology and Medicine at Einstein and a member of the Cancer Therapeutics Program at the Montefiore Einstein Cancer Center.

Distinguish friend from enemy

The surfaces of immune cells are dotted with receptors known as “checkpoint” proteins, which prevent immune cells from straying beyond their usual targets (pathogen-infected cells and cancer cells). When checkpoint receptors on immune cells bind to proteins expressed by the body's normal cells, the interaction slows down a potential attack by immune cells. Devilishly, most types of cancer cells express proteins that bind to checkpoint proteins and trick immune cells into holding back and not attacking the tumor.

Immune checkpoint inhibitors are monoclonal antibodies designed to short-circuit interactions between immune cells and cancer cells by blocking either the tumor proteins or the immune cell receptors that bind to tumor proteins. Without brakes, immune cells can attack and destroy cancer cells.

New focus on natural killer cells

The limited effectiveness of checkpoint inhibitors led Dr. Zang and other scientists to study checkpoint signaling pathways involving NK cells, which, like T cells, play an important role in eliminating unwanted cells. A cancer cell protein called PVR soon caught their attention. “We realized that PVR could be a very important protein used by human cancers to hinder the immune system attack,” said Dr. Zang.

PVR protein is usually absent or very scarce in normal tissues, but is found in many types of tumors, including colon, ovarian, lung, esophageal, head and neck, stomach and pancreatic cancers, as well as myeloid leukemia and melanoma. In addition, PVRs appear to inhibit T cell and NK cell activity by binding to a checkpoint protein called TIGIT-, which has led to efforts to disrupt the TIGIT/PVR pathway through the use of monoclonal antibodies raised against TIGIT. There are currently more than 100 clinical studies of TIGIT underway worldwide. However, several recent clinical trials, including two large Phase 3 clinical trials, have failed to improve cancer outcomes.

Recognize the role of a new receptor

Drug Discovery E-Book

Compilation of the top interviews, articles and news from the last year. Download a free copy

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 to TIGIT, but rather by binding to the recently recognized KIR2DL5,” said Dr. Zang. To find out, he and his colleagues synthesized a monoclonal antibody that targets KIR2DL5 and conducted in vitro and in vivo experiments with the antibody.

In their JCI article, Drs. Zang and colleagues show that KIR2DL5 is a common checkpoint receptor on the surface of human NK cells that PVR cancer proteins use to suppress immune attacks. In studies using humanized animal models of various human cancers, the researchers showed that their monoclonal antibody against KIR2DL5—by blocking the KIR2DL5/PVR signaling pathway—enabled NK cells to vigorously attack and shrink human tumors and prolong animal survival (see accompanying illustration). “These preclinical results give us hope that targeting the KIR2DL5/PVR pathway was a good idea and that the monoclonal antibody we developed could be an effective immunotherapy,” said Dr. Zang.

Einstein has filed a patent application for the KIR2DL5/PVR immune checkpoint including antibody drugs and is interested in a partnership to further develop and commercialize the technology.

Dr. Zang has previously developed and patented more than 10 immune checkpoint inhibitors. One of these inhibitors is now being tested in China in Phase 2 clinical trials involving several hundred patients with advanced solid cancer (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, head and neck cancer, melanoma, lymphoma) or relapsed/refractory blood cancer (acute myeloid leukemia, myelodysplastic syndromes). Another one from Dr. Zang's immune checkpoint inhibitor will be evaluated in cancer clinical trials in the United States starting next year.

Source:

Albert Einstein College of Medicine

Reference:

Ren, X., et al. (2022) Blockade of the immunosuppressive KIR2DL5/PVR signaling pathway triggers potent human NK cell-mediated antitumor immunity. Journal of Clinical Investigation. doi.org/10.1172/JCI163620.

.