Malignant Glioma Patients Research Articles

Abstract PR13: Adjuvant TLR-3 administration enhances proinflammatory immune responses and is associated with extended survival in glioblastoma patients treated with dendritic cell vaccination

Abstract Malignant glioma, associated with a poor prognosis, is the most common primary malignant brain tumor in adults. We and others have documented immune responses following dendritic cell (DC) vaccination as an active immunotherapeutic treatment for these patients. In this phase II clinical trial, we randomized malignant glioma patients to receive autologous tumor lysate pulsed DC vaccination with and without adjuvant Toll-like receptor (TLR) agonists. TLRs are present on dendritic cells and serve to modulate immune responses. Twenty-three patients with WHO grade III or IV glioma were treated with three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 followed by an adjuvant placebo, TLR-7 agonist (resiquimod), or TLR-3 agonist (Poly ICLC). Mass cytometry (CyTOF) was used to analyze immune cell populations of patient peripheral blood mononuclear cells (PBMC) before and following treatment. DC-vaccinated patients who received adjuvant Poly ICLC treatment had a significantly improved median survival of 54 months over placebo (11 months) and adjuvant resiquimod (17 months) groups (P<0.01). CyTOF and single-cell RNA sequencing (scRNseq) gene expression analysis of systemic PBMCs from patients demonstrated increased immune cell activation and expression of proinflammatory genes. Notably, the expansion of a heterogenous myeloid cell population was noted to correlate with increased survival, corroborating preclinical evidence that these cells modulate adaptive immunity in the tumor microenvironment. Overall, these findings suggest that adjuvant Poly ICLC treatment improves outcomes with autologous lysate-pulsed DC vaccine treatment via modulation of proinflammatory pathways. This abstract is also being presented as Poster B27. Citation Format: Joseph P. Antonios, Richard G. Everson, Aaron Mochizuki, Sara Khattab, Horacio Soto, Prashant Romiyo, Matthew Z. Sun, Diana Moughon, Emma Billingslea-Yoon, Sylvia Odesa, Gang Li, Eric Kawaguchi, Alex Salazar, William Yong, Jason Schlossman, Benjamin Ellingson, Anthony C. Wang, Timothy Cloughesy, Robert M. Prins, Linda M. Liau. Adjuvant TLR-3 administration enhances proinflammatory immune responses and is associated with extended survival in glioblastoma patients treated with dendritic cell vaccination [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR13.

Role of the default mode resting-state network for cognitive functioning in malignant glioma patients following multimodal treatment

BackgroundProgressive cognitive decline following multimodal neurooncological treatment is a common observation in patients suffering from malignant glioma. Alterations of the default-mode network (DMN) represent a possible source of impaired neurocognitive functioning and were analyzed in these patients. MethodsEighty patients (median age, 51 years) with glioma (WHO grade IV glioblastoma, n = 57; WHO grade III anaplastic astrocytoma, n = 13; WHO grade III anaplastic oligodendroglioma, n = 10) and ECOG performance score 0–1 underwent resting-state functional MRI (rs-fMRI) and neuropsychological testing at a median interval of 13 months (range, 1–114 months) after initiation of therapy. For evaluation of structural and metabolic changes after treatment, anatomical MRI and amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) were simultaneously acquired to rs-fMRI on a hybrid MR/PET scanner. A cohort of 80 healthy subjects matched for gender, age, and educational status served as controls. ResultsThe connectivity pattern within the DMN (12 nodes) of the glioma patients differed significantly from that of the healthy subjects but did not depend on age, tumor grade, time since treatment initiation, presence of residual/recurrent tumor, number of chemotherapy cycles received, or anticonvulsive medication. Small changes in the connectivity pattern were observed in patients who had more than one series of radiotherapy. In contrast, structural tissue changes located at or near the tumor site (including resection cavities, white matter lesions, edema, and tumor tissue) had a strong negative impact on the functional connectivity of the adjacent DMN nodes, resulting in a marked dependence of the connectivity pattern on tumor location. In the majority of neurocognitive domains, glioma patients performed significantly worse than healthy subjects. Correlation analysis revealed that reduced connectivity in the left temporal and parietal DMN nodes was associated with low performance in language processing and verbal working memory. Furthermore, connectivity of the left parietal DMN node also correlated with processing speed, executive function, and verbal as well as visual working memory. Overall DMN connectivity loss and cognitive decline were less pronounced in patients with higher education. ConclusionPersonalized treatment strategies for malignant glioma patients should consider the left parietal and temporal DMN nodes as vulnerable regions concerning neurocognitive outcome.

