MPC-18 CATEGORIZATION OF LOWER GRADE GLIOMA USING ONCOPANEL

Abstract PURPOSE We are developing a 48-gene OncoPanel (Kagoshima Brain Tumor 48 OncoPanel) specializing in glioma diagnosis. Clinical application of genetic diagnosis derived from genetic alterations detected by OncoPanel, including IDH mutation, 1p/19q-codeletion, and other gene mutations in lower-grade glioma was verified. METHODS The 48 genes consist of 24 genes related to glioma and 24 genes on chromosomes 1 and 19. DNA was extracted from tumor FFPE samples and blood samples, and then single nucleotide variants and copy number variants were detected using next-generation sequencer. RESULTS Among the 99 diffuse glioma cases that had undergone OncoPanel analysis by July 2019, 40 cases diagnosed histologically as WHO grade 2 or 3 diffuse glioma were included. The integrated diagnosis by conventional gene analysis were Diffuse astrocytoma 10 cases, anaplastic astrocytoma 11 cases, oligodendroglioma 10 cases, anaplastic oligodendroglioma 9 cases. IDH1 mutation was detected in 30 cases, of which in 19 cases 1p/19q-codeletion was detected, all with TERT mutation. Among 11 cases with 1p/19q-non-codeletion, ATRX mutation was detected in 10 cases and was almost mutually exclusive with TERT mutation. In 10 cases without IDH mutation, EGFR amplification or mutation was detected in 6 cases, of which 4 cases were accompanied by TERT mutation. DISCUSSION KBT48 can detect TERT and ATRX mutations in a mutually exclusive manner and can improve the classification accuracy of oligodendroglioma and astrocytoma. Groups with gene profiles similar to glioblastoma with EGFR amplification/mutation and TERT mutation can also be classified. CONCLUSIONS In the diagnostic classification of lower-grade glioma, KBT48 can well classify into oligodendroglioma group, astrocytoma group and glioblastoma-like group, and is considered to be applicable in clinical practice.

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NI-06 MOLECULAR DIAGNOSIS, 11C-METHIONINE UPTAKE AND PROGNOSIS IN GRADE 2 AND 3 GLIOMAS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.119 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii26-ii26

Author(s):

Kaoru Tamura ◽

Yaeko Furuhashi ◽

Motoki Inaji ◽

Daisuke Kobayashi ◽

Takahiro Ogishima ◽

...

Keyword(s):

Who Classification ◽

Genetic Alterations ◽

Normal Brain ◽

Lower Grade ◽

Who Grade ◽

Oligodendroglial Tumors ◽

Integrated Diagnosis ◽

Lower Grade Glioma ◽

Methionine Uptake ◽

Grade 3

Abstract OBJECT The revised 2016 WHO Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. In this study, we reclassified 103 consecutive lower grade gliomas using the revised 2016 WHO classification and examined for 11C-methionine uptake and prognosis. METHODS 103 consecutive lower grade glioma patients (Grade 2 in 41 patients, Grade 3 in 62 patients) treated at Tokyo Medical and Dental University Hospital from 2000 to 2018 were included in this study. The IDH1/2, ATRX and 1p19q status were analyzed using tumor samples. The tumor-to-normal ratio (T/N) of 11 C-methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. RESULT In the integrated diagnosis, 11 astrocytomas and 17 anaplastic astrocytomas were diagnosed as “IDH-mutant”, while 14 astrocytomas and 29 anaplastic astrocytomas were diagnosed as “IDH-wild”. In the 32 oligodendroglial tumors, 12 oligodendrogliomas and 9 anaplastic oligodendrogliomas were diagnosed as “IDH-mutant and 1p/19q-codeleted”. The concordance rate with 1p19q co-deletion and ATRX retention was 94.7%. The median T/N ratios in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” were 1.83 in Grade 2 and 2.83 in grade 3, which were significantly higher than those in astrocytic tumors with “IDH-mutant” (G2: 1.38, G3:1.62). Kaplan-Meier survival analysis revealed that oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” had significantly better outcomes regardless of WHO grade. Overall survival was 90.9% at 5 years and 77.9% at 10 years in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted”. CONCLUSIONS The results indicated that lower grade glioma categories reclassified with molecular classification correlate with the T/N ratio of methionine and the prognosis.

