Treatment Of Recurrent Glioblastoma Research Articles

CSIG-25. MAPK/ERK SIGNALING IN GLIOMAS MODULATES INTERFERON RESPONSES, PROMOTES TUMOR-MICROGLIA CROSSTALK, AND CONFERS SUSCEPTIBILITY TO ANTI-PD-1 AND ANTI-CTLA-4 IMMUNOTHERAPY

Abstract While immune checkpoint blockade (ICB) is not effective in unselected glioblastoma (GBM) patients, we previously established that MAPK/ERK signaling is associated with overall survival following anti-PD-1 and anti-CTLA-4 treatment in recurrent GBM. However, the causal relationship between MAPK/ERK signaling and susceptibility to ICB, as well as the mechanisms underlying this association, remain to be determined. We conducted in vivo kinome-wide CRISPR/Cas9 screenings in murine gliomas to identify key regulators of susceptibility to anti-PD-1 and CD8+ T-cell response and performed survival studies to validate the most relevant hits. Additionally, paired scRNA-seq with p-ERK staining, spatial transcriptomics, and ex-vivo slice culture of BRAFV600E mutant GBM tumors treated with BRAFi/MEKi were used to determine the causal relationship between MAPK signaling, tumor cell immunogenicity, and modulation of microglia phenotype. Our CRISPR/Cas9 screening results identified the MAPK pathway, particularly the RAF-MEK-ERK pathway, as the most critical modulator of glioma susceptibility to anti-tumoral immunity across all kinases. Survival studies showed that mice bearing high p-ERK gliomas exhibited prolonged survival with anti-PD-1 treatment, which was not seen when ERK phosphorylation diminished. MAPK activation in murine gliomas led to durable anti-tumoral immunity upon implant re-challenge, with memory T cell infiltration in long-term survivors. Elevated p-ERK in glioma cells was associated with interferon responses and antigen presentation. Moreover, in BRAFV600E human GBM cells with ERK1/2 knockout and in slice cultures of human BRAFV600E GBM tissue analyzed by spatial transcriptomics, we observed modulation of interferon responses by the MAPK/ERK pathway. Notably, in slice cultures from BRAFV600E mutant GBM, BRAFi/MEKi treatment disrupted the interaction between tumor cells and tumor-associated macrophages/microglia. In conclusion, the MAPK/ERK pathway is a critical driver of GBM susceptibility to anti-tumoral immunity, modulating the interferon responses and antigen-presenting machinery in glioma cells, as well as tumor cell interaction with the microenvironment.

Biologically informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post treatment glioblastoma.

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of recurrent glioblastoma. This study addresses the need for non-invasive approaches to map heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We developed BioNet, a biologically-informed neural network, to predict regional distributions of two primary tissue-specific gene modules: proliferating tumor (Pro) and reactive/inflammatory cells (Inf). BioNet significantly outperforms existing methods (p < 2e-26). In cross-validation, BioNet achieved AUCs of 0.80 (Pro) and 0.81 (Inf), with accuracies of 80% and 75%, respectively. In blind tests, BioNet achieved AUCs of 0.80 (Pro) and 0.76 (Inf), with accuracies of 81% and 74%. Competing methods had AUCs lower or around 0.6 and accuracies lower or around 70%. BioNet's voxel-level prediction maps reveal intratumoral heterogeneity, potentially improving biopsy targeting and treatment evaluation. This non-invasive approach facilitates regular monitoring and timely therapeutic adjustments, highlighting the role of ML in precision medicine.

Glioma stem cells remodel immunotolerant microenvironment in GBM and are associated with therapeutic advancements.

Glioma is the most common primary tumor of the central nervous system (CNS). Glioblastoma (GBM) is incurable with current treatment strategies. Additionally, the treatment of recurrent GBM (rGBM) is often referred to as terminal treatment, necessitating hospice-level care and management. The presence of the blood-brain barrier (BBB) gives GBM a more challenging or "cold" tumor microenvironment (TME) than that of other cancers and gloma stem cells (GSCs) play an important role in the TME remodeling, occurrence, development and recurrence of giloma. In this review, our primary focus will be on discussing the following topics: niche-associated GSCs and macrophages, new theories regarding GSC and TME involving pyroptosis and ferroptosis in GBM, metabolic adaptations of GSCs, the influence of the cold environment in GBM on immunotherapy, potential strategies to transform the cold GBM TME into a hot one, and the advancement of GBM immunotherapy and GBM models.

MAPK/ERK signaling in gliomas modulates interferon responses, T cell recruitment, microglia phenotype, and immune checkpoint blockade efficacy.

