Recent Developments in Blood Biomarkers in Neuro-oncology.

PURPOSE OF REVIEW: Given the invasive and high-risk nature of brain surgery, the need for non-invasive biomarkers obtained from the peripheral blood is greatest in tumors of the central nervous system (CNS). In this comprehensive review, we highlight recent advances in blood biomarker development for adult and pediatric brain tumors. RECENT FINDINGS: We summarize recent blood biomarker development for CNS tumors across multiple key analytes, including peripheral blood mononuclear cells, cell-free DNA, cell-free RNA, proteomics, circulating tumor cells, and tumor-educated platelets. We also discuss methods for enhancing blood biomarker detection through transient opening of the blood-brain barrier. Although blood-based biomarkers are not yet used in routine neuro-oncology practice, this field is advancing rapidly and holds great promise for improved and non-invasive management of patients with brain tumors. Prospective and adequately powered studies are needed to confirm the clinical utility of any blood biomarker prior to widespread clinical implementation.

MR susceptibility imaging for detection of tumor-associated macrophages in glioblastoma.

PURPOSE: Tumor-associated macrophages (TAMs) are a key component of glioblastoma (GBM) microenvironment. Considering the differential role of different TAM phenotypes in iron metabolism with the M1 phenotype storing intracellular iron, and M2 phenotype releasing iron in the tumor microenvironment, we investigated MRI to quantify iron as an imaging biomarker for TAMs in GBM patients. METHODS: 21 adult patients with GBM underwent a 3D single echo gradient echo MRI sequence and quantitative susceptibility maps were generated. In 3 subjects, ex vivo imaging of surgical specimens was performed on a 9.4 Tesla MRI using 3D multi-echo GRE scans, and R2* (1/T2*) maps were generated. Each specimen was stained with hematoxylin and eosin, as well as CD68, CD86, CD206, and L-Ferritin. RESULTS: Significant positive correlation was observed between mean susceptibility for the tumor enhancing zone and the L-ferritin positivity percent (r = 0.56, p = 0.018) and the combination of tumor's enhancing zone and necrotic core and the L-Ferritin positivity percent (r = 0.72; p = 0.001). The mean susceptibility significantly correlated with positivity percent for CD68 (ρ = 0.52, p = 0.034) and CD86 (r = 0.7 p = 0.001), but not for CD206 (ρ = 0.09; p = 0.7). There was a positive correlation between mean R2* values and CD68 positive cell counts (r = 0.6, p = 0.016). Similarly, mean R2* values significantly correlated with CD86 (r = 0.54, p = 0.03) but not with CD206 (r = 0.15, p = 0.5). CONCLUSIONS: This study demonstrated the potential of MR quantitative susceptibility mapping as a non-invasive method for in vivo TAM quantification and phenotyping. Validation of these findings with large multicenter studies is needed.

Histopathology-validated machine learning radiographic biomarker for noninvasive discrimination between true progression and pseudo-progression in glioblastoma.

BACKGROUND: Imaging of glioblastoma patients after maximal safe resection and chemoradiation commonly demonstrates new enhancements that raise concerns about tumor progression. However, in 30% to 50% of patients, these enhancements primarily represent the effects of treatment, or pseudo-progression (PsP). We hypothesize that quantitative machine learning analysis of clinically acquired multiparametric magnetic resonance imaging (mpMRI) can identify subvisual imaging characteristics to provide robust, noninvasive imaging signatures that can distinguish true progression (TP) from PsP. METHODS: We evaluated independent discovery (n = 40) and replication (n = 23) cohorts of glioblastoma patients who underwent second resection due to progressive radiographic changes suspicious for recurrence. Deep learning and conventional feature extraction methods were used to extract quantitative characteristics from the mpMRI scans. Multivariate analysis of these features revealed radiophenotypic signatures distinguishing among TP, PsP, and mixed response that compared with similar categories blindly defined by board-certified neuropathologists. Additionally, interinstitutional validation was performed on 20 new patients. RESULTS: Patients who demonstrate TP on neuropathology are significantly different (P < .0001) from those with PsP, showing imaging features reflecting higher angiogenesis, higher cellularity, and lower water concentration. The accuracy of the proposed signature in leave-one-out cross-validation was 87% for predicting PsP (area under the curve [AUC], 0.92) and 84% for predicting TP (AUC, 0.83), whereas in the discovery/replication cohort, the accuracy was 87% for predicting PsP (AUC, 0.84) and 78% for TP (AUC, 0.80). The accuracy in the interinstitutional cohort was 75% (AUC, 0.80). CONCLUSION: Quantitative mpMRI analysis via machine learning reveals distinctive noninvasive signatures of TP versus PsP after treatment of glioblastoma. Integration of the proposed method into clinical studies can be performed using the freely available Cancer Imaging Phenomics Toolkit.