COT-22 TIMING OF SURGERY AND BEVACIZUMAB THERAPY FOR MALIGNANT GLIOMAS

BACKGROUNDThe drug manufacturer recommends postponing initiation of bevacizumab for malignant gliomas at least 4 weeks later postoperatively. Malignant glioma patients with significant neurological deficits due to postoperative residual tumors are preferably needed earlier bevacizumab therapy that expecting improvement of neurological state and brain edema. There is a literature review indicating that the timing for administration of postoperative bevacizumab was at least 2 weeks. The authors assessed the safety,tolerability,efficacy for bevacizumab therapy less than 4 weeks later postoperatively.METHODSSix patients of malignant gliomas with residual tumors and neurological deficits were treated by bevacizumab (10mg /kg every 2 weeks) therapy 2–3 weeks later postoperatively with chemoradiotherapy. Patients included 31-year-old female with thalamic-midbrain glioblastoma (initial),11-year-old female with anaplastic ependymoma (recurrent),71-year-old female with initial cervical cord anaplastic astrocytoma (initial),88-year-old female bilateral frontal glioblastoma (initial),27-year-old female with thalamic midbrain glioblastoma (initial) and 3-year-old female with brain stem glioblastoma (initial).RESULTSAll the patients did not experienced hemorrhage and impair wound healing. Every patient neurological state and perifocal brain edema following bevacizumab therapy demonstrated early improvement. Earlier bevacizumab therapy did not delay and cease postoperative chemoradiotherapy.CONCLUSIONSInitiation of bevacizumab therapy 2–3 weeks later postoperatively seems to be safe and effective for malignant glioma patients with worse neurological state due to residual tumor and perifocal edema. The optimal interval which balances the risk of complications and the risk of tumor progression should be considered.

STMO-04 LOCAL CONVECTION-ENHANCED DELIVERY OF CHEMOTHERAPY AS TREATMENT FOR BRAIN TUMORS

BACKGROUNDConvection-enhanced delivery (CED) of therapeutic agents is a promising local delivery technique that has been extensively studied as a treatment for CNS diseases over the last 2 decades. Applying this technique to treat brain tumors, we have been working to develop novel local chemotherapy against brain tumors. In the meanwhile, clinical trial against diffuse intrinsic brain tumor aiming at Japanese “shonin” approval is recruiting patients. In this study, potential of local CED based chemotherapy against supratentorial brain tumor is discussed.METHODSUntil today, we have evaluated the safety and efficacy of local CED of nimustine hydrochloride against supratentorial malignant glioma patients in the three prospective, single institute, nonrandomized, open-label studies. Among those, one study recruited the recurrent malignant glioma patients whose enhanced tumor can be surgically resected. After the resection of the tumor, CED of ACNU was performed targeting the surrounding brain. Temozolomide was also given for 5 days during this trial.RESULTSSeven patients; 4 male and 3 female, age 33–71 y.o. (median 54 y.o.), were treated in this study. Five patients suffered glioblastoma and two suffered anaplastic astrocytoma. After the treatment, all seven patients lived longer than a year; one survived three years, one survived four and a half years, and one with glioblastoma is still alive after 5 years.DISCUSSIONPotential efficacy of local chemotherapy delivering nimustine hydrochloride with CED against recurrent malignant glioma was suggested. Further study is required to pave the way for this strategy against supratentorial malignant gliomas.