Glioblastoma (GB) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) showing limited efficacy in unselected patients. We previously recently established that MAPK/ERK signaling is associated with overall survival following anti-PD-1 and anti-CTLA-4 treatment in recurrent GB. However, the causal relationship between MAPK/ERK signaling and susceptibility to ICB, as well as the mechanisms underlying this association, remain poorly understood. We conducted in vivo kinome-wide CRISPR/Cas9 screenings in murine gliomas to identify key regulators of susceptibility to anti-PD-1 and CD8+ T cell responses and performed survival studies to validate the most relevant genes. Additionally, paired single cell RNA-sequencing (scRNA-seq) with p-ERK staining, spatial transcriptomics on GB samples, and ex-vivo slice culture of a BRAFV600E mutant GB tumor treated with BRAFi/MEKi were used to determine the causal relationship between MAPK signaling, tumor cell immunogenicity, and modulation of microglia phenotype. CRISPR/Cas9 screens identified the MAPK pathway, particularly the RAF-MEK-ERK pathway, as the most critical modulator of glioma susceptibility to CD8+ T cells, and anti-PD-1 across all kinases. Experimentally-induced ERK phosphorylation in gliomas enhanced survival with ICB treatment, led to durable anti-tumoral immunity upon re-challenge and memory T cell infiltration in long-term survivors. Elevated p-ERK in glioma cells correlated with increased interferon responses, antigen presentation and T cell infiltration in GB. Moreover, spatial transcriptomics and scRNA-seq analysis revealed the modulation of interferon responses by the MAPK/ERK pathway in BRAFV600E human GB cells with ERK1/2 knockout and in slice cultures of human BRAFV600E GB tissue. Notably, BRAFi/MEKi treatment disrupted the interaction between tumor cells and tumor-associated macrophages/microglia in slice cultures from BRAFV600E mutant GB. Our data indicate that the MAPK/ERK pathway is a critical regulator of GB cell susceptibility to anti-tumoral immunity, modulating interferon responses, and antigen-presentation in glioma cells, as well as tumor cell interaction with microglia. These findings not only elucidate the mechanistic underpinnings of immunotherapy resistance in GB but also highlight the MAPK/ERK pathway as a promising target for enhancing immunotherapeutic efficacy in this challenging malignancy.

Local Delivery of Irinotecan to Recurrent GBM Patients at Reoperation Offers a Safe Route of Administration.

Glioblastomas are impossible to completely resect and almost always recur at the borders of the resection margin. There is no established chemotherapy regimen available to patients who recur, while systemic treatment is hampered by the blood-brain barrier. Here, we report on the first evaluation in humans of the intraparenchymal injection of irinotecan into the resection cavity after surgical resection of recurrent glioblastoma patients. The cytotoxicity of irinotecan was compared to SN-38 in primary cells from recurrent glioblastoma patients. Irinotecan was injected at multiple (~30) sites of the resection cavity wall at a depth of 3 to 5 mm. SN-38 was more cytotoxic than irinotecan at concentrations below 1 µM due to enzyme kinetics. The intraparenchymal administration of irinotecan was safe, with good wound healing and an absence of swelling, inflammation, or pseudo-abscess formation. The median survival post irinotecan administration was 32.6 weeks. The median overall survival was 30.5 months, with a two-year survival rate of 56%. This study demonstrates that local delivery of irinotecan into the brain parenchyma offers a safe route of administration over systemic delivery in the treatment of recurrent glioblastoma.

Alterations of the tumor microenvironment (TME) in recurrent glioblastoma following apatinib in combination with temozolomide.

e14018 Background: Glioblastoma (GBM) is the highly malignant primary central nervous system tumor. The standard treatment for glioblastoma is maximal surgical resection followed by concomitant radiotherapy and temozolomide chemotherapy, but patient’s survival still remains poor. At present, apatinib in combination with temozolomide (TMZ) has achieved reasonable clinical efficacy in the treatment of recurrent glioblastoma (rGBM), however, there are currently no clear biomarkers related to clinical efficacy or prognosis. Methods: This retrospective study was enrolled 22 rGBMs treated with apatinib in combination with TMZ and 6 patients who received standard radiotherapy combined with TMZ and experienced recurrence. At the same time, we collected their tissue samples for RNA transcriptome analysis by the Nanostring nCounter platform. In prognosis analysis, long survival benefit is defined as a PFS≥4.2 months, and short survival benefit is defined as a PFS&lt;4.2 months. This PFS threshold was primarily referenced from a Phase III study of bevacizumab combined with chemotherapy for rGBM. The study was approved by the institutional ethics committee of Sanbo Brain Hospital, Capital Medical University (SBNK-YJ-2021-010-02) and informed consent was also obtained from the patients. Results: The differential gene of pre and post standard chemoradiotherapy results suggest that standard treatment has reduced the expression of genes associated with tumor proliferation and up-regulated the expression of the genes associated with the immune response in rGBM. In apatinib combined TMZ patients, compared to the non-response group, the response group had significantly up-regulated expression of genes related to endothelial cells and apoptosis. Enrichment analysis revealed that signaling pathways related to cell proliferation were down-regulated in the response group. In terms of prognosis, compared with the short-survival benefit group (&lt; 4.2 months), four tumor progression-associated genes were down-regulated in response group (≥4.2 months). Hypoxia related-genes was significantly up-regulated in the long survival benefit group. Enrichment analysis showed that genes related to cell proliferation were also down-regulated in the long-survival benefit group, while the expression of signaling pathway genes related to cell activation, and immune response was significantly up-regulated. Conclusions: Our study suggests that the combination of apatinib and TMZ may potentially provide clinical benefits in treating rGBM by modulating genes associated with cell proliferation, promoting apoptosis, regulating hypoxia, and enhancing immune response within the tumor microenvironment. Clinical trial information: NCT04814329 .