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MPC-2 Clinical course and prognosis of lower-grade glioma, IDH wildtype and pTERT mutant

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab159.058 ◽

2021 ◽

Vol 3 (Supplement_6) ◽

pp. vi16-vi16

Author(s):

Yoshinobu Takahashi ◽

Hayato Takeuchi ◽

Seisuke Tanigawa ◽

Takanari Okamoto ◽

Naoya Hashimoto

Keyword(s):

Median Survival ◽

Lower Grade ◽

Diffuse Astrocytoma ◽

Who Grade ◽

Female Ratio ◽

Astrocytic Glioma ◽

Tert Promoter ◽

Lower Grade Glioma ◽

Idh Mutations ◽

Astrocytic Gliomas

Abstract Background and Purpose: In the cIMPACT-Now update 3, it was proposed that grade 2 astrocytic gliomas without IDH-mutations and grade 3 astrocytic gliomas with TERT promoter mutations should be designated as diffuse IDH wildtype astrocytic glioma with molecular features of WHO grade IV glioblastoma. Therefore, we investigated whether this group of tumors actually corresponds to grade IV prognostically in cases that we encountered ourselves. Cases and Methods: Among the 65 patients having primary astrocytic glioma who were operated in our hospital from January 2016 to March 2021, the prognostic values of seven patients with lower-grade glioma, IDH wildtype, and pTERT mutant were investigated. Results: Among the seven patients, the median age was 59 years (50–66 years). Four of them had anaplastic astrocytoma, two had diffuse astrocytoma, and no tumor lesion could be identified upon histological examination for one patient. The male-to-female ratio was 1:6. MGMT methylation was observed in two patients (29%). The median survival was 20 months, with a significantly worse prognosis when compared with lower-grade glioma without the TERT promoter mutation (13 patients: median survival 40 months), but a better prognosis when compared with glioblastoma (45 patients: median survival 13 months) (Log-rank p = 0.0051). Conclusion: Although EGFR amplification, combined whole chromosome 7 gain, and whole chromosome 10 loss were not examined, the prognostic value of lower-grade glioma, IDH wildtype, and pTERT mutant was not as poor as that of glioblastoma. Further investigation is required to confirm whether these groups of tumors should be treated in the same way as grade IV glioblastoma.

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TMOD-06. CREATION OF PATIENT-DERIVED LOWER GRADE GLIOMA ORGANOID MODELS FOR PERSONALIZED TREATMENT RESPONSE ASSESSMENT

Neuro-Oncology ◽

10.1093/neuonc/noab196.868 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi216-vi217

Author(s):

Kalil Abdullah ◽

Joseph Buehler ◽

Cylaina Bird ◽

MIlan Savani ◽

Alex Sternisha ◽

...

Keyword(s):

Treatment Response ◽

Genetic Alterations ◽

Lower Grade ◽

High Grade ◽

Who Grade ◽

Oncology Research ◽

Genetically Engineered Mice ◽

Lower Grade Glioma ◽

Idh Mutations

Abstract Creating in vitro models of lower grade glioma represents a major challenge in neuro-oncology research. There are few such models that are tractable and widely used, which has hindered understanding of the biology of these tumors. Recently, substantial progress has been made in generating patient-derived in vitro organoid models of high grade glioma, but modeling lower grade disease remains difficult. Based on our experience creating neurosphere cultures of lower grade astrocytomas from genetically engineered mice, we hypothesized that modifying patient-derived organoid generation protocols to incorporate physiological oxygen levels would allow establishment and propagation of lower grade glioma organoids. In this study, we show that this approach supports efficient organoid model generation from primary glioma specimens across all histological subtypes and tumor grades (WHO Grade I-IV, n = 20). These organoid models retain key characteristics of their respective parental tumors, including IDH mutations and other genetic alterations, metabolite profiles, intratumoral heterogeneity, cellular composition, and cytoarchitectural features. Importantly, lower grade glioma organoids can be cultured for months and reanimated after biobanking. Our high success rate ( >90%) in establishing organoid models from primary lower grade glioma tissue samples further highlighted opportunities for treatment response assessments. To perform longitudinal measurements of therapy-induced changes in glioma organoid viability, we designed a novel, non-invasive imaging assay (termed rapid apex imaging) to determine real-time treatment response in low and high grade gliomas. We evaluated longitudinal responses of glioblastoma and IDH1 R132H-positive Grade II astrocytoma organoids to temozolomide and olaparib with and without radiation treatment. We quantified topological changes in organoid structure by building a bioinformatics tool to translate imaging data into a cellularity metric as a biomarker of organoid response. Our work unveils an effective new method to create in vitro, personalized models of lower grade glioma that supports elucidation of treatment sensitivity profiles.

