Science: Study finds new target for cancer immunotherapy - VISTA!

Although the body needs a strong immune response to fight infection, the immune system must also control the intensity of the response to avoid harm to healthy tissueOver the past decade, a team of American scientists, DrRandolph Noelle, has discovered many molecules used by the immune system to "moderate" immune responsesHowever, while these molecules, known as "negative checkpoint regulators," are often beneficial in limiting the development of autoimmune disease by regulating The T-cells' immune response to their own antigens, they also limit the immune system's attack on cancer cells like a "brake." VISTA is one of these negative checkpoint regulators and plays a key role in cancer immunosuppressionVISTA is known as V-type immunoglobulin domain-containing binor of T cell activationUnlike other negative checkpoint regulators found so far in activated T lymphocytes, VISTA is an inhibitory receptor expressed on na?ve T lymphocytesThere has been previous evidence that knockout of the VISTA gene significantly increases The anti-tumor immunity of T-cell-mediatedSource: In a new study published January 17 in the journal Science, DrNoelle's team further investigated VISTA's function in maintaining the silence and tolerance of na?ve T cellsVISTA deficiencies led to a decrease in the silent phenotype of na?ve T cells at transcription and epigenetic levels (Source: Science) The study found that THE gene loss of VISTA led to the redistribution of the na?ve T cell subgroup: a significant decrease in the silencing (inactive) subgroup, and an increase in memory-based activation of T-cell subgroupsIn the absence of an inherent VISTA expression, the epigenetic and transcriptionlevel of na?ve T cells are characterized to produce a stronger response to T-cell receptor and cytokine stimulationVista gene deficiency or blocking VISTA with antibodies can lead to significant amplification of antigen-specific T cells and reduced toleranceHowever, under inflammatory conditions, VISTA's expression on antigen-specific T cells decreases, and its ability to limit the response of na?ve T cells disappearsThe researchers believe these findings suggest that VISTA is a unique negative checkpoint receptor for na?ve T cellsDr Noelle says VISTA may be a valuable target for regulating immune responses in cancer and autoimmune diseasesLike other negative checkpoint regulators, blocking VISTA in cancer may enhance the host's ability to produce an antitumor-specific immune responseIn fact, currently, VISTA-targeted drugs have entered clinical research, such as CA-170 CA-170 is an oral small molecule double antagonist that selectively targets PD-L1 and VISTA Vista and PD-L1 have similar structures, both of which are effective inhibitors of T-cell function, according to curis, one of its developers Previous animal studies have shown that PD-1/PD-L1 interactions and combined blocking of VISTA can improve anti-tumor response in some tumor models Preclinical data showed that CA-170 exhibited anti-tumor effects similar to PD-1 or VISTA antibodies in a variety of tumor models, and toxicology studies showed that it was safe On February 6, Curis announced that its partner, Aurigene, would fund and conduct a Phase IIb/III randomized study to evaluate the efficacy of CA-170 combined chemotherapy in approximately 240 patients with non-squamous non-small cell lung cancer (nsNSCLC) Last year, Aurigene published clinical data on the IIA "basket study" of CA-170 for patients with multiple types of tumors, including nsNSCLC, at EMSO The results showed that CA-170 showed good safety and efficacy in nsNSCLC patients compared to various PD-1/PD-L1 antibodies Data support CA-170 has the potential to become a therapeutic option for nsNSCLC In addition to the small molecule CA-170, Curis acquired exclusive global rights from ImmuNext in January to develop and commercialize VISTA antibodies for cancer treatment, including ImmuNext's leading compound, CI-8993 (formerly JNJ-61110588), a clinically advanced VISTA monototaga CI-8993 was originally developed by ImmuNext and Janssen in collaboration In 2016, Janssen initiated a clinical study of CI-8993 to evaluate the safety, pharmacokinetics, and pharmacodynamics of its treatment of advanced solid tumors in phase Ia trials The study recruited 12 patients, one of whom developed dose-limiting side effects associated with cytokine release syndrome After Janssen chose to end the study, ImmuNext regained control of CI-8993 Under the latest agreement, Curis plans to restart CI-8993's Ia/Ib study in 2020 Domestically, NextPharma database shows that Suzhou Stanvi has taken the lead in the development of VISTA antibodies The company's general manager, Dr Zhou Qunmin, introduced to The Pharmaceutical Rubik's Cube Pro that VISTA, also known as PD-1H (Programd Death-1 homolog), was first discovered by Dr Noelle's team in March 2011 The paper, published in the journal of Experimental Medicine, reveals