Clinical activity and safety of sintilimab, bevacizumab, and TMZ in patients with recurrent glioblastoma

PurposeThere are limited and no standard therapies for recurrent glioblastoma. We herein report the antitumour activity and safety of sintilimab, bevacizumab and temozolomide (TMZ) in recurrent glioblastoma.MethodsWe retrospectively analysed eight patients with recurrent glioblastoma treated with sintilimab (200 mg) every three weeks + bevacizumab (10 mg/kg) every three weeks + TMZ (200 mg/m²orally) (5 days orally every 28 days for a total of four weeks). The primary objective was investigator-assessed median progression-free survival(mPFS). Secondary objectives were to assess the 6-month PFS, objective response rate (ORR) and duration of response (DOR) accroding to RANO criteria.ResultsThe mPFS time for 8 patients was 3.340 months (95% CI: 2.217–4.463), The longest PFS was close to 9 months. Five patients were assessed to have achieved partial response (PR), with an overall remission rate of 62.5%, Four patients experienced a change in tumour volume at the best response time of greater than 60% shrinkage from baseline, and one patient remained progression free upon review, with a DOR of more than 6.57 months. The 6-month PFS was 25% (95% CI: 5.0–55.0%). Three patients had a treatment-related adverse events, though no grade 4 or 5 adverse events occurred.ConclusionIn this small retrospective study, the combination regimen of sintilimab, bevacizumab and TMZ showed promising antitumour activity in treatment of recurrent glioblastoma, with a good objective remission rate.

An expanded safety/feasibility study of the EMulate Therapeutics Voyager™ System in patients with recurrent glioblastoma.

Aim: The EMulate Therapeutics Voyager™ is a simple, wearable, home-use device that uses an alternating electromagneticfieldto alter biologic signaling within cells. Objective: To assess the safety/feasibility of the Voyager in the treatment of recurrent glioblastoma (rGBM). Methods: In this study, patients with rGBM were treated with Voyager as monotherapy or in combination with standard chemotherapy at the Investigator's discretion. Safety was assessed by incidence of adverse events associated with the Voyager. Patients were followed until death. Results: A total of 75 patients were enrolled and treated for at least one day with the Voyager (safety population). Device-related adverse events were uncommon and generally did not result in interruption or withdrawal from treatment. There were no serious adverse events associated with Voyager. A total of60 patients were treated for at least one month (clinical utility population). The median progression-free survival (PFS) was 17weeks (4.3months) in the Voyager only group (n=24) and 21weeks (5.3months) in the Voyager+ concurrent therapy group (n=36). The median overall survival (OS) was 7months in the Voyager only group and 9months in the Voyager+ concurrent therapy group. In patients treated with Voyager+ concurrent therapy, the median OS for patients enrolled with their 1st or 2nd recurrence (n=26) was 10months, while in patients enrolled with their 3rd or 4th recurrence (n=10) OS was 7months. Conclusion: The data support the safety and feasibilityof the Voyager for the treatment of rGBM. Further prospective study of the device is warranted. Trial Registration Number: NCT02296580 (ClinicalTrials.gov).

Relative cerebral blood volume as response predictor in the treatment of recurrent glioblastoma with anti-angiogenic therapy

BackgroundGlioblastoma is one of the most common brain tumors in adult populations, usually carrying a poor prognosis. While several studies have researched the impact of anti-angiogenic therapies, especially anti-VEFG treatments in glioblastoma, few have attempted to assess its progress using imaging studies. PurposeWe attempted to analyze whether relative cerebral blood volume (rCBV) from dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) could predict response in patients with glioblastoma undergoing Bevacizumab (BVZ) treatment. MethodsWe performed a retrospective study evaluating patients with recurrent glioblastoma receiving anti-angiogenic therapy with BVZ between 2012 and 2017 in our institution. Patients were scheduled for routine MRIs at baseline and first-month follow-up visits. Studies were processed for DSC-MRI, cT1, and FLAIR images, from which relative cerebral blood volume measurements were obtained. We assessed patient response using the Response Assessment in Neuro-Oncology (RANO) working group criteria and overall survival. Results40 patients were included in the study and were classified as Bevacizumab responders and non-responders. The average rCBV before treatment was 4.5 for both groups, and average rCBV was 2.5 for responders and 5.4 for non-responders. ROC curve set a cutoff point of 3.7 for rCBV predictive of response to BVZ. Cox Multivariate analysis only showed rCBV as a predictive factor of OS. ConclusionA statistically significant difference was found in rCBV between patients who responded and those who did not respond to BVZ treatment. rCBV may be a low-cost and effective marker to assess response to Bevacizumab treatment in GBM.

High VEGFA Expression Is Associated with Improved Progression-Free Survival after Bevacizumab Treatment in Recurrent Glioblastoma.

Glioblastoma (GB) is one of the deadliest human cancers. Many GB patients do not respond to treatment, and inevitably die within a median of 15-18 months post-diagnosis, highlighting the need for reliable biomarkers to aid clinical management and treatment evaluation. The GB microenvironment holds tremendous potential as a source of biomarkers; several proteins such as MMP-2, MMP-9, YKL40, and VEGFA have been identified as being differentially expressed in GB patient samples. Still to date, none of these proteins have been translated into relevant clinical biomarkers. This study evaluated the expression of MMP-2, MMP-9, YKL40, and VEGFA in a series of GBs and their impact on patient outcome. High levels of VEGFA expression were significantly associated with improved progression-free survival after bevacizumab treatment, thus having potential as a tissue biomarker for predicting patients' response to bevacizumab. Noteworthily, VEGFA expression was not associated with patient outcome after temozolomide treatment. To a lesser extent, YKL40 also provided significant information regarding the extent of bevacizumab treatment. This study highlights the importance of studying secretome-associated proteins as GB biomarkers and identifies VEGFA as a promising marker for predicting response to bevacizumab.

Impact of fractionated stereotactic radiotherapy on activity of daily living and performance status in progressive/recurrent glioblastoma: a retrospective study

BackgroundThe prognosis of recurrent glioblastoma (GBM) is poor, with limited options of palliative localized or systemic treatments. Survival can be improved by a second localized treatment; however, it is not currently possible to identify which patients would benefit from this approach. This study aims to evaluate which factors lead to a lower Karnofsky performance status (KPS) score after fractionated stereotactic RT (fSRT).MethodsWe retrospectively collected data from patients treated with fSRT for recurrent GBM at the Institut de Cancérologie de Lorraine between October 2010 and November 2017 and analyzed which factors were associated with a lower KPS score.Results59 patients received a dose of 25 Gy in 5 sessions spread over 5–7 days (80% isodose). The median time from the end of primary radiotherapy to the initiation of fSRT was 10.7 months. The median follow-up after fSRT initiation was 8.8 months. The incidence of KPS and ADL impairment in all patients were 51.9% and 37.8% respectively with an adverse impact of PTV size on KPS (HR = 1.57 [95% CI 1.19–2.08], p = 0.028). Only two patients showed early grade 3 toxicity and none showed grade 4 or late toxicity. The median overall survival time, median overall survival time after fSRT, median progression-free survival and institutionalization-free survival times were 25.8, 8.8, 3.9 and 7.7 months, respectively. Initial surgery was associated with better progression-free survival (Hazard ratio (HR) = 0.48 [95% CI 0.27–0.86], p = 0.013).ConclusionsA larger PTV should predicts lower KPS in the treatment of recurrent GBM using fSRT.

