Recent advances and future challenges of tumor vaccination therapy for recurrent glioblastoma

Abstract

Glioblastoma (GBM) is the most malignant CNS tumor with a highest incidence rate, and most patients would undergo a recurrence. Recurrent GBM (rGBM) shows an increasing resistance to chemotherapy and radiotherapy, leading to a significantly poorer prognosis and the urgent need for novel treatments. Immunotherapy, a rapidly developing anti-tumor therapy in recent years, has shown its potential value in rGBM. Recent studies on PD-1 immunotherapy and CAR-T therapy have shown some efficacy, but the outcome was not as expected. Tumor vaccination is the oldest approach of immunotherapies, which has returned to the research focus because of the failure of other strategies and subversive understanding of CNS. The isolation effect of blood brain barrier and the immunosuppressive cell infiltration could lead to resistance existing in all phases of the anti-tumor immune response, where novel tumor vaccines have been designed to overcome these problems through new tumor antigenic targets and regulatory of the systematic immune response. In this review, the immunological characteristics of CNS and GBM would be discussed and summarized, as well as the mechanism of each novel tumor vaccine for rGBM. And through the review of completed early-phase studies and ongoing large-scale phase III clinical trials, evaluation could be conducted for potential immune response, biosecurity and initial clinical outcome, which further draw a panorama of this vital research field and provide some deep thoughts for the prospective tendency of vaccination strategy. Video Abstract.

Keywords: Clinical trial; Immunotherapy; Recurrent glioblastoma; Tumor vaccine.

Fig. 1

Glioma local microenvironment and main associated changes. The glioblastoma (GBM) has highly immunosuppressive tumor microenvironment (TME) consisting of considerable cells, cytokines, chemokines and microvessels. TGF-β will transfer the fibroblast into cancer-associated fibroblast (CAF); there will be more epithelial mesenchymal transition (EMT) under IL-1β, IL-6 and TNF-α; with VEGF, there will be more abnormal vessel growth. With IL-10, TGF-β, M-CSF and IL-35, M2-macrophage polarization will be enhanced and regulatory T cells (Tregs) will inhibit immune activity of CD8 + T cells by secreting IL-10, TGF-β, M-CSF and IL-35. The tumor cells highly express immune suppressive factors like programmed cell death ligand 1 (PD-L1), IDO and decreases the level of MHC to inhibit tumor antigen recognition and presentation. In GBM TME, the microglial cells always downregulate potential immune response and promotes systematic immunosuppression by secreting TGF-β and IL-10. Tumor-associated macrophages (TAMs) has two subtypes, namely immunopromoting subtype (M1) and immunosuppressive subtype (M2). TAMs mediate and balance tumor immune activity by highly expressing PD-L1 and secreting TGF-β, IDO, CXCR4, IL-10, CXCL12, CCL20, CCL22 etc. MDSCs highly secrete IL-10, IL-12, TGF-β, TNF-α, IDO to inhibit immunotherapy response. Immature DCs can secrete some factors and express PD-L1, however, role of immature dendritic cells (DCs) is not determined. Tregs mediate immunosuppressive effects through upregulation of various soluble factors, immune checkpoints and metabolic pathways. Due to the increased levels of checkpoint exhaustion molecules, exhausted T cells downregulates immune response. Neutrophil and natural killer cells (NK cells) participates in the regulation of immunotherapy by upregulating G-CSF, S100A4 and IFN-γ, while clear role of B cell in GBM TME is not well established. Extracellular matrix (ECM) also serves as an important component in GBM TME. Vascularization is observed to be reinforced in GBM immunosuppressive TME, therefore anti-vascularization can be useful target to treat GBM. Immune cells, for example DCs, can migrate via tumor draining lymph nodes of the brain to deep cervical lymph nodes and promote tumor antigen to promote an adaptive antitumor immune response. The process can also be suppressed by the local immunosuppressed TME. On one hand, the bone marrow can restore and release suppressed T cells, on the other hand, chemotherapy (eg., TMZ) to GBM can induce lymphopenia that is exacerbated by bone marrow sequestration of T cells. Specific T cells to tumor antigens can be destroyed by spleen. Green arrow indicates the factors or activities are upregulated. CSF, colony stimulating factor; APC, antigen-presenting cells; IDO, indolamine 2,3-dioxygenase; MHC, major histocompatibility complex