that VISTA is a new type of immunomodulatory molecule that regulates The Response of Negative T Cells and may play a role in the development of autoimmune and in cancer immunity surveillance In July of the same year, a study published in the journal Journal of The Journal, the Yale University's team of professors, said they had discovered PD-1H (later confirmed to be VISTA) and confirmed that PD-1H was widely expressed in a variety of tissues in mice, including the spleen, heart, brain, lungs, muscles, kidneys, testicles, etc., as well as on the surface of hematopoietic cells Since then, vista (PD-1H)-related studies have been published Two or three years ago, Stenway focused on VISTA (PD-1H), an immunomodulatory molecule, while developing PD-1 antibodies, and initiated the development of related antibodies However, drug development against the target has been hampered by the fact that VISTA (PD-1H) ligands or receptors have not previously been identified In the last two years, however, scientists have reported some related developments For example, in September 2018, researchers from R.D Systems first reported VISTA (PD-1H) ligand, VSIG-3, and confirmed that VSIG-3 inhibits human T-cell function through a new VSIG-3/VISTA pathway In October 2019, a team from BMS revealed in a Nature paper that VISTA (PD-1H) selectively participates in and inhibits T cells under acidic pH conditions, as in tumor microenvironments, while VISTA's extracellular edge selectively participates in and inhibits T cells (as in the case of tumor microspheres) Histidine) residuals mediate its binding with adhesion and co-inhibitor receptor (adhesion and co-receptor) P-opting glycoprotein ligand-1 (P-selectin glycoprotein ligand-1, PSGL-1) The study also confirmed that the antibodies that selectively block VISTA (PD-1H)-PSGL-1 interactions in acidic environments are sufficient to reverse VISTA-mediated immunosuppression in the body In addition to these findings, Professor Hemping and his co-authors published an important result in January this year in the journal PNAS, revealing the structure of the human VISTA (PD-1H) extracellular crystal structure (resolution 1.9?), and focusing on the contribution of VISTA (PD-1H) characteristic structures to its function, which are of great significance for future drug development Vista (PD-1H) crystal structure shows a striking number of group anine clusters and a long, curvature of CC's ring (Source: PNAS) Overall, Dr Zhou said that although not as popular as PD-1, VISTA (PD-1H) should be more and more interesting and an interesting target Previous studies have shown that different antibody binding sites targeted at VISTA (PD-1H) may yield two opposite outcomes, one that activates VISTA (PD-1H) to suppress the immune response, and the other is to inhibit VISTA (PD-1H) activation of the immune response Increasingly clear understanding of VISTA (PD-1H) ligands or receptors will facilitate subsequent drug development Whether the target will eventually become a drug depends on the ability to screen out "appropriate antibodies" Although there is still much unknown in this area, because VISTA (PD-1H) antibodies have the potential to treat autoimmune diseases (supplement: A study published in December 2019 in Science Translational Medicine by Professor Showing' team found that mice that injected PD-1H excited antibodies into lupus model mice not only delayed the onset of the disease, but also had a palpable skin disease, and there was hope for anti-tumor, so it is worth exploring Related paper: Mohamed A El Tanbouly et al VISTA is acheckpoint regulator for na?ve T cell quiescence and peripheral tolerance Science (2020) S2 Jun Liu et al Immune-checkpoint proteins VISTA and PD-1 non-rwyny regulate murine T-cell responses PNAS (2015) Li Wang et al VISTA, a novel mouse superfamily ligand that negatively regulates t cell JEM (2011) Dallas B Flies et al A Monoclonal Antibody Specific for Programme-1 Death-1 Homolog Prevents Graft Versus Host Disease in Mouse Models The Journal of The E Immunology (2011) Jinghua Wang et al VSIG-3 as a ligand of VISTA's bars human T-cell function Immunology (2018) Robert J Johnston et al VISTA is an acidic pH-selective ligand for PSGL-1 Nature (2019) Benjamin T Slater et al R R Insight Into Cell Coinhibition by PD-1H (VISTA) PNAS (2020) S8 Xue Han et al PD-1H (VISTA) - mediated of the nosiwis in the inanda noibet lupus erythematosus Science Translational Medicine (2019) References: 1 s Researchers sifer, VISTA, what-keep immunse system quiet against cancer (Source: Dartmouth-Hitchcock Medical Center) 2 s Agreement with ImmuNext for the Development and Commercialization of Anti-VISTA Anti-Vista Antibodies (Source: Curis) 6?ImmuNext Enters Options and License Agreement with Curis for the Development and Commercialization of Antagon Anti-Vista Antibodies in Oncology (Source: ImmuNext) 7- Display Flat Team Report on the role of PD-1H immunosuppressive pathways in the immunodeficiency pathway (Source: