Research at the Albert Einstein College of Medicine

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image: The image on the left shows the binding of the tumor cell PVR protein with the NK cell receptor KIR2DL5 to prevent NK cell attack. In the image on the right, the monoclonal antibody bypasses the tumor cell/NK cell interaction, allowing the NK cell to attack and destroy the tumor cell.
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Credit: Tatyana Harris/Albert Einstein College of Medicine

November 15, 2022—(BRONX, NY)—Immune checkpoint inhibitors such as Keytruda and Opdivo work by releasing T cells from the immune system to attack tumor cells. Their introduction a decade ago marked a major advance in cancer treatment, but only 10-30% of treated patients experience long-term improvement. In an article published online today in The Journal of Clinical Investigation (JCI), scientists at the Albert Einstein College of Medicine describe findings that could boost the effectiveness of immune checkpoint therapy.

Rather than rallying T cells against cancer, Einstein’s research team used different human immune cells known as natural killer (NK) cells, with dramatic results. “We believe that the new immunotherapy we have developed has great potential to move into clinical trials involving various types of cancer,” said study leader Xingxing Zang, M.Med., Ph.D., incumbent. 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 Therapy Program at Montefiore Einstein Cancer Center.

Say friend of foe
The surface of immune cells is dotted with receptors called “checkpoint” proteins, which prevent immune cells from straying from their usual targets (cells infected with pathogens and cancer cells). When checkpoint receptors on immune cells bind to proteins expressed by the body’s own normal cells, the interaction dampens a possible immune cell attack. Devilishly, most types of cancer cells express proteins that bind to checkpoint proteins, tricking immune cells into withdrawing and not attacking the tumor.

Immune checkpoint inhibitors are monoclonal antibodies designed to bypass immune cell/cancer cell interactions by blocking either tumor proteins or immune cell receptors that bind to tumor proteins. Without brakes to prevent them, immune cells can attack and destroy cancer cells.

New focus on natural killer cells
The limited effectiveness of checkpoint inhibitors prompted Dr. Zang and other scientists to examine checkpoint pathways involving NK cells, which, like T cells, play a major role in cell elimination. unwanted. A cancer cell protein called PVR quickly caught their attention. “We realized that PVR could be a very important protein that human cancers use to hamper the attack of the immune system,” Dr. Zang said.

The PVR protein is usually absent or very rare in normal tissues, but is found in abundance in many tumor types, including colorectal, ovarian, lung, esophageal, head and neck, stomach, and pancreatic cancer, as well as myeloid leukemia and melanoma. Additionally, PVRs appeared to inhibit T-cell and NK-cell activity by binding to a checkpoint protein called TIGIT, prompting disruption of the TIGIT/PVR pathway using monoclonal antibodies directed against TIGIT. More than 100 clinical trials targeting TIGIT are currently underway worldwide. However, several clinical studies, including two large phase 3 clinical trials, have recently failed to improve cancer outcomes.

Recognize the role of a new receiver
Meanwhile, the PVR protein from cancer cells 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 by binding to the recently recognized KIR2DL5,” Dr. Zang said. To find out, he and his colleagues synthesized a monoclonal antibody targeting KIR2DL5 and performed in vitro and in vivo experiments using the antibody.

In their JCI paper, Dr. Zang and colleagues demonstrated that KIR2DL5 is a common checkpoint receptor on the surface of human NK cells, which PVR cancer proteins use to suppress immune attacks. 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 – enabled NK cells to vigorously attack and shrink human tumors and prolong animal survival (see attached illustration) . “These preclinical findings 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 antibodies and is interested in partnering 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 currently being tested in China in phase 2 clinical trials involving several hundred patients with advanced solid cancers (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer , head and neck cancer, melanoma, lymphoma) or recurrent. / refractory blood cancers (acute myeloid leukemia, myelodysplastic syndromes). Another of Dr. Zang’s immune checkpoint inhibitors will be evaluated starting next year in cancer clinical trials in the United States.

The title of the JCI study is “Blocking the KIR2DL5/PVR immunosuppressive pathway elicits potent human NK cell-mediated antitumor immunity.” Other authors include lead authors Xiaoxin Ren, Ph.D., and Mou Peng, MD, Ph.D., Peng Xing, MD, Ph.D., Yao Wei, MD, Phillip M. Galbo Jr., Ph. .D., Devin Corrigan, BS, Hao Wang, Ph.D., Yingzhen Su, Ph.D., Xiaoshen Dong, MD, Ph.D., Qizhe Sun, Ph.D., Yixian Li, MD, Xiaoyu Zhang , MD, Ph.D., Winfried Edelmann, Ph.D., Deyou Zheng, Ph.D., all at Einstein.

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About Albert Einstein College of Medicine
The Albert Einstein College of Medicine is one of the nation’s leading centers for research, medical education, and clinical investigation. In the 2022-23 academic year, Einstein enrolls 740 medical students, 194 doctoral students. students, 118 students in the combined MD/Ph.D. program and approximately 225 postdoctoral fellows. The College of Medicine has over 1,900 full-time faculty members located on the main campus and at its clinical affiliates. In 2022, Einstein received over $202 million in awards from the National Institutes of Health. This includes funding for major Einstein research centers in cancer, aging, intellectual developmental disorders, diabetes, clinical and translational research, liver disease and AIDS. Other areas in which the College of Medicine focuses its efforts include research in brain development, neuroscience, heart disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore, University Hospital and Einstein University Medical Center, advances clinical and translational research to accelerate the rate at which new discoveries become the treatments and therapies that benefit patients. For more information, visit einsteinmed.edu, follow us on Twitter, Facebook, Instagram, LinkedIn, and watch us on YouTube.


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