Fig. 2

Major available immunotherapies for newly diagnosed and recurrent glioblastoma. A Treatment of monoclonal antibodies. There are three phase III clinical trials involving immune checkpoint inhibitors on GBM, namely CheckMate143 in rGBM, CheckMatre498 in uMGMT nGBM and CheckMate548 in MGMT nGBM. However, all the three clinical trials failed to prolong OS of nGBM/rGBM. B Treatment of oncolytic virus/vectors. Virus potentially releases neoantigen and modulates damage-associated molecular patterns, it also helps to deliver gene therapy and release key inflammatory factors to activate immune system. Herpesviruses, reoviruses, pox virus, adenoviruses and Zika viruses are commonly used in vaccines in clinical manner. Briefly, virus vaccines and vectors have showed favorable anti-tumor activity in preclinical models and small clinical trials. C Treatment of chimeric antigen receptor. Chimeric antigen receptor (CAR) therapies mainly include CAR-T, TCR-T and CAR-NK. Common CAR-T targets involve EGFR vIII, HER2, IL-13αR2, NKG2D etc., common CAR-NK targtes involve NKG2D, glioma stem cell etc. CAR therapies demonstrate promising efficacy in preclinical glioma models, the large-scale clinical trials are still ongoing. D Treatment of peptide vaccines. EGFR vIII is also regarded as a target for peptide vaccine in glioma, the ACT IV trial administrates Rindopepimut in nGBM, the ReACT trial uses Rindopepimut to treat rGBM. OS of rGBM is prolonged in ReACT trial. E Treatment of DC vaccines. Tumor antigen, stem cell antigen and CMV antigen can be degraded to peptide, distinct peptide will invoke DCs to secrete immune activators to enhance the anti-tumor immunity. After the process by the peptide, sensitive DCs will be selected to generate DC vaccines. A phase III randomized controlled trial conducted on nGBM and rGBM reveales DCVax-L prolongs the OS with acceptable toxicity. F Other novel therapies include nanoparticles therapy, gene therapy and oligonucleotide therapy. The check mark in green indicates OS of glioma patients can be prolonged in clinical trials; the cross in red indicates OS of glioma patients can not be significantly prolonged. PD-1, programmed cell death 1; PD-L1 programmed cell death ligand 1; GBM, glioblastoma; nGBM, newly diagnosed GBM; rGBM, recurrent GBM; uMGMT, MGMT promoter unmethylated; MGMT, MGMT promoter methylated; DCs, dendritic cells; CAR, chimeric antigen receptor; TCR, T cell receptor-T; NK cells, natural killer cells; CMV, cytomegalovirus; OS, overall survival

Fig. 3

Available modalities and targets of immunotherapy for glioma/glioblastoma. Cell therapy mainly involves CAR-T and TCR-T therapy. As for cell therapy, the glioma-specific and glioma-associated targets for CAR-T therapy includes EGFR VIII (NCT01454596, NCT02664363, NCT02209376, NCT03283631) and IL-13Rα2 (NCT02208362), Her2 (NCT03500991), GD2 (NCT04196413), EphA2, B7-H3 (NCT05241392, NCT04077866), (NCT05241392, NCT05366179); the glioma-specific and glioma-associated targets include H3K27M (NCT04808245), CICR215W, IDH1R132H (NCT02454634) and NLGN4X, PTPRZ1. Tumor vaccines mainly include DC vaccine, DNA/RNA vaccine, neoantigens and peptide targets. As for vaccines immunotherapy, DC vaccine includes DCvax-L (NCT00045968) and ICT-107 (NCT00045968); DNA/RNA vaccine include VEGFR2-VXMO1 (NCT02410733, NCT03750071); neoantigen as peptide targets includes IDH1R132H-IDH-vac (NCT03343197, NCT04056910, NCT02073994, NCT04195555), H3K27M-H3-vac (NCT04943848, NCT04749641, NCT04808245), EGFR VIII-CDX-110 (NCT02573324, NCT01520870, NCT01480479, NCT01498328), multi-peptide targets include APVAC1/2 (GAPVAC) (NCT03422094, NCT02287428), IMA950, NeoVax (NCT03422094). The combined therapy indicates the combination of two or more lines of immunotherapy (including checkpoint inhibitors) as well as small molecule mutant IDH inhibitors. Briefly, there are mIDH inhibitors (mIDHi) + IDH-vac (NCT03750071), AHRi + anti-PD-L1 (NCT03893903), VXM01 + anti-PD-L1, IDH1vac + anti-PD-L1, H3-vac + anti-PD-1 (NCT02960230), H3-vac + anti-PD-L1 (NCT02960230), vorasidenib/ivosidenib/BAY1436032 (NCT02481154, NCT02746081, NCT03030066, NCT03343197, NCT04164901). CAR, chimeric antigen receptor; TCR, T cell receptor-T; DCs, dendritic cells; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1