Recurrent Malignant Glioma Patients Research Articles

Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study.

Blood-brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant brain tumors. Radiation therapy (RT), despite being the mainstay adjuvant modality regardless of BBB, the effect of radiation induced cell death is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). We aimed to provide preclinical evidence of RT-FUS combination in GBM animal model, and to report an interim analysis of an ongoing single arm, prospective, pilot study (NCT01628406) of combining RT-FUS for recurrent malignant high grade glioma patients, of whom re-RT was considered for disease control. In both preclinical and clinical studies, FUS-BBB opening was conducted within 2h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. Survival analysis was performed in preclinical study and descriptive analysis was performed in clinical study. In mouse GBM model, the survival analysis showed RT-FUS (2Gy) group was significantly longer than RT (2Gy) group and control, but not RT (5Gy) group. In the pilot clinical trial, an interim analysis of six recurrent malignant high grade glioma patients underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33days after RT-FUS, while another three patients had at least stable disease (mean 323days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis. Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the interim analysis of an ongoing clinical trial (NCT01628406) showed a combination of RT-FUS was safe (no FUS-related adverse effect). A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

515P A MRI-based radiomics model for predicting the response to anlotinb combined with temozolomide in recurrent malignant glioma patients

515P A MRI-based radiomics model for predicting the response to anlotinb combined with temozolomide in recurrent malignant glioma patients

A MRI-based radiomics model for predicting the response to anlotinb combined with temozolomide in recurrent malignant glioma patients

ObjectiveAnlotinib is a multitarget anti-angiogenic drug that combined with temozolomide (TMZ) can effectively prolongs the overall survival (OS) of recurrent malignant glioma(rMG),but some patients do not respond to anlotinib combined with TMZ. These patients were associated with a worse prognosis and lack effective identification methods. Therefore, it is necessary to differentiate patients who may have good response to anlotinb in combination with TMZ from those who are not, in order to provide personalized targeted therapies.MethodsFifty three rMG patients (42 in training cohort and 11 in testing cohort) receiving anlotinib combined with TMZ were enrolled. A total of 3668 radiomics features were extracted from the recurrent MRI images. Radiomics features are reduced and filtered by hypothesis testing and Least Absolute Shrinkage And Selection (LASSO) regression. Eight machine learning models construct the radiomics model, and then screen out the optimal model. The performance of the model was assessed by its discrimination, calibration, and clinical usefulness with validation.ResultsFifty three patients with rMG were enrolled in our study. Thirty four patients displayed effective treatment response, showed a higher survival benefits than non-response group, the median progression-free survival(PFS) was 8.53 months versus 5.33 months (p = 0.06) and the median OS was 19.9 months and 7.33 months (p = 0.029), respectively. Three radiomics features were incorporated into the model construction as final variables after LASSO regression analysis. In testing cohort, Logistic Regression (LR) model has the best performance with an Area Under the Curve (AUC) of 0.93 compared with other models, which can effectively predict the response of rMG patients to anlotinib in combination with TMZ. The calibration curve confirmed the agreement between the observed actual and prediction probability. Within the reasonable threshold probability range (0.38–0.88), the radiomics model shows good clinical utility.ConclusionsThe above-described radiomics model performed well, which can serve as a clinical tool for individualized prediction of the response to anlotinb combined with TMZ in rMG patients.

A phase 1 trial of D2C7-it in combination with an Fc-engineered anti-CD40 monoclonal antibody (2141-V11) administered intratumorally via convection-enhanced delivery for adult patients with recurrent malignant glioma (MG).