Stages of stereotactic radiosurgery in the treatment of recurrent glioblastomas

Objective: to evaluate the effectiveness of stereotactic radiosurgery as a therapy method taking into account overall survival in patients with recurrent glioblastoma at all stages of treatment. Materials and methods. A sample of patients (66 ailments) who were treated in 2016-2021 with a molecularly confirmed diagnosis of wild-type glioblastoma was analyzed. Only patients, who, were treated in several stages and as a rule, underwent stereotaxic radiosurgery (SRS), or SRS alone after a biopsy, or SRS in case of relapse, after surgery and radiotherapy, or SRS for subsequent relapses were selected. When evaluating the results, the following were taken into account: 1) age at the diagnosis, 2) volume of surgical resection, 3) use of radiation therapy, 4) use of adjuvant chemotherapy after SRS and response evluation criteria in solid tumors. Overall survival (OS) was assessed after diagnosis and at the time of SRS. Results. Patients received SRS at an average 10 months after initial diagnosis. Median duration of follow-up was 8 months after SRS and 12 months after diagnosis, median OS for all patients was nine months (1 to 42 months) after SRS and 20 months (4 to 64 months) respectively. The median survival after SRS was 9 months (p=0.008; χ2=7.008). The median OS for younger patients (&lt;50 years) was 32.5 months, for elderly patients (&gt;50 years) was 14.8 months (p=0.04; χ2=3.870). The median overall survival rate was 32.2 months in patients who received SRS 10 months after the diagnosis was made, and 16 months in those who received SRS earlier than 10 months (p=0.004, χ2=8.145). Radiosurgical doses ≥15 Gy were correlated with a mean survival rate of nine months and seven months in patients treated at doses &lt;15 Gy (p=0.01; χ2=6.756). In patients who received adjuvant therapy with bevacizumab and/or chemotherapy after SRS, the median OS was 12 months, in patients who did not receive additional therapy after SRS, it was 7 months (p=0.04, χ2=4.19). Conclusions. Stereotactic radiosurgery promotes the effectiveness of glioblastoma treatment due to the possibility of carrying out this method at various stages of treatment. The overall survival of our patients depended on the period of SRS after diagnosis, patient age, radiation dose, and adjuvant chemotherapy.

Real-world analysis of outcomes of patients receiving bevacizumab for recurrent glioblastoma in British Columbia.

e14017 Background: Bevacizumab (Bev) has been publicly funded in British Columbia (BC) since 2011 for treatment of recurrent glioblastoma (rGBM). We performed a retrospective outcomes assessment of patients with rGBM treated with Bev to evaluate treatment practices and outcomes. Methods: Patients with rGBM treated at BC Cancer centers with Bev between January 2011 and December 2017 were reviewed. Patient demographics, tumor characteristics, treatment regimens, and dates of radiographic progression and death were collected. Kaplan-Meier method was used to assess survival, and comparisons were made using the log-rank test. Results: 182 patients were reviewed. There were 180 reported deaths with median PFS 3 months (CI95 = 2.5 - 3.5) and OS 7 months (CI95 = 6.2-7.8) from Bev initiation. Higher corticosteroid dose prior to Bev initiation was associated with worse OS on univariate and multivariate analysis ( p = 0.40 and 0.01, respectively). 67% of patients on corticosteroids reduced their dose shortly after Bev initiation. Most patients (68%) were treated with multiple lines of therapy prior to Bev, with a median time from chemoradiation to Bev initiation of 8 months (range 1-67). Patients started on Bev &lt; 6 months from completion of chemoradiation (prior to adjuvant temozolomide completion) had improved PFS ( p = 0.02) and OS compared to those who started Bev later ( p = 0.05), but there was no association between extent of treatment prior to Bev and outcomes ( p = 0.09). Addition of chemotherapy to Bev did not improve survival over Bev monotherapy ( p = 0.10). Conclusions: Bev combinations with chemotherapy did not confer survival advantage over Bev monotherapy. Furthermore, our results show that patients receiving Bev before completion of adjuvant chemotherapy have better outcomes, suggesting pseudoprogression may have prompted the therapeutic switch. Despite limited benefits to overall survival, Bev is associated with reduction in corticosteroid use and likely improvement in quality of life. Therefore, further research is required to optimize patient selection for and administration of Bev. Additional analysis of rGBM patients prescribed Bev until 2020 in BC is currently underway.

Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma: A Systemic Review and Meta-Analysis.

BackgroundChimeric antigen receptor (CAR) T-cell therapy is a promising treatment option for patients with refractory hematological malignancies. However, its efficacy in glioblastoma remains unclear. Here, we performed a systematic review to summarize the safety and efficacy of CAR T-cell therapy in glioblastoma.MethodsThe PubMed, EMBASE, and Cochrane databases were searched to identify articles published before June 30, 2021 describing the use of CAR T-cell therapy in glioblastoma. Information on the toxicity of CAR T-cell therapy was summarized. The pooled objective response rate (ORR) and overall survival (OS) of patients who underwent CAR T-cell therapy were estimated using a random-effects model with an inverse-variance weighting model and quantile estimation method, respectively.ResultsOf 397 articles identified, eight studies including 63 patients with recurrent glioblastoma treated with various CAR T-cell regimens were included in the analysis. Six (9.5%) patients developed cytokine release syndrome (grade ≤2), and 16 (25.4%) experienced non-critical neurological events. The pooled ORR was 5.1% (95% confidence interval [CI], 0.0–10.4; I2 = 0.05%), and the pooled median OS was 8.1 months (95% CI, 6.7–9.5; I2 = 0.00%).ConclusionAlthough CAR T-cell therapy is a relatively safe therapeutic option in patients with glioblastoma, it shows marginal efficacy, suggesting that further research is necessary for its translation into clinical practice for the treatment of recurrent glioblastoma.

