Glioma vs Glioblastoma
In general, glioma is a type of tumor arising from the glial group of cells within the brain, which provide support functions to neurons throughout the brain. There are four grades of glioma, and each has different types of cells present and different treatment strategies. A glioblastoma is a grade IV glioma, which is the most aggressive form. This means that all glioblastomas are gliomas, but not all gliomas are glioblastomas.
Novel treatment urgently needed
Despite advances in surgery, radiation and chemotherapy, the prognosis of patients with malignant glioma is still very poor; therefore, the development of a novel therapeutic modality is urgently needed. There are numerous reports demonstrating that systemic immunotherapy using dendritic cells or a peptide vaccine are capable of inducing an anti-glioma response. Peptide vaccine immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and prolong survival in patients with glioma without major side effects. Now, peptide vaccine immunotherapy could be a new treatment modality for patients with brain tumors.
Peptide vaccine therapies
Cancer peptide vaccines are a promising cancer immunotherapy that can induce cancer-specific cytotoxic T lymphocytes (CTLs) in tumors. The peptides are designed based on tumor biomarkers or mutations to bind to histocompatibility complex (MHC) class I and MHC class II.
Putative mode of action of peptide vaccine therapy for glioma. Administration of the vaccine along with an appropriate adjuvant, such as GM-CSF, results in antigen-presenting cell (APC) activation and subsequent priming of T helper cells. These processes ultimately induce CD8+ T cell antitumor immune responses (Weller M et al. Nature Reviews Neurology, 2017).
IMA950 peptide vaccine
IMA950 is a therapeutic multi-peptide vaccine for HLA A2+ phenotype containing 11 tumor-associated peptides (TUMAPs) found in a majority of glioblastomas and is designed to activate TUMAP-specific T cells. The use of 11 TUMAPs increases the likelihood of a multi-clonal, highly specific T-cell response against tumor cells leading to decreased likelihood of immune evasion of the tumor by down-regulation of target antigens. In a recent phase I/II trial [1], IMA950 peptide vaccine was combined with adjuvant poly-ICLC to dose glioblastoma (n=16) and grade III astrocytoma (n=3) patients. After optimization of vaccine formulation, multi-peptide CD8 and sustained T helper 1 CD4 T-cell responses were observed. For the entire cohort, CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients.
VEGFR peptide vaccine
The expression of vascular endothelial growth factor (VEGF)-A/ VAGF receptors (VEGFRs) signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas. Vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs.
Shibao S et al.[2] reported a pilot study to evaluate the safety and immunogenicity of VEGFRs peptide vaccine in patients with recurrent/progressive high grade gliomas. Eight patients received intranodal vaccinations weekly eight (8) times. T-lymphocyte responses against VEGFR epitopes were found in the peripheral blood mononuclear cells in 87.5% of patients. Two achieved progression-free status lasting at least 6 months and two patients with recurrent GBM demonstrated stable disease. An exploratory clinical study of VEGFRs peptide vaccine was conducted by Tamura R et al.[3] in seven patients with progressive NF2-derived schwannomas. Hearing improved in two out of five assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which VEGF antibody (bevacizumab) had not been effective. Both VEGFR1- and VEGFR2-specific CTLs were induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2 and cytotoxic T lymphocytes (CTLs) induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and immunosuppressive cells Treg expressing VEGFR1 and/or 2.
WT1 peptide vaccine
Wilms' tumor 1 protein (WT1) possesses oncogenic functions and is expressed in various kinds of malignancies suggesting WT1 should be one of the most promising cancer antigens. In fact, the WT1 was shown to be highly immunogenic in cancer patients. WT1 peptides that could induce WT1-specific CTLs (WT1 CTL peptides) were identified, and vaccination of cancer patients with these WT1 CTL peptides induced immunological responses led to clinical responses such as solid tumor shrinkage, a decrease in leukemia cells, and reduction of M-protein (multiple myeloma).