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MPC-13 The evaluation of the shift of trend in lower grade glioma diagnoses based on each era`s criteria

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab159.065 ◽

2021 ◽

Vol 3 (Supplement_6) ◽

pp. vi17-vi18

Author(s):

Eriel Sandika Pareira ◽

Makoto Shibuya ◽

Kentaro Ohara ◽

Yu Nakagawa ◽

Tokunori Kanazawa ◽

...

Keyword(s):

Molecular Characteristics ◽

Lower Grade ◽

Comparative Genome Hybridization ◽

Diffuse Glioma ◽

Idh Mutation ◽

Morphological Criteria ◽

Lower Grade Glioma ◽

Sanger Sequence ◽

Grade Ii ◽

Grade Iii

Abstract It is found that molecular characteristics in lower grade gliomas (LrGGs) such as codeletion of 1p/19q and IDH mutation was found to be more accurate to predict the patient`s clinical outcome compared to morphological diagnoses alone. Since the revision WHO2016 classification of LrGGs, molecular characteristics were implemented as diagnostic standard for LrGGs diagnoses. In the other hand, morphological diagnostic standard before WHO2016 classification era was determined by different considerations and therapeutic strategies. The malignancy grades were also majorly determined by morphological diagnoses only. This study re-evaluated 20 years of LrGG cases in single institution based on WHO2007 morphological criteria and compared them to the original institutional diagnoses from each era. The study samples were originally grade II-III diffuse glioma-diagnosed cases resected from 1990 to 2016. Biopsy cases were excluded. IDH mutation was analyzed by Sanger sequence and 1p/19 codeletion status was analyzed by Comparative Genome Hybridization (CGH). As the result 93 cases were collected and based on original diagnoses, more than 50% cases are astrocytomas. Compared to re-assessment by morphological diagnoses (WHO 2007), case numbers of astrocytoma diagnoses are decreased whereas oligodendroglioma and oligoastrocytoma case numbers are increased. But, based on WHO2016 criteria, the case number of astrocytomas is again found to be increased. From comparison between original institutional diagnoses and re-assessment results, it is found that there is a shift of trend from astrocytoma to oligodendroglioma and from grade II to grade III. Comparison between morphological diagnoses (WHO2007) and molecular (WHO2016) found that astrocytoma diagnoses remain unchanged meanwhile 45% of oligodendroglioma diagnoses were shifted into astrocytomas. There is a probability that there are high frequency of morphologically diagnosed oligodendroglioma tumors which are having molecular characteristics of astrocytoma. There is a trend that diagnosed grade II LrGGs are actually grade III based on re-assessment diagnosis.

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A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20190131 ◽

2020 ◽

Vol 78 (1) ◽

pp. 34-38

Author(s):

Burcu BITERGE-SUT

Keyword(s):

Glioblastoma Multiforme ◽

Malignant Gliomas ◽

Genetic Alterations ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Lower Grade ◽

Nonsense Mutations ◽

Lower Grade Glioma ◽

Cancer Genome Atlas ◽

Genome Atlas

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.

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CTNI-22. RETROSPECTIVE ANALYSIS OF THE COMBINED TREATMENT OF VINCRISTINE, ACNU, CARBOPLATIN AND INTERFERON-β PLUS RADIOTHERAPY (VAC-FERON-R)IN PATIENTS WITH DIFFUSE ASTROCYTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.189 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii47-ii47

Author(s):

Yoshiki Arakawa ◽

Yasuhide Makino ◽

Takeshi Kawauchi ◽

Masaharu Tanji ◽

Yohei Mineharu ◽

...

Keyword(s):

Combined Treatment ◽

Diffuse Astrocytoma ◽

Wild Type ◽

Interferon Β ◽

Mutant Type ◽

Who Grade ◽

Integrated Diagnosis ◽

Significant Difference ◽

Favorable Clinical Outcome ◽

The Impact

Abstract OBJECTIVE Diffuse astrocytomas are classified as WHO grade II and its median overall survival (mOS) is 10 to 11 years. The efficacy of chemoradiation in the high-risk feature has been reported. The prognosis is associated with IDH and TERT promoter (TERTp) mutations. Here, we retrospectively analyzed the patients with diffuse astrocytoma treated with vincristine, ACNU, carboplatin and interferon-β plus radiotherapy (VAC-feron-R)in our institute. PATIENTS AND METHODS Between December 2003 to January 2016, 44 patients were diagnosed as diffuse astrocytoma with integrated diagnosis of histological and molecular analysis. The average age was 43.1 years (22–71 years). They received VAC-feron-R as initial treatment in our institute. We analyzed the IDH1/2 and the TERTp mutation using Sangar sequencing and determined the 1p/19q codeletion by the fluorescence in situ hybridization or the multiplex ligation-dependent probe amplification. RESULTS Median follow-up period was 76.5 months, mPFS was 126 months, mOS did not reach, and 10-year survival rate was 60%.IDH status was determined in 29 patients, 9 mutant and 20 wild types. There was no significant difference in PFS and OS between the two groups. TERTp status was determined in 18 patients with IDH wild type, 6 mutant and 12 wild types. mPFS of patients with TERTp wild type did not reach, but that with TERTp mutant type was 34.5 months (p = 0.0356). CONCLUSION Compared with previous clinical studies, VAC-feron-R showed a favorable clinical outcome in diffuse astrocytoma. The impact of TERTp status on prognosis was identified but not IDH status in this cohort.

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MPC-06 LRG1 HAS MULTIPLE POTENTIAL FOR CLINICOPATHOLOGICAL BIOMARKER OF GLIOBLASTOMA

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.103 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii23-ii23

Author(s):

Takuya Furuta ◽

Yasuo Sugita ◽

Satoru Komaki ◽

Kouichi Ohshima ◽

Motohiro Morioka ◽

...

Keyword(s):

Extent Of Resection ◽

Tumor Location ◽

High Expression ◽

Karnofsky Performance Scale ◽

Lower Grade ◽

Diffuse Glioma ◽

Tumor Tissues ◽

Lower Grade Glioma ◽

Expression Rate ◽

Tumor Types

Abstract BACKGROUND AND AIM Leucine-rich α-2 glycoprotein 1 (LRG1) is one of the candidate proteins as a diagnostic marker for glioblastoma. Although association with angiogenesis has been reported, it has been suggested that the role as a biomarker differs depending on the tumor types. The role of LRG1 as a biomarker in glioblastoma was examined clinicopathologically. METHODS Tumor tissues of 156 cases diagnosed as diffuse glioma (27 astrocytomas, 15 oligodendrogliomas, 114 glioblastomas) according to WHO 2016 classification at Kurume University from January 2001 to April 2019 were used. The immunohistochemical intensity of LRG1 was scoring as 4 stages and classified into 2 groups; score 0–1 was defined as low expression and score 2–3 was defined as high expression. Mutations of IDH1/2 and TERT promoter were analyzed by Sanger method. In glioblastoma, the relationship between LRG1 expression and clinical parameters such as age, preoperative Karnofsky Performance Scale, tumor location, extent of resection, MGMT promoter, and prognosis were examined. RESULTS LRG1 high expression rate was 41.2% (47/114) in glioblastoma, 3.7% (1/27) in astrocytoma, 20% (3/15) in oligodendroglioma, and glioblastoma showed significant higher expression level of LRG1 compared with lower-grade glioma (p = 0.0003). High expression of LRG1 was an independent favorable prognostic factor (HR 0.41, 95% CI 0.18–0.86, p=0.019) in IDH-wildtype glioblastoma, and correlated with gross total resection (p = 0.002) and the tumor location of the non-subventricular zone (SVZ) (p = 0.00007). CONCLUSION LRG1 demonstrated multiple potential as diagnostic, prognostic, and regional biomarker for glioblastoma.

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IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas

Neuro-Oncology ◽

10.1093/neuonc/noy088 ◽

2018 ◽

Vol 20 (11) ◽

pp. 1505-1516 ◽

Cited By ~ 15

Author(s):

Lei Zhang ◽

Liqun He ◽

Roberta Lugano ◽

Kenney Roodakker ◽

Michael Bergqvist ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Lower Grade ◽

Idh Mutation ◽

Wild Type ◽

Who Grade ◽

Mutation Status ◽

Grade Ii ◽

Grade Ii Glioma

Abstract Background Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype. Methods Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro. Results Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro. Conclusion IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

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P14.95 Is the pathological-grade relevant in “IDH-wild type, TERT-mutant” diffuse-gliomas? An analysis in 147 patients

Neuro-Oncology ◽

10.1093/neuonc/noz126.330 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii90-iii90

Author(s):

A E Danyeli ◽

C B Akyerli ◽

A Dinçer ◽

E Coşgun ◽

U Abacıoğlu ◽

...

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Genetic Alterations ◽

Lower Grade ◽

Wild Type ◽

Ki 67 ◽

Who Grade ◽

Free Survival ◽

Tert Promoter ◽

Diffuse Gliomas

Abstract BACKGROUND Although the word “glioblastoma” still denotes a grade-IV pathology, basic molecular studies have clearly indicated that a significant proportion of lower-grade gliomas harbor genetic alterations typical of glioblastomas. Based on these findings cIMPACT-NOW update 3 has defined an entity called the “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. A TERT-promoter mutation is one of these typical molecular markers of glioblastomas. In this study we analyzed IDH-wild type, TERT-mutant diffuse gliomas of different pathological grades to look for differences in demographic, clinical and survival characteristics. MATERIAL AND METHODS 147 adult hemispheric diffuse-gliomas with wild-type IDH1/2 and mutant TERT-promoter (C228T or C250T) were retrospectively analyzed. Primary thalamic, cerebellar brainstem or spinal cases were excluded. 126 (86%), 16(11%) and 5(3%) patients were WHO grade IV, III and II respectively. After surgical treatment or stereotactic biopsy all patients underwent chemoradiation. Median follow-up was 16mo (1–110). Tumors of different grades were compared for age, gender, multifocality, gliomatosis pattern, Ki-67 index, progression-free survival and overall-survival. RESULTS Mean age at presentation for grade II, III and IV were comparable (58.1, 58 and 58.1; ANOVA, p=0.72). There was a slight male predominance in both lower-grades and WHO-grade IV (M:F ratios 1.625 and 1.74). Mean Ki-67 index was significantly higher in higher grades (0.06, 0.14 and 0.25 for grades II, III and IV; ANOVA, p=0.001). Multifocality was comparable (chi-sq, p=1) in lower-grades (3/21; 14.3%) vs. WHO-grade IV (18/126; 14.3%). Gliomatosis pattern was comparable (chi-sq, p=0.095) in lower-grades (2/21; 9.5%) vs. (3/126; 2.3%). Median recurrence free survival (RFS) was 16 months (0–63) in lower-grades and 8months (1–50) in WHO-grade IV. PFS was significantly different between 3 WHO-grades (Log rank, p=0.007) and also between lower-grades and WHO-grade IV (Log rank, p=0.002). Median overall survival was 26 months(2–110) in lower-grades and 15mo(1–91) in WHO-grade IV. OS was significantly different between 3 WHO-grades (Log rank, p=0.014) and also between lower-grades and WHO-grade IV (Log rank, p=0.007). CONCLUSION Increasing pathological grades of hemispheric “IDH-wild type, TERT-mutant diffuse gliomas” have similar demographic and clinical characteristics but incrasing proliferation indices, decrasing progression free survival and shorter overall survival. The findings may be suggesitve of different grades of one common tumor entity.

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IMT-01 THERAPEUTIC EFFECT AGAINST LOWER GRADE GLIOMA INDUCED BY DENDRITIC CELL BASED IMMUNOTHERAPY

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.076 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii17-ii17

Author(s):

Yasuharu Akasaki ◽

Jun Takei ◽

Yuko Kamata ◽

Yohei Yamamoto ◽

Ryosuke Mori ◽

...

Keyword(s):

Glioma Cells ◽

Progression Free Survival ◽

Cervical Region ◽

Lower Grade ◽

Mri Findings ◽

Who Grade ◽

Lower Grade Glioma ◽

Major Interest ◽

Grade Ii

Abstract BACKGROUND This trial was designed to evaluate the safety and clinical responses to an immunotherapy with fusions of dendritic and glioma cells in patients with lower grade glioma (LGG; WHO grade II-III glioma). METHOD Autologous cultured glioma cells obtained from surgical specimens were fused with autologous dendritic cells (DC) using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region of subjects. Toxicity, progression-free survival (PFS), overall survival (OS), and MRI findings were evaluated. DNA for whole exome and RNA for whole transcriptome extracted from HLA-A*24:02 positive glioma cells were analyzed by next generation sequencer. Variant peptides showing strong binding affinity to HLA-A*24:02 but not the corresponding wild type peptides were selected as candidate of neo-antigens. RESULTS The number of subjects of this trial were 24 (initially diagnosed cases: 20, recurrence cases: 4). WHO grade III cases were 20, and grade II cases were 4. Male were 15, and female were 9. Mean of follow up periods were 53.0 months (the longest follow up period: 1322 months). The number of events on PFS and OS were 8 and 6, respectively. Mean of candidate of neo-antigen peptides in HLA-A*24:02 positive patients (n=8) was 34. Among these candidates, twelve types of common neo-antigen peptide were identified. Neo-antigen peptides specifically expressed in the glioma cells from the effective group were not identified. CONCLUSIONS These results indicate that the efficacy of FC-immunotherapy may not always depend on the number of gene mutations or the expression of the specific neo-antigens. FC-immunotherapy, as a means of producing specific immunity against neo-antigens may safely induce anti-tumor effects in patients with LGG. Analysis of prognostic factor in glioma immunotherapy may be the next area of major interest.

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