New assisted anti-PD-1 therapy benefits survival benefits for patients with recurrent glioblastoma

To see if PD-1 blocking therapy can alter immune function and prolong patient survival, a team led by Robert Prins and Timothy Cloughesy of the University of California, Los Angeles conducted a randomized, multicenter early clinical trial to assess 35 recurrent, surgically removed GBM patients receiving pembrolizumab as an immune response and survival rate after new or complementary treatments, and identified potential reaction biomarkersThe findings were published online in Nature Medicine in February 2019- From the article:: Timothy FCloughesy, et alNat Med2019 Mar; 25 (3): 477-486doi: 10.1038/s41591-018-0337-7Epub 2019 Feb 11glioblastoma multicell(glioblastoma multi-forme, GBM) is the most malignant and aggressive central nervous system tumor with a very poor prognosisThe incidence rate of GBM was 3.2 per 100,000 cases, which was the most common primary, malignant central nervous system tumor, and its 3-year survival rate was only 10.1%The median progression-free survival, PFS in primary GBM was 6.9 months, while standard treatment: surgery and radiation therapy combined with tamoxide, the average total survival time (median overall survival, mOS) was only 14.6 months, while in recurrent GBM, mOS was only about 24 to 44 weeksTherefore, the treatment of GBM patients is in urgent need of new treatmentTo date, although PD-1 blocking has been shown to have limited efficacy on GBM, preclinical studies have shown that PD-1/PD-L signaling shafts have immune correlation and potential therapeutic effectsSo to see if PD-1 blocking therapy can alter immune function and prolong patient survival, a team led by Robert Prins and Timothy Cloughesy of the University of California, Los Angeles conducted a randomized, multicenter early clinical trial to evaluate 35 recurrent, surgically removable GBM patients receiving pembrolizumab as an immune response and survival rate after new or complementary treatments, and identifying potential biomarkersThe findings were published online in Nature Medicine in February 2019 in this study, 16 of the 35 recurrent GBM cases were anti-PD-1 antibody new assisted therapy (Neoadjuvant group, new auxiliary group) prior to surgery, and with the remaining 19 people who also experienced postoperative anti-PD-1 antibody-assisted therapy (Adjuvant treatment, auxiliary group), for details shown in Table 1 The results showed that the median survival of the new assisted treatment group was 417 days, while the median survival in the assistive group was 228.5 days, according to figure 2 The study found that patients in the new auxiliary group showed elevated expression of T-cells and INF-sylgen-related genes, and tumor cell cycle-related gene reduction, which was not the case in the auxiliary group Compared to the auxiliary group, the tumor in the new auxiliary group decreased the cloning amplification of T cells in the local microenvironment and the reduction of PD-1 expression in peripheral blood T cells, and the decrease of mononucleosis The principle of the specific mechanism is shown in Figure 3, Figure 4 Table 1 Baseline data sheet for two groups of patients Figure 2 The new assistive pembrolizumab can significantly improve the total and no progressive survival of patients with recurrent GBM note: Patients in the new auxiliary group (red) received 200 mg pembrolizumab treatment before the surgical removal of 14 ?5 d; patients in the auxiliary group (blue) did not receive this treatment; and as an auxiliary treatment, 200 mg pembrolizumab was received every 3 weeks after the operation a: Kaplan-Meier for total survival The mOS for patients receiving assisted treatment only is 228.5 days, while the mOS in the new assisted treatment group is 417 days (HR:0.39; P is 0.04) b: Start and stop time of dexamethasone or equivalent drug or belate monoantigen c: A representative patient in the new auxiliary group A 66-year-old female patient with the first recurrence of GBM, IDH-1 (-), MGMT demethylation PD: progression of disease; pembro: pembrolizumab; Tx: Treatment Figure 3 Tumor gene expression spectrum in patients in the new auxiliary group a: Tumor INF-associated genomic expression heat map In the figure, "A" represents the patients in the new secondary group and "B" represents the patients in the secondary group The tree chart indicates that Ward minimizes unsupervised hierarchical clustering Green: Decreased expression; b: Figure above: rich analysis of the genome, quartile s1 The gene set is divided into three categories: (i) interferon pathway induction (ii) T cell activity (iii) cell cycle/proliferation Figure: MRNA expression corresponding to the above gene set, typical gene Basemap: Heat map of no progress and total survival for each patient (log 2) MHC: major tissue compatibility complex; OS: overall survival; PFS: No progression lifetime The mechanism of new complementary PD-1 blocking therapy for the treatment of recurrent polymorphic GBM normal, tumors soak lymphocytes and inhibit PD-1/PD-L1 In the new complementary treatment, PD-1 blockers restore the checkpoint and regulate T-cell receptor (TCR) clones through systemic activation and tumor-specific T-cell cloning In turn, activated T-cells increase interferon-sym related signaling conduction, while lowering tumor cell cycle-related genes After surgery, tumor-specific T cells continue to remove residual tumor cells and gradually convert to memory T cells through continuous auxiliary anti-PD-1 monoclonal antibodies In the auxiliary group, surgery occurs before the checkpoint blocks release Due to the reduction of residual tumor antigens, TCR regulation is less stable and fewer tumor-specific T cells are activated As tumor-specific T cells decrease, residual tumor cells continue to proliferate rapidly authors concluded that the new assisted PD-1 blocking therapy may enhance the local and systemic anti-tumor immune response and may be a more effective way to treat GBM finally, given the significant improvement in survival rates and the potential bias of small samples, the authors will next expand the sample size and conduct clinical trials of new complementary immunotherapy, as well as in-depth biological analysis.