Contrast enhancing pattern on pre-treatment MRI predicts response to anti-angiogenic treatment in recurrent glioblastoma: comparison of bevacizumab and temozolomide treatment.

To evaluate the value of the contrast enhancing pattern on pre-treatment MRI for predicting the response to anti-angiogenic treatment in patients with IDH-wild type recurrent glioblastoma. This retrospective study enrolled 65 patients with IDH wild-type recurrent glioblastoma who received standard therapy and then received either bevacizumab (46 patients) or temozolomide (19 patients) as a secondary treatment. The contrast enhancing pattern on pre-treatment MRI was visually analyzed and dichotomized into contrast enhancing lesion (CEL) dominant and non-enhancing lesion (NEL) dominant types. Quantitative volumetric analysis was used to support the dichotomization. The Kaplan-Meier method and Cox proportional hazards regression analysis were used to stratify progression free survival (PFS) according to the treatment in the entire patients, CEL dominant group, and NEL dominant group. In all patients, the PFS of those treated with bevacizumab was not significantly different from those treated with temozolomide (log-rank test, P = 0.96). When the contrast enhancing pattern was considered, bevacizumab was associated with longer PFS in the CEL dominant group (P = 0.031), whereas temozolomide showed longer PFS in the NEL dominant group (P = 0.022). Quantitative analysis revealed mean values for the proportion of solid-enhancing tumor of 13.7% for the CEL dominant group and 4.3% for the NEL dominant group. Patients with the CEL dominant type showed a better treatment response to bevacizumab, whereas NEL dominant types showed a better response to temozolomide. The contrast enhancing pattern on pre-treatment MRI can be used to stratify patients with IDH wild-type recurrent glioblastoma according to the effect of anti-angiogenic treatment.

GammaTile® brachytherapy in the treatment of recurrent glioblastomas.

BackgroundGammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform. Here, we report clinical outcomes for recurrent glioblastoma patients after GT treatment following maximal safe resection.MethodsWe prospectively followed twenty-two consecutive Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients (6 O6-Methylguanine-DNA methyltransferase methylated (MGMTm); sixteen MGMT unmethylated (MGMTu)) who underwent maximal safe resection of recurrent tumor followed by GT placement.ResultsThe cohort consisted of 14 second and eight third recurrences. In terms of procedural safety, there was one 30-day re-admission (4.5%) for an incisional cerebrospinal fluid leak, which resolved with lumbar drainage. No other wound complications were observed. Six patients (27.2%) declined in Karnofsky Performance Score (KPS) after surgery due to worsening existing deficits. One patient suffered a new-onset seizure postsurgery (4.5%). There was one (4.5%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. The mean follow-up was 733 days (range 279–1775) from the time of initial diagnosis. Six-month local control (LC6) and twelve-month local control (LC12) were 86 and 81%, respectively. Median progression-free survival (PFS) was comparable for MGMTu and MGMTm patients (~8.0 months). Median overall survival (OS) was 20.0 months for the MGMTu patients and 37.4 months for MGMTm patients. These outcomes compared favorably to data in the published literature and an independent glioblastoma cohort of comparable patients without GT treatment.ConclusionsThis clinical experience supports GT brachytherapy as a treatment option in a multi-modality treatment strategy for recurrent glioblastomas.

Myo-Inositol Levels Measured with MR Spectroscopy Can Help Predict Failure of Antiangiogenic Treatment in Recurrent Glioblastoma.