Comparative Effectiveness of Carboplatin/Pemetrexed With Versus Without Bevacizumab for Advanced Nonsquamous Non-Small Cell Lung Cancer.

BACKGROUND: Despite recent advances in targeted therapy and immunotherapy for advanced non-small cell lung cancer (NSCLC), carboplatin/pemetrexed/bevacizumab remains a commonly used first-line regimen. However, it is unknown whether the addition of bevacizumab to carboplatin/pemetrexed improves overall survival (OS). MATERIALS AND METHODS: Using nationally representative curated electronic health record data from Flatiron Health, we performed a retrospective cohort study of patients diagnosed with advanced nonsquamous NSCLC who received ≥1 cycle of carboplatin/pemetrexed ± bevacizumab as initial systemic therapy for stage IV or metastatic/recurrent disease. The OS impact of adding bevacizumab to carboplatin/pemetrexed was assessed using a Cox proportional hazards model to adjust for age, sex, race, original tumor stage, time between diagnosis of metastatic disease and start of chemotherapy, and performance status. In a secondary analysis of patients at a single academic institution, we also adjusted for the presence of brain metastases, hemoptysis, and anticoagulation. RESULTS: A total of 4,724 patients were included, of which 2,759 patients (58%) received carboplatin/pemetrexed and 1,965 (42%) received carboplatin/pemetrexed/bevacizumab. Median OS was 12.1 months (95% CI, 11.2-12.9 months) in the carboplatin/pemetrexed/bevacizumab group compared with 8.6 months (95% CI, 8.1-9.1 months) in the carboplatin/pemetrexed group (P<.001). Bevacizumab use remained associated with improved OS in a multivariate model (hazard ratio, 0.80; 95% CI, 0.75-0.86; P<.001). In the secondary, institutional analysis (N=539), the effect of bevacizumab was unchanged (hazard ratio, 0.75; 95% CI, 0.59-0.96; P=.02). CONCLUSIONS: In this large, real-world dataset, the addition of bevacizumab to first-line carboplatin/pemetrexed for metastatic nonsquamous NSCLC was associated with improved OS.

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma.

INTRODUCTION: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM). METHODS: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG). RESULTS: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p = 0.003), CD137 (p = 0.042), VEGF-A (p < 0.001), CTLA4 (p = 0.028), CD40 (p = 0.023), GITR (p = 0.020), IL6 (p = 0.02), and OX40 (p < 0.001). In CGCG (n = 52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant. CONCLUSIONS: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

Histopathologic quantification of viable tumor versus treatment effect in surgically resected recurrent glioblastoma.