DRES-02. PARYLATION OF MGMT BY PARP IS REQUIRED FOR MGMT MEDIATED TEMOZOLOMIDE-INDUCED O6-METHYLGUANINE REPAIR: A NOVEL MECHANISM OF MGMT ACTION

Abstract Temozolomide (TMZ) is the standard chemotherapy for malignant gliomas (MG), and resistance to this drug is mediated by the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in about 40% patients is associated with loss of MGMT expression that compromises DNA repair leading to favorable response to TMZ therapy. Understanding the mechanism of MGMT mediated repair and modulating MGMT activity will enhance TMZ activity in MGMT unmethylated MG. Here we report a novel mode of regulation of MGMT protein activity by Poly-ADP-ribose polymerase (PARP). We found that PAPR physically interacts with MGMT and PARylates MGMT in response to TMZ treatment. We further showed PARylation of MGMT by PAPR is required for MGMT binding to DNA and to remove O6-methylguanine adducts in damaged DNA induced by TMZ. All 4 PARP inhibitors (trapping and non-trapping) tested (Talazoparib, Pamiparib, Veliparib, Olaparib) can inhibit PARP-MGMT binding, PARylation of MGMT, binding to DNA and subsequent removal of O6 - lesions in damaged DNA. We showed combination of PARP inhibitor with TMZ potentiated TMZ cytotoxicity in both MGMT methylated and unmethylated Glioma stem cell lines, but more profoundly in unmethylated group in vitro and in vivo. PARP inhibition acted as a double-edged sword in MGMT unmethylated MG: blocking BER/SSBR pathway to repair TMZ induced N7-MetG and O3-MetA, and more importantly, suppressing PARP-mediated PARylation of MGMT and thus silencing MGMT activity to repair O6-MetG, resulting in augmented cytotoxicity. This is the first study to show that PARylation of MGMT by PARP is required for repairing TMZ-induced O6-methylguanine adducts, and inhibition of MGMT PARylation abolishes MGMT function and renders sensitization to TMZ treatment. This finding provides a rationale for combining TMZ/CCNU and PARP inhibitors in MGMT unmethylated MG patients to enhance the benefit of adjuvant chemotherapy.

GENE-12. ANALYSIS OF FAILURE PATTERNS IN MALIGNANT GLIOMA: EXPLORING THE GENETIC LANDSCAPE OF PATTERN OF FAILURE

Abstract Failure patterns in malignant gliomas have been described in previous literatures, however, studies were limited to analyze clinical features to account for predisposition to distinct failure patterns. Present study aimed to describe the landscape of failure patterns in malignant glioma from large cohort by integrating multi-omics data and investigate the genetic backgrounds of distinct failure patterns. A total of 423 cases from 325 patients who enrolled at the registry of IRCR at SMC were reviewed for their pattern of failure. Failure patterns were categorized into local, distant recurrence and leptomeningeal seeding regarding recurrent tumors’ spatial relation to primary location. Genomic data was available for 327 (DNAseq) and 259 samples (RNAseq), respectively. Glioblastoma was the most prevalent histologic type in study cohort (81.2%)) and majority of cases experienced the recurrence (79.0%). None of clinical parameters (e.g. age, sex, extent of operation and history of prior therapy) failed to show any significant association with failure patterns. Although local recurrence was most prevalent (63.8%) among failure patterns in malignant gliomas, considerable portion of patients (37.8%) demonstrated other types of failure patterns even in their initial relapse. Multivariate analysis demonstrated that failure pattern was significant prognostic factor to overall survival (remote recurrence, HR=1.59, p-value=0.009; leptomeningeal seeding, HR=2.17, p-value< 0.001). Genomic analysis including mutational profile revealed distinct molecular landscape of malignant gliomas according to failure patterns, which suggested that innate biologic characteristics of tumors might contribute to develop distinct failure patterns upon recurrence. PTEN mutation was significantly enriched in tumors of distant recurrence (p-value=0.026). We described the landscape of failure patterns in malignant gliomas by integrating clinical and genomic data. Considerable amount of malignant glioma patients experienced distinct failure patterns other than local recurrence and their clinical outcome as well as genetic background demonstrated invasive characteristic of these tumors.

Defining the Speech and Language Therapist role in palliative care of neuro-oncology patients: A qualitative research study.

Abstract Speech and language therapists (SLTs) are experts in the management of swallowing and communication disorders. Although there is increasing recognition of SLTs in palliative care, evidence specifically supporting their role with primary malignant gliomas (PMG) patients is lacking, despite the prevalence of swallowing and communication difficulties in this non-curable disease. This study aimed to explore the contribution of SLT to PMG, as perceived by SLTs themselves and by members of the regional neuro-oncology multidisciplinary team (MDT). Following ethical approval, semi-structured one-to-one interviews were conducted with ten SLTs working with PMG in outpatients and community settings across South East Wales. In addition, five members of the regional neuro-oncology MDT were interviewed. Thematic analysis was used to analyse the data and to identify and pinpoint salient themes. The findings indicate that despite lack of professional guidance and previous evidence, SLTs provided evidence to suggest that they contribute beyond swallowing and communication management, to areas such as shared decision-making, key-working, patient advocacy, advanced care planning and support for psychological wellbeing. However, these extended roles are inconsistently recognised by the MDT. Five barriers were identified which hampered SLT contributions: a perceived identity crisis affecting PMG patients, lack of confidence from SLTs, inconsistent MDT integration, reduced resources and strategic direction. The study suggests that SLTs need to promote and educate the MDT in order to achieve routine integration and enhance patient-centred and holistic care. The profession may also benefit from capturing the value of their involvement with PMG to drive service developments.

P14.37 Depression in patients with primary brain tumors: Relation to clinical variables and tumor characteristics

Abstract BACKGROUND Patients with brain tumor have an increased risk for depressive disorder, however, the association between depression and clinical or tumor-related variables remains mostly unclear. In this study, we analyzed the relation of depression to several clinical and tumor-related characteristics in patients with primary brain tumors. MATERIAL AND METHODS Sixty patients with newly-diagnosed (n=34) or recurrent (n=26) primary brain tumors (50 gliomas, 10 meningiomas) underwent testing with the Beck Depression Inventory-II (BDI-II). Relation of BDI-II scores to clinical and tumor-related characteristics, including age, Karnofsky Performance Status (KPS) scores, presence of antiepileptic, antidepressant, or steroid treatment, as well as tumor grade, lateralization, and lobar localization, were analyzed. In a subset of recurrent malignant glioma patients, the prognostic value of BDI-II scores on overall survival was also analyzed. RESULTS The mean total BDI-II score was 10±8 (range: 0–37); while 27% of patients (n=16) had BDI-II scores indicating at least mild depressive disorder (≥13), only a portion of them (17%) was on antidepressant treatment. No BDI-II difference was found between gliomas vs. meningiomas or newly-diagnosed vs. recurrent tumors; also, no association was found with any tumor-related characteristics. Antiepileptic or steroid therapy had no association with BDI-II scores, while higher BDI-II scores were observed in patients with ongoing antidepressant therapy (15±10 vs. 8±7, p=0.017). Higher BDI-II total and somatic subscale scores correlated with lower KPS scores (r=-0.32, p=0.014 and r=-0.31, p=0.017, respectively). In recurrent malignant glioma patients (n=18), higher depression scores were associated with shorter survival (hazard ratio: 3.7; 95% confidence interval: 1.0–13.6; p=0.048). CONCLUSION Depression affected more than ¼ of patients with primary brain tumors in this single-center cohort and was independent from most clinical and tumor-related characteristics, except KPS scores. Although most of these patients have mild depression that is often overlooked without targeted screening, higher BDI-II scores may predict shorter overall survival in recurrent malignant glioma patients. These data reinforce the importance of early recognition and treatment of depressive symptoms in patients with primary brain tumors.

Convection-Enhanced Delivery in Malignant Gliomas: A Review of Toxicity and Efficacy.

Malignant gliomas are undifferentiated or anaplastic gliomas. They remain incurable with a multitude of modalities, including surgery, radiation, chemotherapy, and alternating electric field therapy. Convection-enhanced delivery (CED) is a local treatment that can bypass the blood-brain barrier and increase the tumor uptake of therapeutic agents, while decreasing exposure to healthy tissues. Considering the multiple choices of drugs with different antitumor mechanisms, the supra-additive effect of concomitant radiation and chemotherapy, CED appears as a promising modality for the treatment of brain tumors. In this review, the CED-related toxicities are summarized and classified into immediate, early, and late side effects based on the time of onset, and local and systemic toxicities based on the location of toxicity. The efficacies of CED of various therapeutic agents including targeted antitumor agents, chemotherapeutic agents, radioisotopes, and immunomodulators are covered. The phase III trial PRECISE compares CED of IL13-PE38QQR, an interleukin-13 conjugated to Pseudomonas aeruginosa exotoxin A, to Gliadel® Wafer, a polymer loaded with carmustine. However, in this case, CED had no significant median survival improvement (11.3 months vs. 10 months) in patients with recurrent glioblastomas. In phase II studies, CED of recombinant poliovirus (PVSRIPO) had an overall survival of 21% vs. 14% for the control group at 24 months, and 21% vs. 4% at 36 months. CED of Tf-diphtheria toxin had a response rate of 35% in recurrent malignant gliomas patients. On the other hand, the TGF-β2 inhibitor Trabedersen, HSV-1-tk ganciclovir, and radioisotope 131I-chTNT-1/B mAb had a limited response rate. With this treatment, patients who received CED of the chemotherapeutic agent paclitaxel and immunomodulator, oligodeoxynucleotides containing CpG motifs (CpG-ODN), experienced intolerable toxicity. Toward the end of this article, an ideal CED treatment procedure is proposed and the methods for quality assurance of the CED procedure are discussed.

Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial.

2060 Background: We completed a study evaluating a single intratumoral delivery of PVSRIPO in recurrent WHO grade IV MG patients (N Engl J Med. 2018 Jul 12;379(2):150-161). Some patients who originally benefitted from the infusion of PVSRIPO demonstrated tumor recurrence, and we hypothesized that retreatment could trigger an immune recall effect, further extending their survival. We now report the impact of second and third intratumoral reinfusion of PVSRIPO in patients treated in the original dose finding study. Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG who were experiencing disease recurrence after having benefitted from the first infusion of PVSRIPO. Additional eligibility criteria included: solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. One patient each was retreated at 1 x 107 TCID50 and 1 x 1010 TCID50, and three patients were retreated on the identified phase 2 dose of 5 x 107 TCID50. Results: As of 2/09/2019, five patients have received a second intratumoral dose of PVSRIPO on study, one of which received a total of 3 doses. The patients who received two infusions of PVSRIPO were retreated 72 months, 43 months, 34 months, and 6 months after the first infusion. One additional patient received a second infusion of PVSRIPO 60 months after the first infusion and a third infusion of PVSRIPO 78 months after the first infusion. All patients demonstrated soap bubble degeneration on imaging, and two patients demonstrated tumor contraction. No grade 3 or higher adverse events related to PVSRIPO were observed after retreatment. Three of these patients remain alive more than 81, 80 and 52 months following the first PVSRIPO infusion and more than 9, 20 and 18 months after the second infusion, respectively. Two patients died 63 months and 20 months after the first infusion of PVSRIPO and 19.6 and 14 months after the second, respectively. The patient treated 3 times received the third infusion more than 2 months ago. Conclusions: Intratumoral reinfusion of PVSRIPO via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT01491893.

Incidence trends of adult malignant brain tumors in Finland, 1990–2016

Background: Several studies have reported increased incidence trends of malignant gliomas in the late 1900s with a plateau in the 2000s, but also some recent increases have been reported. The purpose of our study was to analyze incidence trends of malignant gliomas in Finland by morphology and tumor location.Material and methods: Data on 4730 malignant glioma patients were obtained from case notifications to the nationwide, population-based Finnish Cancer Registry (FCR), and less detailed data on 3590 patients up to 2016. Age-standardized incidence rates (ASR) and average annual percent changes (APCs) in the incidence rates were calculated by histological subtype and tumor location.Results: The incidence rate of gliomas was 7.7/100,000 in 1990–2006 and 7.3 in 2007–2016. The incidence of all gliomas combined was stable during both study periods, with no departure from linearity. In an analysis by age group, increasing incidence was found only for ages 80 years and older (1990–2006). During both study periods, incidence rates were increasing in glioblastoma and decreasing in unspecified brain tumors. In 1990–2006, rates were also increasing for anaplastic oligodendroglioma, oligoastrocytoma and unspecified malignant glioma, while decreasing for astrocytoma. As for tumor location, incidence in 1990–2006 was increasing for frontal lobe and brainstem tumors, as well as those with an unspecified location, but decreasing for the parietal lobes, cerebrum and ventricles.Conclusions: No increasing incidence trend was observed for malignant gliomas overall. An increasing incidence trend of malignant gliomas was found in the oldest age group during 1990–2006.

Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation.

Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Our recent preclinical work has suggested that PD-1/PD-L1 plays an important immunoregulatory role to limit effective antitumor T-cell responses induced by active immunotherapy. However, little is known about the functional role that PD-1 plays on human T lymphocytes in patients with malignant glioma.Experimental Design: In this study, we examined the immune landscape and function of PD-1 expression by T cells from tumor and peripheral blood in patients with malignant glioma. We found several differences between PD-1+ tumor-infiltrating lymphocytes (TIL) and patient-matched PD-1+ peripheral blood T lymphocytes. Phenotypically, PD-1+ TILs exhibited higher expression of markers of activation and exhaustion than peripheral blood PD-1+ T cells, which instead had increased markers of memory. A comparison of the T-cell receptor variable chain populations revealed decreased diversity in T cells that expressed PD-1, regardless of the location obtained. Functionally, peripheral blood PD-1+ T cells had a significantly increased proliferative capacity upon activation compared with PD-1- T cells. Our evidence suggests that PD-1 expression in patients with glioma reflects chronically activated effector T cells that display hallmarks of memory and exhaustion depending on its anatomic location. The decreased diversity in PD-1+ T cells suggests that the PD-1-expressing population has a narrower range of cognate antigen targets compared with the PD-1 nonexpression population. This information can be used to inform how we interpret immune responses to PD-1-blocking therapies or other immunotherapies.

Delta-24-RGD Adenoviral Therapy Directs Oncolytic and Immune-Mediated Anti-Tumor Effects in Recurrent Malignant Glioma Patients.

Delta-24-RGD Adenoviral Therapy Directs Oncolytic and Immune-Mediated Anti-Tumor Effects in Recurrent Malignant Glioma Patients.

Human Glioma Migration and Infiltration Properties as a Target for Personalized Radiation Medicine.

Gliomas are primary brain tumors that present the majority of malignant adult brain tumors. Gliomas are subdivided into low- and high-grade tumors. Despite extensive research in recent years, the prognosis of malignant glioma patients remains poor. This is caused by naturally highly infiltrative capacities as well as high levels of radio- and chemoresistance. Additionally, it was shown that low linear energy transfer (LET) irradiation enhances migration and invasion of several glioma entities which might counteract today’s treatment concepts. However, this finding is discussed controversially. In the era of personalized medicine, this controversial data might be attributed to the patient-specific heterogeneity that ultimately could be used for treatment. Thus, current developments in glioma therapy should be seen in the context of intrinsic and radiation-enhanced migration and invasion. Due to the natural heterogeneity of glioma cells and different radiation responses, a personalized radiation treatment concept is suggested and alternative radiation concepts are discussed.

Non-conventional fotemustine schedule as second-line treatment in recurrent malignant gliomas: Survival across disease and treatment subgroup analysis and review of the literature.

Fotemustine (FTM) is a treatment option in recurrent malignant gliomas (MGs) after first-line Stupp treatment. The efficacy and the safety of fractionated FTM schedule proposed by Addeo et al was analysed in the present study in recurrent MGs patients. A retrospective analysis on 40 recurrent MGs patients and second-line fractionated FTM chemotherapy was performed. Response evaluation was assessed using RANO criteria and safety was assessed using CTCAE v.4.03. Subgroup analyses based on MGMT methylation, resurgery and reirradiation were performed. A review of the literature was also performed. The results revealed 5 partial responses (13%) and 19 stable diseases (47%) with a disease-control rate of 60%. Median progression-free survival (PFS) was 4 months, with a PFS of 33% at 6 months and 13% at 1 year. The median overall survival (OS) was 9 months and OS at 6 months was of 55% and at 1 year of 30%. Methylated patients experienced longer mPFS (6 vs. 3 months; p=0.004) and mOS (10 vs. 4 months; p<0.0001) compared with unmethylated patients. Patients treated with reirradiation experienced longer mPFS (5 vs. 3.5 months; p=0.48) and mOS (10 vs. 5 months; p=0.11). No survival benefit with resurgery was observed. Furthermore, the fractioned schedule was well tolerated, only 15% of patients developed severe myelotoxicities. Considering the present findings, fractionated FTM schedule is an efficient second-line option for MGs associated with an acceptable myelotoxicity profile. Additionally, MGMT methylation is associated with improved survival outcomes. However, this study highlights the requirement for further prospective randomized studies on resurgery and reirradiation.