Background Patients with recurrent glioblastoma (GBM) are often treated with antiangiogenic agents, such as bevacizumab (BEV). Despite therapeutic promise, conventional MRI methods fail to help determine which patients may not benefit from this treatment. Purpose To use MR spectroscopic imaging (MRSI) with intermediate and short echo time to measure corrected myo-inositol (mI)normalized by contralateral creatine (hereafter, mI/c-Cr) in participants with recurrent GBM treated with BEV and to investigate whether such measurements can help predict survivorship before BEV initiation (baseline) and at 1 day, 4 weeks, and 8 weeks thereafter. Materials and Methods In this prospective longitudinal study (2016-2020), spectroscopic data on mI-a glial marker and osmoregulator within the brain-normalized by contralateral creatine in the intratumoral, contralateral, and peritumoral volumes of patients with recurrent GBM were evaluated. Area under the receiver operating characteristic curve (AUC) was calculated for all volumes at baseline and 1 day, 4 weeks, and 8 weeks after treatment to determine the ability of mI/c-Cr to help predict survivorship. Results Twenty-one participants (median age ± standard deviation, 62 years ± 12; 15 men) were evaluated. Lower mI/c-Cr in the tumor before and during BEV treatment was predictive of poor survivorship, with receiver operating characteristic analyses showing an AUC of 0.75 at baseline, 0.87 at 1 day after treatment, and 1 at 8 weeks after. A similar result was observed in contralateral normal-appearing tissue and the peritumoral volume, with shorter-term survivors having lower levels of mI/c-Cr. In the contralateral volume, a lower ratio of mI to creatine (hereafter, mI/Cr) predicted shorter-term survival at baseline and all other time points. Within the peritumoral volume, lower mI/c-Cr levels were predictive of shorter-term survival at baseline (AUC, 0.80), at 1 day after treatment (AUC, 0.93), and at 4 weeks after treatment (AUC, 0.68). Conclusion Lower levels of myo-inositol normalized by contralateral creatine within intratumoral, contralateral, and peritumoral volumes were predictive of poor survivorship and antiangiogenic treatment failure as early as before bevacizumab treatment. Adapting MR spectroscopic imaging alongside conventional MRI modalities conveys critical information regarding the biologic characteristics of tumors to help better treat individuals with recurrent glioblastoma. Clinical trial registration no. NCT02843230 © RSNA, 2021 Online supplemental material is available for this article.

Image-Guided Rhenium-186 NanoLiposome (186RNL) Brachytherapy in the Treatment of Recurrent Glioblastoma: Technique, Image Analysis, Dosimetry, and Monitoring

While external beam radiation therapy (EBRT) remains a central component of the management of gliomas, it is limited by tolerance of the surrounding normal brain tissue. We hypothesized that Rhenium-186 NanoLiposome (186RNL) brachytherapy will permit the selective delivery of high specific activity beta-emitting radiation with excellent retention in the tumor and that the emitted gamma rays will permit real time image-guided delivery and monitoring. Herein, we report the technique used, imaging of the nanoliposome distribution and retention, image analysis, radiation dosimetry, and therapy monitoring.A Phase 1 clinical trial of 186RNL administered by convection enhanced delivery (CED) through a flexible subacute catheter to treat recurrent glioblastoma was conducted. Rhenium-186 (186Re) is a therapeutic radionuclide (half-life: 89.24 hours) emitting beta-radiation particles (path range: 1.8 mm). One of every 10 emissions is associated with a 137 KeV gamma ray allowing imaging of in vivo drug distribution, retention, and absorbed dose determination. Treatment planning software and a frameless universal instrument holder system were used for treatment planning and catheter placement. The retention and distribution of 186RNL within the tumor and whole body were obtained by planar and SPECT/CT imaging from mid-infusion to 8 days following drug administration. Locoregional and whole-body drug retention were analyzed from whole body planar images. SPECT/CT and follow-up MR images were co-registered to planning MR images for 3D drug distribution and therapy evaluation. Radiation absorbed doses to local volumes and whole-body organs were calculated.186RNL delivered by CED to patients with recurrent glioblastoma results in predictable and stable drug distribution to the targeted tissues, providing days of sustained, localized radiation treatment to the tumor. The use of up to four catheters effectively enhances locoregional drug distribution and tumor volume coverage. The mean locoregional retention in the brain volume at the end of infusion was 85.9% ± 17.1% ID (n = 18) and at 8 days post-infusion was 46.6% ± 16.7% ID (n = 17). Following dose escalation, the mean radiation absorbed dose in the two most recent cohorts to the tumor volume was 354.7 ± 144.0 Gy, to the whole brain was 1.32 ± 1.06 Gy, and to the whole body was 0.16 ± 0.04 Gy (n = 6). An analysis of 3D drug distribution and tumor response as measured by follow-up MR images will be presented.186RNL brachytherapy provides a high radiation absorbed dose to the tumor with minimal brain and whole-body radiation exposure. The image monitoring capability can provide a predictive tool to evaluate therapy delivery and treatment effectiveness.J. Floyd: Department of Neurosurgery; University of Texas Health Science Center San Antonio. A. Bao: Consultant; Plus Therapeutics. Consultant of an NIH grant supported clinical trial; University of Texas Health Science Center San Antonio. Partnership; NanoTx. W. Phillips: Consultant; Plus Therapeutics. Partnership; NanoTx. T. Patel: Partner; Surgical Group of North Texas. Honoraria; Elekta. Stock; Edwards Life Sciences, Gilead, Stryker, Ziopharm. Secretary; Texas Association of Neurological Surgeons. G. Stein: None. M. Hedrick: None. C. Rice: None. A. Brenner: Consultant; Plus Therapeutics. Partnership; NanoTx. Administrative; NanoTx.

