Cell: a new generation of immunosuppressive checkpoint inhibitors is on the way

January 12, 2020 news / BIOON / - -- three conventional methods for cancer treatment are surgical removal, radiotherapy and chemotherapy In recent years, cancer immunotherapy, such as immunocheckpoint therapy, has been attracting more and more attention This kind of therapy can treat cancer by activating the human immune system, which has relatively less side effects and relatively better anti-cancer effect In addition, for some cancers, even in the late stage of cancer, such treatment can significantly improve the long-term survival rate of patients, or even achieve complete cure Immunocheckpoint refers to some inhibitory signaling pathways in the immune system, such as PD-1 / PD-L1 pathway and CTLA-4 pathway Under normal circumstances, in order to prevent activated T cells from destroying normal human cells, the immune system can control the activation process of T cells by activating PD-1 / PD-L1 and other immune checkpoints, so as to prevent T cells from mistakenly attacking normal cells However, by expressing the surface protein PD-L1, cancer cells can specifically recognize PD-1 on the surface of T cells, steal this control mechanism, thus activating the immune checkpoint to inhibit the immune activity of T cells, which will lead to cancer cells escape immune recognition and thrive This has created a new idea of immunotherapy for cancer treatment - blocking immunocheckpoint such as CTLA-4 or PD-1 by immunocheckpoint inhibitors, preventing cancer cells from stealing this control mechanism, so as to release the immune system's own ability to attack cancer Immunocheckpoint therapy can inhibit the activity of immunocheckpoint, release the immune brake in tumor microenvironment, reactivate the immune response of T cells to tumor, so as to achieve the anti-tumor effect PD-1 has two natural ligands, PD-L1 and PD-L2 At present, PD-1 / PD-L1 is one of the most widely used immunosuppressive checkpoint inhibitors However, only about 20% - 40% of patients can benefit from PD-1 / PD-L1 inhibitors Two important factors are the lack of tumor specific T cells and the functional depletion of T cells in the immunosuppressive tumor microenvironment As one of the deadliest cancers, pancreatic cancer is known for its resistance to immunocheckpoint therapy Recently, scientists have found that vista is overexpressed in immune cells (especially macrophages) infiltrating into pancreatic tumors, so when PD-L1 is inhibited, the active Vista pathway can significantly reduce the T-cell immune response in this tumor This suggests that the reason why PD-1 / PD-L1 inhibitors may fail in the treatment of pancreatic cancer is that the active Vista pathway still suppresses T cell immune response, and blocking Vista may improve the efficacy of PD-L1 inhibitors in the treatment of pancreatic cancer This also means that it is possible to target other immune checkpoints to improve the efficacy of existing cancer immunotherapy In a new study, researchers from research institutions such as the French National Center for scientific research found that as a new immunosuppressant, nkg2a antibody can potentially promote the anti-tumor ability of T cells and natural killer cells (NK cells), and can better treat cancer patients when combined with existing cancer immunotherapy The relevant research results were recently published in the journal Cell, and the title of the paper is "anti nkg2a mAb is a checkpoint inhibitor that promotes anti tumor immunity by leaving both T and NK cells" Picture from cell, DOI: 10.1016/j.cell.2018.10.014 The key to this study is a receptor molecule called nkg2a The researchers found that blocking the receptor enhanced the immune activity of NK cells and T cells in mice, thus enhancing the anti-tumor immune response They developed an antibody to nkg2a called monalizumab It is a humanized monoclonal antibody In the experiment, the researchers divided the mice into four groups, the first group of mice only gave monalizumab monoclonal antibody, the second group of mice only gave PD-L1 monoclonal antibody, the third group of mice gave monalizumab monoclonal antibody and PD-L1 monoclonal antibody, the fourth group of mice as the control group The mice were inoculated with B-cell lymphoma cells by subcutaneous injection They found that compared with the control group, only given PD-L1 mAb can make up to 40% of the mice survive, and only given monalizumab mAb alone did not bring significant anti-cancer effect, but the combination of the two mAbs can make up to 75% of the mice survive, which revealed that nkg2a mAb combination has strong anti-cancer potential More importantly, the researchers also conducted phase II trials in 31 patients with squamous cell head and neck cancer These patients can be divided into several groups and given different doses of monalizumab In addition, these patients received cetuximab Cetuximab, an EGFR inhibitor, has been approved for the treatment of head and neck cancer The results of the mid-term clinical trial showed that the combination of monalizumab and cetuximab achieved an objective remission rate of 31%, 50% of the patients were under stable control, and one patient's focus completely disappeared Monalizumab is also safe in clinical trials As of October 2018, 40 patients had participated in the treatment, without any additional safety issues The most common adverse reactions are fatigue, fever and headache These data show that the combination of monalizumab and cetuximab has a high remission rate and long-term response Therefore, as a new immunosuppressive checkpoint inhibitor, nkg2a antibody can promote the anti-tumor immune response by enhancing the activity of T cells and NK cells, so it can be used as a supplement to the first generation of cancer immunotherapy (bio Com) reference: Pascale Andr é et al Anti nkg2a mAb is a checkpoint inhibitor that promotes anti tumor immunity by unlashing both T and NK cells Cell, 2019, DOI: 10.1016/j.cell.2018.10.014