Multimodal treatment for local recurrent malignant gliomas: Resurgery and/or reirradiation followed by chemotherapy.

The therapeutic management of recurrent malignant gliomas (MGs) is not determined. Therefore, the efficacy of a multimodal approach and a combination systemic therapy was investigated. A retrospective analysis of 26 MGs patients at first relapse treated with multimodal therapy (chemotherapy plus surgery and/or reirradiation) or chemotherapy alone was performed. Second-line chemotherapy consisted of fotemustine (FTM) in combination with bevacizumab (BEV) (cFTM/BEV) or followed by third-line BEV (sFTM/BEV). Subgroup analyses were performed. Multimodal therapy provided a higher overall response rate (ORR) (73 vs. 47%), disease control rate (DCR) (82 vs. 67%), median progression-free survival (mPFS) (11 vs. 7 months; P=0.08) and median overall survival (mOS) (13 vs. 8 months; P=0.04) compared with chemotherapy. Concomitant FTM/BEV resulted in higher ORR (84 vs. 36%), DCR (92 vs. 57%), mPFS (10 vs. 5 months; P=0.22) and mOS (11 vs. 5.2 months; P=0.15) compared with sFTM/BEV. Methylated patients did not experience additional survival benefits with multimodality treatment but had higher mPFS (10 vs 7.1 months; P=0.33) and mOS (11 vs. 8 months; P=0.33) with cFTM/BEV. Unmethylated patients experienced the greatest survival benefit with the multimodal approach (mPFS: 10 vs. 5 months; mOS 11 vs 6 months; both P=0.02) and cFTM/BEV (mPFS: 5 vs. 2 months; mOS 6 vs. 3.2 months; both P=0.01). In conclusion, in recurrent MGs, multimodal therapy and cFTM/BEV provide survival and response benefits. Methylated patients benefit from a cFTM/BEV but not from a multimodal approach. Notably, unmethylated patients had the highest survival benefit with the two strategies.

P01.122 Safety, immunogenicity and optimization of the IMA950 multipeptide vaccine combined with Poly-ICLC in newly diagnosed HLA-A2 malignant glioma patients

P01.122 Safety, immunogenicity and optimization of the IMA950 multipeptide vaccine combined with Poly-ICLC in newly diagnosed HLA-A2 malignant glioma patients

Abstract CT161: Clinical study of PD-1 inhibitor with mTOR inhibitor for relapsed and refractory brain tumors

Abstract In this phase I/II study the combination regimen is used to treat recurrent or refractory malignant glioma patients. The inclusion criteria: 1) Histologically confirmed WHO IV. Participants will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of glioblastoma. 2) Patients must be at first or second relapse following initial radiation-chemotherapy therapy. 3) Must provide tumor tissue. 4) Molecular diagnosis includes the mutation of PIK3CA, KRAS, TSC1 and PTEN expression decreased, meet the above 2 and above. High expression of PD-L1 in tumor and tumor infiltrating lymphocytes consider as drug specifically targeting T-cell checkpoint pathways. 5) KPS&amp;gt;/= 60. 6) Measurable contrast-enhancing tumor consists of a miaxmal volume of 3*3 cm. 7) Stable doses of steroids for 5 days, no more than 2 mg dexamethasone total per day. 8) Absolute neutrophil count (ANC) &amp;gt;/=1,500 /mcL; platelets &amp;gt;/=100,000/mcL; hemoglobin &amp;gt;/= 9 g/dL; serum creatinine /= 60 mL/min for subject with creatinine levels &amp;gt; 1.5 × institutional ULN. 9) Both sexual and age &amp;gt;/= 18 years on day of signing informed consent, 5 to 18 years of age signing informed consent by parents. Exclusion criteria: 1) Treated previously with bevacizumab. 2) Has tumor localized primarily to the brainstem or spinal cord. 3) Has received prior interstitial brachytherapy, implanted chemotherapy, or CAR-T cell therapy. 4) Currently participating in or has participated in a study of an investigational agent or using an investigational device 4 weeks since last dose of agent administration. 5) Has a diagnosis of immunodeficiency or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial. 6) Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 7) Has an active infection requiring systemic therapy. 8) Pregnant or breastfeeding. 9) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 antibody. 10) History of HIV, HBV, HCV. 11) Has received a live vaccine within 30 days prior to the first dose of trial treatment. According to the results of tumor molecular evaluation, patients would be divided into three intervention groups. The interventions are EVE group (Everolimus 10mg PO QD), PD-1 inhibitor monotherapy group (PD-1 inhibitor 2mg/kg ivgtt Q3W) and combination group (Everolimus 10mg PO QD + PD-1 inhibitor 2mg/kg ivgtt Q3W). Primary outcome measure: 6 month progression-free survival rate, progression will be determined by review of MRI exams every month, assessed using iRANO criteria. Secondary outcome measures: 1) Overall survival (OS) and progression-free survival (PFS). 2) Incidence of grade 3+ toxicities. 3) Helper and effecter T cells active percent, T reg and MDSC percent in peripheral blood will be detected before and after treatment Day 1, 3, 7 and 3 weeks in every cycle. This clinical trial has supported by IRB of Renji hospital and registered on ICTRP identifier: ChiCTR-OON-16008330. Citation Format: zhihua Chen, Yongming Qiu. Clinical study of PD-1 inhibitor with mTOR inhibitor for relapsed and refractory brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT161.