e14015 Background: D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR wild-type and mutant-specific (EGFRvIII) monoclonal antibody (Ab) fragment and a genetically engineered form of the Pseudomonas exotoxin. When injected directly into the tumor by convection enhanced delivery (CED), immunotoxins induce both direct tumor killing and secondary immune responses by activation of CD4+ and CD8+ T-cells. Tumor-associated macrophages (TAMs) are the most prominent glioma-infiltrating immune cells and constitute up to 40% of the tumor mass. Upon binding of D2C7-IT to EGFR and cellular internalization, the Pseudomonas exotoxin moiety of the D2C7-IT kills residual GBM cells, upregulates proinflammatory CD40, and induces pattern recognition receptor pathway transcriptome expression. This potentially creates a proinflammatory glioma microenvironment where TAM activation may be further stimulated by sequential CED of 2141-V11, an Fc engineered anti-human CD40 agonist antibody developed at Rockefeller University. We are conducting a first in human trial of the combination of D2C7-IT + 2141-V11 administered via CED in recurrent MG patients. Methods: Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade 3 or 4 MG; ≥ 4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing levels of 2141-V11 to determine the maximum tolerated dose (MTD) of the compound administered intratumorally in conjunction with D2C7-IT. Dose escalation and de-escalation are managed using a modified Bayesian optimal interval (BOIN) design to identify the MTD. Intratumoral administration of D2C7-IT via CED (4612 ng/mL over 72 hours) is followed by a 7-hour infusion of 2141-V11, both infused at 0.5 mL/hr. 2141-V11 is dose-escalated to determine the MTD when combined with D2C7-IT. Four dose levels (DL) are planned: #1: 0.70 mg; #2: 2.0 mg; #3: 7.0 mg; #4: 21.0 mg. Results: As of February 7, 2022, three patients were treated at DL1 and DL2, and two patients at DL3. No DLTs have been observed, and all eight patients remain alive and in observation on study after 7.0, 6.5, 6.0, 4.4, 2.8, 2.4, 0.9 and 0.5 months. Early signs of tumor response have been observed, with one patient at DL1 and 2 patients at DL2 without radiographic evidence of active tumor. Grade 2 or higher AEs due to D2C7-IT and/or 2141-V11 include: headache (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1; grade 2, n = 1); dysphasia (grade 3, n = 1); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 1); and depressed level of consciousness (grade 2, n = 1). Enrollment is ongoing. Conclusions: Intratumoral administration of D2C7-IT + 2141-V11 via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT04547777.

Alterations of the Gut Microbiome in Recurrent Malignant Gliomas Patients Received Bevacizumab and Temozolomide Combination Treatment and Temozolomide Monotherapy.

The online version contains supplementary material available at 10.1007/s12088-021-00962-2.

Effect of temozolomide combined with radiotherapy on survival and MGMT protein expression in recurrent malignant glioma patients

Purpose: To investigate the effect of temozolomide (TMZ) combined with radiotherapy (RT) on O-6- methylguanine-DNA methyltransferase (MGMT) protein and survival of recurrent malignant glioma patients.
 Methods: Ninety-two patients with malignant glioma in our hospital from January 2014 to January 2015 were assigned to study and control groups using the random table method. Subjects in the control group received radiotherapy (total dose in the range of 60 – 75 Gy), while those in the study group were given TMZ orally (75 mg/m2) daily in addition to radiotherapy, as well as TMZ at 150 – 200 mg/m2. After treatment, clinical effectiveness was compared for the two groups. Changes in methylation of MGMT gene were determined in the two groups. The patients were followed up for 3 years, and the degrees of survival and recurrence were recorded.
 Results: Total effectiveness of clinical treatment was markedly higher in the study group (76.09 %) than in the control group (45.65 %; p < 0.05). One month after radiotherapy, significant decrease in MGMT gene methylation was seen in patients in the study group, relative to control patients (p < 0.05). Patients in the study group had lower median recurrence but higher degree of survival in the 2nd and 3rd years, relative to control patients (p < 0.05).
 Conclusion: The combination of temozolomide and radiotherapy is more effective than radiotherapy in the treatment of recurrent malignant glioma. The combined treatment significantly inhibits tumor recurrence in patients, and improves their prognosis and standard of life.

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.

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.

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.

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.

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.

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).