Diffuse midline glioma (DMG) in children is a highly aggressive, malignant brain tumor that is fatal when relapsed. Hashii Y et al. [4] published an encouraging case report of a pediatric patient who had DMG that regrew after chemoradiotherapy and underwent WT1 peptide vaccination. A 13-year-old Japanese boy was diagnosed with DMG, a grade IV glioma. The patient underwent radiotherapy and chemotherapy with temozolomide. After three cycles of chemotherapy, tumor regrew and translated into deteriorated clinical manifestations. Immunohistochemically, the H3.3K27M mutation in the biopsy specimen was confirmed and the specimen was positive for WT1 protein. The patient received a WT1-specific peptide vaccination because of having human leukocyte antigen A-A*24 (HLA-A*24) Consequently, his quality of life drastically improved so much so that the patient became capable of conducting nearly normal daily activities at weeks 8 to 12 of vaccination. MRI at week 8 of vaccination revealed an obvious reduction in the signal intensity of the tumor. Furthermore, beta-methasone dose could be reduced successively without deteriorating clinical manifestations. The pediatric patient exhibited an encouraging clinical evolution as manifested by stable disease.
Simultaneous induction of tumor antigen-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) is required for an optimal anti-tumor immune response. A peptide containing MHC class I and II epitopes could induce an effective CD4 and CD8 T-cell response[5]. A phase I clinical trial of a cocktail vaccine of WT1 MHC class I and II peptides for patients with recurrent malignant gliomas was performed by Tsuboi A group[6] and the immunological responses and survival data were assessed. Fourteen HLA-A*24:02-positive patients with recurrent malignant glioma were enrolled. Eleven of the 14 patients completed WT1 vaccination for 6 weeks, while 3 patients dropped out earlier due to disease progression. Six of the 14 patients had stable disease at 6 weeks. Median OS and 1-year OS rates were 24.7 weeks and 36%, respectively. In another clinical trial with WT1 peptide-pulsed dendritic cell (DC) vaccine[7], five of seven treated glioma patients had stable disease clinical response, in two of five patients with stable disease, neurological findings improved, and MR images showed tumor shrinkage. This study of WT1-pulsed DC vaccination therapy demonstrated safety, immunogenicity, and feasibility in the management of relapsed malignant gliomas.
Survivin peptide vaccine
Survivin is an anti-apoptotic protein that is highly expressed in many cancers, including malignant gliomas. Preclinical studies established that the conjugated survivin peptide mimic SurVaxM (SVN53-67/M57-KLH) could stimulate an anti-tumor immune response against murine glioma in vivo, as well as human glioma cells ex vivo. A clinical study was conducted to test safety, immunogenicity and clinical effects of the vaccine by Fenstermaker RA et al. [8]. Recurrent malignant glioma patients whose tumors were survivin-positive, and who had either HLA-A*02 or HLA-A*03 MHC class I allele-positivity, were given subcutaneous injections of SurVaxM in Montanide adjuvant at 2-week intervals. SurVaxM was well tolerated, and six of eight immunologically evaluable patients developed both cellular and humoral immune responses to vaccine. The vaccine also stimulated HLA-A*02, HLA-A*03 and HLA-A*24 restricted T cell responses. Three patients maintained a partial clinical response or stable disease for more than six months. Median progression-free survival was 17.6 weeks, and median overall survival was 86.6 weeks from study entry with seven of nine patients surviving more than 12 months.
IDH1 peptide vaccine
Mutation-specific vaccines have become increasingly important in glioma immunotherapy. Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbors a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+tumors in syngeneic MHC-humanized mice in a few periclinal studies. Platten M et al. [9] conducted a multicenter, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed WHO grade 3 and 4 IDH1 (R132H)+ astrocytomas. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 63% and 84%, respectively. Patients with immune responses showed a two-year progression-free rate of 82%. Two patients without an immune response showed tumor progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumor tissue. There was a high frequency of pseudo progression, which indicates intertumoral inflammatory reactions. Pseudo progression was associated with increased vaccine-induced peripheral T cell responses.
Summary
Malignant glioma remains one of the most-studied tumors in the context of cancer-associated immunosuppression. Effective antitumor immunotherapies for malignant glioma depends on overcome the immunosuppression and specific CTL response against tumor cells. Although proof of efficacy is not yet available for any of the glioma-specific peptide vaccines currently in clinical development, the addition of immune checkpoint inhibitors or other approaches that boost immune responses in vaccinated patients might ultimately be able to demonstrate that active immunotherapy can control the growth of human intracranial cancer.
Written by: Feng Lin, M.D., Ph.D.
Keywords: glioma, astrocytoma, Wilms Tumor, DMG
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