Immune checkpoint inhibitors, such as Keytruda and Opdivo, work by releasing the immune system’s T cells to attack tumor cells. Its introduction a decade ago marked a breakthrough in cancer therapy, but only 10-30% of treated patients experience long-term improvement. In an article published online today in The Journal of Clinical Research (JCI), scientists from the Albert Einstein College of Medicine describe findings that could bolster the efficacy of immune checkpoint therapy.
Instead of pooling cancer T cells, Einstein’s research team used different human immune cells known as natural killer (NK) cells, with spectacular results. “We believe that the novel 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., Louis Professorship Chair. Goldstein Swan in Cancer Research and Einstein Professor of Microbiology and Immunology, Oncology, Urology, and Medicine and a member of the Cancer Therapeutics Program at the Montefiore Einstein Cancer Center.
distinguish friend from foe
The surfaces of immune cells are packed 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 own 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, tricking immune cells into stopping and not attacking the tumor.
Immune checkpoint inhibitors are monoclonal antibodies designed to short-circuit interactions between immune cells and cancer cells by blocking tumor proteins or receptors on immune cells that bind to tumor proteins. Without brakes to stop them, immune cells can attack and destroy cancer cells.
New focus on natural killer cells
The limited efficacy of checkpoint inhibitors led Dr. Zang and other scientists to look at checkpoint pathways involving NK cells, which, like T cells, play an important role in removal of unwanted cells. A cancer cell protein called PVR soon caught his attention. “We realized that PVR may be a very important protein that human cancers use to hinder the immune system’s attack,” said Dr. Zang.
The PVR protein is usually absent or very little in normal tissues, but it is found in abundance in many types of tumors, including colorectal, ovarian, lung, esophageal, head and neck, stomach, and pancreatic cancers. , as well as myeloid leukemia and melanoma. Furthermore, PVRs appeared to inhibit T cell and NK cell activity by binding to a checkpoint protein called TIGIT, prompting efforts to disrupt the TIGIT/PVR pathway using monoclonal antibodies made against TIGIT. More than 100 clinical trials targeting TIGIT are now in progress around the world. 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 cancer cell protein PVR was found to have another “binding partner” on NK cells: KIR2DL5. “We hypothesize that PVR suppresses NK cell activity not by binding to TIGIT but by binding to the newly recognized KIR2DL5,” Dr. Zang said. 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.
In their JCI paper, Dr. Zang and colleagues demonstrated that KIR2DL5 is a commonly occurring checkpoint receptor on the surface of human NK cells, which cancer PVR proteins use to suppress immune attack. In studies involving humanized animal models of various types of human cancers, the researchers demonstrated that their monoclonal antibody against KIR2DL5, by blocking the KIR2DL5/PVR pathway, enabled NK cells to vigorously attack and shrink human tumors and prolong the survival of tumors. animals (see attached illustration). . “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,” Dr. Zang said.
Einstein has filed a patent application for the KIR2DL5/PVR immune checkpoint that includes antibody drugs and is interested in a partnership to further develop and commercialize the technology.
Dr. Zang has previously developed and patented over 10 immune checkpoint inhibitors. One such inhibitor is now 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). neck, melanoma, lymphoma) or recurrent/refractory blood cancers (acute myeloid leukaemia, myelodysplastic syndromes). Another of Dr. Zang’s immune checkpoint inhibitors will be tested starting next year in cancer clinical trials in the United States.
Reference: Ren X, Peng M, Xing P, et al. Blockade of the KIR2DL5/PVR immunosuppressive pathway elicits potent human NK cell-mediated antitumor immunity. J Clin invest. 2022;132(22). do: 10.1172/JCI163620
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