Application of PD-1/PD-L1 checkpoint blocker immunotherapy glioblastoma

PD-L1 is highly expressed in GBM, but the predictive effect of PD-L1 expression on the benefits of GBM immunotherapy is still unclearIn addition, PD-L1's expression of the value of survival prognosis in GBM also has conflicting resultsIt can be inferred that the PD-1/PD-L1 signal conduction pathway is not a key role in the occurrence and progress of GBM and may be influenced by other factorsTherefore, it may be difficult to obtain satisfactory therapeutic results by simply blocking the PD-1/PD-L1 pathway- Excerpted from the article chapter
(Ref: Wang X), etJ Exp Clin Cancer Res2019 Feb 18;38 (1):87(1): 10.1186/s13046-019-1085-3PD-1/PD-checkpoint-L1 checkpoint blocker (PD-1/PD-L1) has a significant effect on the treatment of tumorsPablo Zumata has been approved as a first-line drug for the treatment of advanced non-small cell lung cancer (NSCLC) for PD-L1-positive expressionThe treatment of GBM by PD-1/PD-L1 checkpoint blockers did not make a breakthrough due to the weak immunogenic response of glioblastoma (GBM) and the inhibition of the immune microenvironment caused by cytokines and immune cellsClinically, there are many problems to overcome, such as different genomic subtypes on PD-1/PD-L1 checkpoint blockers, PD-1/PD-L1 checkpoint blocker treatment of new diagnosis and recurrent GBM effect comparison, and how to form the best combination therapyXin Wang of Shandong Cancer Hospital, affiliated with Shandong University, and others published an overview article on the treatment of GBM for PD-1/PD-L1 checkpoint blockers in February 2019 in Journal of Experimental and Clinical Cancer ResearchPD-L1 is highly expressed in GBM cells, and combined checkpoint blockers have shown better efficacy in preclinical GBM mouse model experimentsHowever, the effect of PD-1/PD-L1 checkpoint blockers in clinical treatment of GBM is controversialThe results of a Phase III clinical trial (Checkmate-143) suggest that navubutradosa, which is targeted at PD-1, did not extend the survival of patients compared to the use of baval-monoantigen for recurrent GBMIn subsequent Phase III clinical trials, which included Checkmate-498 (NCT02617589) and Checkmate-548 (NCT02667587), the researchers looked at the clinical efficacy of Navu mono-anti-radiation (RT) and TMZ treatment streating in newly diagnosed GBM patients Checkmate-498 compared the differences in the benefits of the standard treatment of Navu-TMZ in newly diagnosed Patients with unmethylated GBM at MGMT In Checkmate-548's newly diagnosed MGMT methylated GBM patients, navaisa-resistant and RT-TMZ-TMZ were effective in addition to the characteristics of the above molecular markers, TIL and NK cells are also considered to be effective predictors of PD-1/PD-L1 immunocheckpoint blockers A certain amount of TIL in TME is still the basis for judging the efficacy of checkpoint blockers Therefore, the prognosis and predictive role of TIL is worth exploring further In addition to TIL, NK cells have also been shown to play an integral role in PD-1/PD-L1 checkpoint blocking Some studies have shown that NK cells can react directly to PD-1/PD-L1 checkpoint blockers In addition to individual molecular markers, bioinformatics analyzed genetic data from 297 GBM samples Eight genes (FOXO3, IL6, IL10, ZBTB16, CCL18, AIMP1, FCGR2B and MMP9) have significant prognosis value for GBM Patients were classified into two categories using topical immune-related risk characteristics: low-risk patients with high expression protective genes (FOXO3, AIMP1 and ZBTB16) and high-risk patients with high-risk gene expression levels (IL6, IL10, CCL18, FCGR2B, and MMP9) Which group of patients is more likely to benefit from PD-1/PD-L1 checkpoint blocking and is worth exploring , in contrast to NSCLC and melanoma with higher levels of tumor mutation load (TML), GBM showed lower levels of TML in most cases Different sensitivities to PD-1/PD-L1 checkpoint blocking can also be observed in GBM Lower "new antigen" mutation loads in GBM reduce the immune system's chances of identifying tumor cells In addition, some specific gene mutations in GBM induce immunosuppressive microenvironments by regulating cytokines and immune cells GBM's immunosuppressive microenvironment consists of a variety of immunosuppressive cells and cytokines Immune-effect cells, including CD4-T cells, CD8-T cells, NK cells, and tumor-suppressing M1-TAM, are consumed or inhibited Immune suppressost cells, including Tregs, M2-TAM, bone marrow cells and myelin inhibitory cells (MDSC) Tumor cells express high levels of PD-L1 and IDO, lower MHC and co-stimulating molecules, express or activate STAT3, cause PTEN deficiency, and then reduce immunogenicity and induce the collection of Tregs Tumor cells secrete MICA/B, IL-10, TGF-beta, and HLA-E to collect Tregs and inhibit T-cell and NK cell activity Tregs penetration was attracted and induced by secreting various chemate factors and other factors, such as CCL2, CSF1, MCP-3, CXCL12, CX3CL1, GDNF, ATP, and GM-CSF In addition, tumor cells secrete immunomodulating cytokines, which polarize TAM to immunosuppressive M2 phenotypes Immune suppresses cells that secrete a variety of cytokines (including IL-6, IL-10, IL-4Ra, FasL, CCL2, PGE2, EGF, VEGF, and MMP9) to inhibit their function Tregs lowers the production of IL-2, inhibits the production of IFN-thain, and increases the secretion of TH2 cytokines, thereby inhibiting T-cell function PD-L1 is highly expressed in GBM, but the predictive effect of PD-L1 expression on the benefits of GBM immunotherapy is still unclear In addition, PD-L1's expression of the value of survival prognosis in GBM also has conflicting results It can be inferred that the PD-1/PD-L1 signal conduction pathway is not a key role in the occurrence and progress of GBM and may be influenced by other factors Therefore, it may be difficult to obtain satisfactory therapeutic results by simply blocking the PD-1/PD-L1 pathway tumor-specific new antigen, EGFRvIII, mutations occur in 31%-50% of GBM patients and 37%-86% of tumor cells express mutations in the EGFR protein Given EGFRvIII's high expression and carcinogenic characteristics, it may be an ideal target and biomarker for GBM immunotherapy In addition to EGFRvIII, the IDH1/2 mutation also plays an important role in GBM In primary GBM, the incidence of IDH1/2 mutation sympathises was about 5%, but in recurrent GBM, the incidence of IDH1/2 mutations was about 84.6% The efficacy of PD-1/PD-L1 checkpoint blockers depends on the effective leaching of activated T lymphocytes in the tumor Kohanbash et al confirmed that idh1/2 mutation inhibited the accumulation of the intra-effect T-cell in glioma tumors, while the use of IDH1 inhibitors to treat significantly enhanced effect T-cell immersion Therefore, the mutation of IDH1/2 in glioma provides a new perspective on the clinical efficacy of PD-1/PD-L1 checkpoint blocking overall, it is necessary to establish a subgroup indicator with multiple molecular markers in GBM, which can be used to determine the therapeutic effect of combination therapy based on PD-1/PD-L1 checkpoint blockers, which can maximize the survival time of GBM patients and enable the treatment to truly achieve the goal of precision medicine.