Retrospective Study of the Safety and Efficacy of Anlotinib Combined With Dose-Dense Temozolomide in Patients With Recurrent Glioblastoma.

PurposeThe purpose of this study was to retrospectively analyze the safety and clinical efficacy of anlotinib combined with dose-dense temozolomide (TMZ) as the first-line therapy in the treatment of recurrent glioblastoma (rGBM).Patients and MethodsWe collected the clinical data of 20 patients with rGBM. All patients received anlotinib (12 mg daily, orally for 2 weeks, discontinued for 1 week, repeated every 3 weeks) combined with dose-dense TMZ (100 mg/m2, 7 days on with 7 days off) until the disease progressed (PD) or adverse effects (AEs) above grade 4 appeared. Grade 3 AEs need to be restored to grade 2 before continuing treatment, and the daily dose of anlotinib is reduced to 10 mg. The patients were reexamined by head magnetic resonance imaging (MRI) every 1 to 3 months. The therapeutic effect was evaluated according to Response Assessment in Neuro-Oncology (RANO) criteria. The survival rate was analyzed by Kaplan-Meier survival curve analysis. The baseline of all survival index statistics was the start of anlotinib combined with dose-dense of TMZ. National Cancer Institute-Common Terminology Criteria Adverse Events version 4.0 (NCI-CTCAE 4.0) was used to evaluate AEs.ResultsTwenty cases of rGBM were evaluated according to the RANO criteria after treatment with anlotinib and dose-dense TMZ, including five cases of stable disease (SD), thirteen cases of partial response (PR), one case of complete response (CR), and one case of PD. The median follow-up time was 13.4 (95% CI, 10.5–16.3) months. The 1-year overall survival (OS) rate was 47.7%. The 6-month progression-free survival (PFS) rate was 55%. In the IDH wild type group, the median PFS and median OS were 6.1 and 11.9 months, respectively. We observed that AEs associated with treatment were tolerable. One patient stopped taking the drug because of cerebral infarction. There were no treatment-related deaths.ConclusionAnlotinib combined with dose-dense TMZ for the first-line therapy showed good efficacy in OS, PFS, ORR, and DCR in the treatment of rGBM, and the AEs were tolerant. Randomized controlled clinical trials investigating the treatment of rGBM with anlotinib are necessary.

Abstract CT238: Phase 2 study of dianhydrogalactitol (VAL-083) inpatients with MGMT-unmethylated, bevacizumab-naivepatients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent and adjuvant setting

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1-5 every 28 days). Almost all GBM patients experience recurrent/progressive disease, with a median survival of 3-9 months after recurrence. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter status for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor prognosis. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. VAL-083's cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. The trial described here is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring adjuvant therapy after chemoradiation with TMZ (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/day on days 1, 2, and 3 of a 21-day cycle. For Group 1 the primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients compared to historical control. For Group 2, the primary objective of this study is to determine the effect of VAL-083 on progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemoradiation with TMZ, compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS) (Group 1), overall response rate (ORR), duration of response (DOR), and quality-of-life (QoL). Tumor response will be assessed by MRI approximately every 42 days, as per RANO criteria. The initial starting dose in this study was 40 mg/m2/day, which was subsequently reduced to 30 mg/m2/day to improve tolerance due to myelosuppression. As of January 11, 2021, 35 evaluable subjects have enrolled at a starting dose of 40 mg/m2/day, and 46 evaluable subjects have enrolled at a starting dose of 30 mg/m2/day in Group 1. In Group 2, 31 evaluable subjects had enrolled at a starting dose of 30 mg/m2/day. As anticipated from prior studies with VAL-083, myelosuppression (thrombocytopenia and neutropenia) has been the most common adverse event observed. The trial is continuing as planned, and an enrollment, efficacy and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962 Citation Format: Barabara J. O'Brien, Carlos Kamiya-Matusoka, Shaio-Pei Weathers, WK Alfred Yung, WK Alfred Yung, Monica Loghin, Rebecca Harrison, Nazanin Majd, Stephanie Knight, Ying Yuan, Jeffrey Bacha, Dennis Brown, Anne Steino, Gregory Johnson, Sarath Kanekal, John Langlands, Lorena Lopez, Richard Schwartz, Marta Penas-Prado, John de Groot. Phase 2 study of dianhydrogalactitol (VAL-083) inpatients with MGMT-unmethylated, bevacizumab-naivepatients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent and adjuvant setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT238.