Concordant association validates MGMT methylation and protein expression as favorable prognostic factors in glioma patients on alkylating chemotherapy (Temozolomide)

O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and its subsequent loss of protein expression has been identified to have a variable impact on clinical outcome of glioma patients indicated for chemotherapy with alkylating agents (Temozolomide). This study investigated methylation status of MGMT gene along with in situ protein expression in malignant glioma patients of different histological types to evaluate the associated clinical outcome vis-a-vis use of alkylating drugs and radiotherapy. Sixty three cases of glioma were evaluated for MGMT promoter methylation by methylation-specific PCR (MS-PCR) and protein expression by immunostaining (IHC). Methylation status of MGMT and loss of protein expression showed a very high concordant association with better survival and progression free survival (PFS) (p < 0.0001). Multivariate Cox regression analysis showed both MGMT methylation and loss of protein as significant independent prognostic factors in glioma patients with respect to lower Hazard Ratio (HR) for better OS and PFS) [p < 0.05]. Interestingly concordant MGMT methylation and lack of protein showed better response in TMZ therapy treated patient subgroups with HR of 2.02 and 0.76 (p < 0.05). We found the merits of prognostication of MGMT parameters, methylation as well as loss of its protein as predictive factors for favorable outcome in terms of better survival for TMZ therapy.

Retrospective analysis to evaluate the efficacy and the safety of Bevacizumab in the treatment of recurrent malignant gliomas

BackgroundThere is no consensus therapy recommended for recurrent malignant gliomas (MGs). In 2009, Bevacizumab (BEV) was approved by the FDA as single-agent for recurrent glioblastoma (GBM). The aim of this retrospective study was to evaluate the efficacy and the safety of BEV alone or in combination with Fotemustine (FTM) in recurrent MGs. This represents an interim analysis of a larger study on BEV in MGs patients.MethodsWe analyzed 17 recurrent MGs patients, 12 GBM (70.6%) and 5 anaplastic gliomas (29.4%), underwent first-line therapy with Stupp regimen. BEV was administered as off-label therapy, at a dose of 10 mg/kg every 14 days, in 13 patients as third-line therapy and in 4 patients as second-line therapy associated with FTM. The assessment of MGMT methylation and IDH1 mutation was conducted.ResultsOne complete response (5.9%), 7 partial responses (41.2%), 3 stable diseases (17.6%) and 6 progression diseases (35.3%) were assessed using RANO criteria. Median PFS (mPFS) and OS (mOS) were 5 and 8.3 months respectively, with a 6 months-PFS of 41.2%. Methylated patients and wild-type IDH1 patients showed longer mPFS and mOS without statistical significance. Six patients (35.3%) experienced long response with high number of cycles (11-40), long PFS (11-40 months) and OS (12-42 months). BEV was well-tolerated with grade 1-2 proteinuria and hypertension in 53% and 47.1% of patients respectively. Only one patient developed grade 3 proteinuria after 30 cycles and another one developed pulmonary embolism. No other grade 3-4 toxicities were observed.ConclusionsThis retrospective study showed the efficacy and the safety of BEV alone or in association with FTM in the treatment of MGs.The protocol (No: Beva-Glio/Sep 2016).