Assessment of Concurrent Stereotactic Radiosurgery and Bevacizumab Treatment of Recurrent Malignant Gliomas Using Multiparametric MRI Imaging and Radiomics Analysis

To assess the response and predict the overall survival (OS) of recurrent malignant gliomas (MG) patients treated with concurrent BVZ/SRS using multi-modality MRI imaging and radiomics analysis.Methods and materials: SRS was delivered in a single fraction (18/24Gy) or 25Gy in 5 fractions. BVZ was administered immediately before SRS and 2 weeks after. MRI scans were performed before SRS, 1 week and 2 months after SRS. The MR protocol included 2 anatomical (T1w and T2w) and 2 functional (dynamic contrast-enhanced DCE-MRI and diffusion weighted DW-MRI) modalities. Functional biomarkers including apparent diffusion coefficient (ADC), micro-vascular transfer constant Ktrans, brain blood flow FB, and blood volume VB were analyzed. Radiomics analysis was performed to extract imaging features from anatomical MRI images and functional biomarker maps. Wicoxon signed rank tests were performed to evaluate treatment-induced changes, and Mann-Whitney U tests were performed to compare the differences of treatment-induced changes between different patient groups. Selected biomarkers and radiomics features were used to predict the OS after treatment using Support Vector Regression (SVR) with leave-one-out cross validation (LOOCV).Twelve patients with recurrent MG were studied. The median OS was 13.8 months post SRS. DCE results showed that Ktrans (p=0.035) and VB (p=0.035) showed significant decrease 2 months after SRS, and FB showed significant decrease as early as 1 week (p=0.017) after SRS. No functional parameters reflected statistically significant treatment response 1 week after SRS. A total of 888 radiomics features were extracted. 31/126 features demonstrated significant changes 1 week/2 months after SRS, respectively. 9 features' changes were significantly different between WHO Grade III vs IV patient groups, and 6 features' changes were found to be linearly correlated with OS. Using 5 selected features, 9 patients' survival time could be accurately predicted (Mean absolute error = 1.47 months, RMSE = 2.10 months).The results of this work demonstrate the potential of combined radiomics analysis and functional MR imaging in quantitatively identifying early treatment response of concurrent SRS/BVZ.

Abstract 2725: Circulating CD9-GFAP-survivin exosomes during active specific immunotherapy, a potential biomarker for glioma

Abstract Background: We evaluated circulating exosomes isolated from the serum of malignant glioma patients enrolled in a completed phase I clinical trial of an anti-survivin vaccine (SurVaxM). Exosomes are microvesicular bodies with potential mechanisms for cell-cell communication. Identifying circulating exosomes from cancer patients as potential indicators of disease status and response to therapy is of interest. The inhibitor of apoptosis protein (IAP) survivin (SVN) promotes cancer cell proliferation and resistance to chemotherapy. Survivin is expressed in many cancer types including malignant gliomas and is a potential target for active immunotherapy. In the above mentioned clinical trial, five patients experienced early tumor progression with a mean of 2.8 months (1.9-5.4 months) from study entry, while three patients had either late (20.5-22.5 months) or no tumor progression (no evident disease at 48 months in one patient). Methods: To determine whether changes in CD9+/GFAP+/SVN+ exosomes correlated with disease progression, patient serum was evaluated prior to treatment (study entry), 8-10 weeks after initial vaccination, and at the time of MRI-defined tumor progression. By employing ImageStream flow cytometry technology we were able to analyze multiple markers on individual exosomes, identifying highly specific populations of survivin+ exosomes which co-expressed the brain/tumor marker protein GFAP. The combination of these markers made it possible to differentiate patient exosomes from those of healthy individuals. Results: The levels of CD9+/GFAP+, CD9+/SVN+, and CD9+/GFAP+/SVN+ (SVN+) exosomes were significantly increased in patients. Serum from three patients who experienced the longest progression-free intervals, showed 98-99% decreases in SVN+ exosomes after treatment with SurVaxM, and maintained similarly low exosome levels over several months. Five early progressing patients experienced a detectable persistence of, or increase in SVN+ exosomes at 9 weeks following initial vaccination. One patient had rising SVN+ exosomes detectable 16 weeks prior to the discovery of tumor progression by brain MRI scan. One patient with no tumor progression sustained a 99% reduction in serum SVN+ exosomes which was sustained over 48+ months. Conclusion: This study demonstrates that increased numbers of CD9+/GFAP+/SVN+ specific exosomes appear to be associated with early tumor progression in recurrent malignant glioma patients. Larger studies are needed to determine whether the correlation between SVN+ exosome levels and disease progression is specific to SurVaxM treatment, and whether rises in SVN+ exosomes levels are predictive of generalized glioma progression. Our study suggests that levels of circulating SVN+ exosomes may be altered during anti-survivin immunotherapy and could serve as a potential biomarker for clinical trials and tumor monitoring. Citation Format: Michael J. Ciesielski, Phillip Galbo, Sheila Figel, Laura Wiltsie, Cheryl Frank, Jingxin Qiu, Robert A. Fenstermaker. Circulating CD9-GFAP-survivin exosomes during active specific immunotherapy, a potential biomarker for glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2725. doi:10.1158/1538-7445.AM2017-2725

