Telling Friend from Foe
The surfaces of immune cells are studded with receptors known as “checkpoint” proteins, which avoid immune cells from wandering off beyond their normal targets (pathogen-infected cells and cancer cells). When checkpoint receptors on immune cells bind with proteins revealed by the bodys own typical cells, the interaction puts the brakes on a possible immune-cell attack. Diabolically, most kinds of cancer cells express proteins that bind with checkpoint proteins, fooling immune cells into standing down and not attacking the tumor.
Xingxing Zang, Ph.D. Credit: Albert Einstein College of Medicine
Immune checkpoint inhibitors are monoclonal antibodies developed to short-circuit immune-cell/cancer-cell interactions by blocking either the growth proteins or the immune-cell receptors that bind with growth proteins. With no brakes to hinder them, immune cells can destroy and attack cancer cells.
New Focus on Natural Killer Cells
The limited effectiveness of checkpoint inhibitors triggered Dr. Zang and other researchers to look at checkpoint paths involving NK cells, which– like T cells– play significant roles in getting rid of unwanted cells. A cancer-cell protein called PVR soon recorded their attention. “We recognized that PVR may be a really important protein that human cancers utilize to hobble the immune systems attack,” stated Dr. Zang.
PVR protein is generally missing or really scarce in typical tissues but is discovered in abundance in many types of growths including colorectal, ovarian, lung, neck, esophageal and head, stomach, and pancreatic cancer as well as myeloid leukemia and melanoma. PVRs appeared to inhibit T cell and NK cell activity by binding to a checkpoint protein called TIGIT– triggering efforts to disrupt the TIGIT/PVR path by utilizing monoclonal antibodies made versus TIGIT.
Acknowledging the Role of a New Receptor
The cancer-cell protein PVR was found to have another “binding partner” on NK cells: KIR2DL5. “We assumed that PVR reduces NK cell activity not by binding with TIGIT but by binding with the just recently acknowledged KIR2DL5,” said Dr. Zang. To discover, he and his colleagues synthesized a monoclonal antibody targeting KIR2DL5 and carried out in vitro and in vivo experiments utilizing the antibody.
” We believe the unique immunotherapy weve established has terrific prospective to move into medical trials involving various types of cancer.”– Xingxing Zang, M.Med, Ph.D
. In their JCI paper, Dr. Zang and associates demonstrated that KIR2DL5 is a commonly occurring checkpoint receptor on the surface area of human NK cells, which PVR cancer proteins utilize to suppress immune attack. In research studies including humanized animal models of a number of types of human cancers, the scientists revealed that their monoclonal antibody versus KIR2DL5– by obstructing the KIR2DL5/PVR path– permitted NK cells to vigorously assault and diminish human growths and lengthen animal survival (see the illustration at the top of this article). “These preclinical findings raise our hopes that targeting the KIR2DL5/PVR path was an excellent concept which the monoclonal antibody weve established might be a reliable immunotherapy,” stated Dr. Zang.
Einstein has filed a patent application for KIR2DL5/PVR immune checkpoint including antibody drugs and has an interest in a partnership to additional establish and advertise the innovation.
Dr. Zang has formerly developed and patented more than 10 immune checkpoint inhibitors. One of those inhibitors is now being evaluated in China in phase 2 medical trials involving several hundred patients with advanced strong cancers (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, head and neck cancer, cancer malignancy, lymphoma) or recurrent/refractory blood cancers (acute myeloid leukemia, myelodysplastic syndromes). Another of Dr. Zangs immune checkpoint inhibitors will be examined starting next year in cancer clinical trials in the United States.
Discover about immune checkpoint inhibitors, one type of immunotherapy used to deal with cancer.
Reference: “Blockade of the immunosuppressive KIR2DL5/PVR path elicits potent human NK cell– mediated antitumor immunity” by Xiaoxin Ren, Mou Peng, Peng Xing, Yao Wei, Phillip M. Galbo Jr., Devin Corrigan, Hao Wang, Yingzhen Su, Xiaoshen Dong, Qizhe Sun, Yixian Li, Xiaoyu Zhang, Winfried Edelmann, Deyou Zheng and Xingxing Zang, 15 November 2022, Journal of Clinical Investigation.DOI: 10.1172/ JCI163620.
Extra authors include lead authors Xiaoxin Ren, Ph.D., and Mou Peng, M.D., Ph.D., Peng Xing, M.D., Ph.D., Yao Wei, M.D., Phillip M. Galbo Jr., Ph.D., Devin Corrigan, B.S., Hao Wang, Ph.D., Yingzhen Su, Ph.D., Xiaoshen Dong, M.D., Ph.D., Qizhe Sun, Ph.D., Yixian Li, M.D., Xiaoyu Zhang, M.D., Ph.D., Winfried Edelmann, Ph.D., Deyou Zheng, Ph.D., all at Einstein.
In image at right, monoclonal antibody short-circuits growth cell/NK cell interaction, permitting the NK cell to attack and destroy the growth cell. Rather than rally T cells versus cancer, the Einstein research study team utilized various human immune cells known as natural killer (NK) cells. The surface areas of immune cells are studded with receptors known as “checkpoint” proteins, which prevent immune cells from wandering off beyond their usual targets (pathogen-infected cells and cancer cells). The minimal effectiveness of checkpoint inhibitors triggered Dr. Zang and other researchers to look at checkpoint pathways including NK cells, which– like T cells– play major roles in eliminating unwanted cells. One of those inhibitors is now being checked in China in phase 2 scientific trials including numerous hundred patients with innovative strong cancers (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, head and neck cancer, cancer malignancy, lymphoma) or recurrent/refractory blood cancers (acute myeloid leukemia, myelodysplastic syndromes).
Image at left reveals the tumor-cell protein PVR binding with the NK-cell receptor KIR2DL5 to prevent NK-cell attack. In image at right, monoclonal antibody short-circuits growth cell/NK cell interaction, allowing the NK cell to attack and destroy the tumor cell. Credit: Tatyana Harris/Albert Einstein College of Medicine
Their function is to prevent an immune reaction from being so effective that it ruins healthy cells in the body. Immunotherapy drugs called immune checkpoint inhibitors, such as Keytruda and Opdivo, work by unleashing the immune systems T cells to assault growth cells.
Now, researchers at Albert Einstein College of Medicine explain findings that could reinforce the efficiency of immune-checkpoint treatment in a study released in The Journal of Clinical Investigation (JCI) on November 15.
Instead of rally T cells versus cancer, the Einstein research team used different human immune cells called natural killer (NK) cells. Their remarkable outcomes were significant. “We think the unique immunotherapy weve developed has great prospective to move into medical trials including various types of cancer,” said study leader Xingxing Zang, M.Med., Ph.D. He is the Louis Goldstein Swan Chair in Cancer Research and teacher of microbiology & & immunology, of oncology, of urology, and of medication at Einstein and a member of the Cancer Therapeutics Program of the Montefiore Einstein Cancer Center.