PO-0798: Bevacizumab treatment in recurrent malignant glioma patients – mono-institutional experience in 125 patients

PO-0798: Bevacizumab treatment in recurrent malignant glioma patients – mono-institutional experience in 125 patients

Recurrence pattern analysis after re-irradiation with bevacizumab in recurrent malignant glioma patients.

BackgroundThe aim of the present analysis was to evaluate the recurrence pattern in patients with recurrent malignant glioma after re-irradiation in combination with bevacizumab as there is limited data on how to optimally choose dose, fractionation and delineation margins.MethodsThirty-one patients with recurrent malignant glioma treated with re-irradiation and bevacizumab after previous chemoradiotherapy (concurrent temozolomide 75 mg/m2/d according to the EORTC/NCIC trial) and [18 F]FET-PET and/or MRI confirmed recurrence were retrospectively analyzed. Bevacizumab was applied twice during fractionated re-irradiation (10 mg/kg, d1 + d15, median 36 Gy, conventionally fractionated). Recurrence patterns were assessed by means of [18 F]FET-PET and/or MRI.ResultsMedian follow-up was 34.0 months for all patients [95%-CI, 27.7-40.3] and median post-recurrence survival 10.8 months [95%-CI, 9.2-12.4]. Concerning the recurrence patterns, 61.3% of these were located in-field (19 patients), 22.6% were marginal (7 patients) and 16.1% ex-field (5 patients). No influence on the recurrence pattern was observed according to sex, WHO grade, maintenance chemotherapy or MGMT methylation status whereas planning target volume (PTV) size had a significant influence on the recurrence pattern (p = 0.032). PTV sizes > 75 ml were associated with a higher in-field recurrence rate and lower median post-recurrence progression-free survival (8.5 vs. 4.9 months, p = 0.016).ConclusionsAfter the administration of re-irradiation with bevacizumab the recurrence pattern seems to be mainly centrally located. The PTV size was the main predictor for a marginal/ex-field recurrence.

P17.64 * ANGIOGENIC AND PROCOAGULANT FACTORS IN PLASMA OF BRAIN TUMOUR PATIENTS TREATED WITH BEVACIZUMAB

BACKGROUND: Glioblastoma (GBM) is one of the most vascularized human tumors and GBM cells produce proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (BV), a monoclonal antibody against VEGF, has shown antitumor activity, but so far no biomarkers have been identified to predict outcome. The purpose of the present study was to investigate the possible predictive value of circulating VEGF, von Willebrand factor (vWF) and procoagulant factors in patients with recurrent GBM. METHODS: We conducted a prospective analysis of recurrent malignant gliomas (MG) patients treated with BV alone or in combination with chemotherapy performing serial evaluations of plasma VEGF levels, vWF antigen and procoagulant factors such as thrombin-antithrombin complex (TAT), prothrombin fragment F1 + 2 (F1 + 2), Factor VIII and D-Dimer. Baseline, and post-treatment samples were collected at each administration of BV. RESULTS: Forty-nine recurrent MGs (glioblastoma = 26, astrocytoma = 17, oligodendroglioma = 6) who received BV at 10 mg/kg intravenously every 3 weeks, of whom 26 in association with chemotherapy were included in the study. Median age was 45 years (22-73), median Karnofsky performance status was 80 (60-100). Out of the 48 evaluable, 17 partial responses (35%), 7 stable disease (15%) and 24 disease progressions (50%) were observed. At baseline all patients presented with laboratory signs of coagulation activation (i.e. high TAT and FVIII levels). Circulating plasma levels of VEGF and vWF antigen significantly increased in all patients post-treatment of BV (p = 0.0001 and 0.009 respectively). No responder patients showed significantly higher vWF antigen levels than responders (p = 0.01) after second administration of BV. CONCLUSIONS: These preliminary data suggest that low vWF antigen levels might help predict response in recurrent MG patients treated with BV. This marker should help clinicians to decide the right therapy, advise them of the generation of mechanisms of drug resistance during antiangiogenic treatment.

Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Provokes Lymphocyte Activation and Specific Antitumor Immunity in Patients with Recurrent Glioblastoma

We have previously reported the safety and feasibility of vaccinating recurrent malignant glioma patients with irradiated autologous cells mixed with irradiated GM-K562 cells. Here, we report the impact of vaccination on the expression of T-lymphocyte co-stimulatory and co-inbhibitory molecules as well as on regulatory T-lymphocytes. Furthermore, we explored the impact of vaccination on patient humoral immune responses with particular attention to antibody titers against molecules associated with tumor angiogenesis. Blood was collected from 9 of 10 treated patients at regular intervals and submitted for immune analysis. 5-color flow cytometry was employed after staining of whole blood by an immunophenotyping antibody panel. Antibody titers to tumor-associated antigens were measured by ELISA of patient plasma - all assays were performed in duplicate. Treatment-associated change in percent expression of various markers was analyzed via the non-parametric sign-rank test. p < 0.05 was considered statistically significant. In patients undergoing craniotomy for recurrent malignant glioma, vaccination with irradiated autologous tumor cells and irradiated GM-K562 cells was associated with statistically significant increases in CD4+ T-lymphocyte expression of costimulatory molecules OX40 and 4-1BB (CD137). CD8+ T-lymphocytes saw increased expression of 4-1BB as well. Likewise, there were increases in CD4+ T-lymphocyte expression of CTLA-4, PD1, and FOXP3 - each of which is associated with negative immune regulation and are targetable with existing monoclonal antibodies. 7 of 9 patients had marked treatment-driven increases in antibody titers to Angiopoietin 2, which may represent a novel glioma vasculature-associated antigen. Vaccination with irradiated autologous tumor cells mixed with irradiated GM-K562 cells in patients with recurrent malignant glioma is biologically active and activates both T-lymphoctes and humoral antitumor immunity. Vaccine-induced expression of costimulatory molecules may provide the rationale for combination therapies with either co-stimulatory receptor agonist or co-inhibitory receptor antagonist molecules.

Angiogenic and procoagulant factors in plasma of brain tumor patients treated with bevacizumab.

2085 Background: Glioblastoma (GBM) is one of the most vascularized human tumors and GBM cells produce proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (BV), a monoclonal antibody against VEGF, has shown antitumor activity, but so far no biomarkers have been identified to predict outcome. The purpose of the present study was to investigate the possible predictive value of circulating VEGF, von Willebrand factor (vWF) and procoagulant factors in patients with recurrent GBM. Methods: We conducted a prospective analysis of recurrent malignant gliomas (MG) patients treated with BV alone or in combination with chemotherapy performing serial evaluations of plasma VEGF levels, vWF antigen and procoagulant factors such as thrombin-antithrombin complex (TAT), prothrombin fragment F1+2 (F1+2), Factor VIII and D-Dimer. Baseline, and post-treatment samples were collected at each administration of BV. Results: Forty-nine recurrent MGs (glioblastoma=26, astrocytoma=17, oligodendroglioma=6) who received BV at 10 mg/kg intravenously every 3 weeks, of whom 26 in association with chemotherapy were included in the study. Median age was 45 years (22-73), median Karnofsky performance status was 80 (60-100). Out of the 48 evaluable, 17 partial responses (35%), 7 stable disease (15%) and 24 disease progressions (50%) were observed. At baseline all patients presented with laboratory signs of coagulation activation (i.e. high TAT and FVIII levels). Circulating plasma levels of VEGF and vWF antigen significantly increased in all patients post-treatment of BV (p=0.0001 and 0.009 respectively). No responder patients showed significantly higher vWF antigen levels than responders (p=0.01) after second administration of BV. Conclusions: These preliminary data suggest that low vWF antigen levels might help predict response in recurrent MG patients treated with BV. This marker should help clinicians to decide the right therapy, advise them of the generation of mechanisms of drug resistance during antiangiogenic treatment.