PURPOSE: The prognostic impact of the histopathologic features of recurrent glioblastoma surgical specimens is unknown. We sought to determine whether key histopathologic characteristics in glioblastoma tumors resected after chemoradiotherapy are associated with overall survival (OS). METHODS: The following characteristics were quantified in recurrent glioblastoma specimens at our institution: extent of viable tumor (accounting for % of specimen comprised of tumor and tumor cellularity), mitoses per 10 high-power fields (0, 1-10, > 10), Ki-67 proliferative index (0-100%), hyalinization (0-6; none to extensive), rarefaction (0-6), hemosiderin (0-6), and % of specimen comprised of geographic necrosis (0-100%; converted to 0-6 scale). Variables associated with OS in univariate analysis, as well as age, eastern cooperative oncology group performance status (ECOG PS), extent of repeat resection, time from initial diagnosis to repeat surgery, and O6-methylguanine-DNA methyltransferase promoter methylation, were included in a multivariable Cox proportional hazards model. RESULTS: 37 specimens were assessed. In a multivariate model, high Ki-67 proliferative index was the only histopathologic characteristic associated with worse OS following repeat surgery for glioblastoma (hazard ratio (HR) 1.3, 95% CI 1.1-1.5, p = 0.003). Shorter time interval from initial diagnosis to repeat surgery (HR 1.11, 95% CI 1.02-1.21, p = 0.016) and ECOG PS ≥ 2 (HR 4.19, 95% CI 1.72-10.21, p = 0.002) were also independently associated with inferior OS. CONCLUSION: In patients with glioblastoma undergoing repeat resection following chemoradiotherapy, high Ki-67 index in the recurrent specimen, short time to recurrence, and poor PS are independently associated with worse OS. Histopathologic quantification of viable tumor versus therapy-related changes has limited prognostic influence.

Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma.

PURPOSE: Young adults with isocitrate-dehydrogenase wild-type (IDH-WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma, IDH-mutant GBM, or IDH-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (EGFR CN gain), one of the most common genetic alterations in IDH-WT glioma, in young adults with IDH-WT GBM. METHODS: We performed a retrospective cohort study of patients 18-45 years old with newly diagnosed, IDH-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of EGFR CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18-45 years old with IDH-WT GBM was analyzed from The Cancer Genome Atlas (TCGA). RESULTS: Ten of 28 patients (36%) from our institution had EGFR CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of EGFR CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3-31.0, p = 0.02). In the TCGA cohort (N = 43), EGFR CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18). CONCLUSIONS: EGFR CN gain may be associated with inferior outcomes in young adults with newly diagnosed, IDH-WT GBM, suggesting a potential role for targeting EGFR in this population.

Strategies for Translating Evidence-Based Medicine in Lung Cancer into Community Practice.

The landscape of non-small cell lung cancer (NSCLC) treatment has rapidly evolved over the past decade. This is exemplified by the use of molecular targeted agents, immunotherapies, and newer technologies such as stereotactic body radiotherapy (SBRT). As the translation of preclinical discoveries into clinical practice continues, the effective dissemination and implementation of evidence-based treatment of NSCLC will remain a foremost challenge for oncologists. To further extend evidence-based medicine into the community setting, community oncologists are being engaged on multiple fronts including leadership and participation in national clinical trials and utilization of internet-based resources.

Acute cholecystitis is a common complication after allogeneic stem cell transplantation and is associated with the use of total parenteral nutrition.

The incidence and risk factors for acute cholecystitis after allogeneic hematopoietic stem cell transplantation (HSCT) are not well defined. Of 644 consecutive adult transplants performed at our institution between 2001 and 2011, acute cholecystitis occurred in the first year of transplant in 32 patients (5.0%). We conducted 2 retrospective case-control studies of this population to determine risk factors for cholecystitis after HSCT and to evaluate the performance of different methods of imaging to diagnosis cholecystitis in patients undergoing HSCT compared with non-HSCT patients. In the HSCT population, development of cholecystitis was associated with an increased 1-year overall mortality rate (62.5% versus 19.8%, P < .001). The risk of developing cholecystitis was higher in patients who received total parenteral nutrition (TPN) (adjusted odds ratio, 3.41; P = .009). There was a trend toward more equivocal abdominal ultrasound findings in HSCT recipients with acute cholecystitis compared with nontransplant patients (50.0% versus 30.6%, P = .06). However, hepatobiliary iminodiacetic acid (HIDA) scans were definitively positive for acute cholecystitis in most patients in both populations (80.0% of HSCT recipients versus 77.4% of control subjects, P = .82). In conclusion, acute cholecystitis is a common early complication of HSCT, the risk is increased in patients who receive TPN, and it is associated with high 1-year mortality. In HSCT recipients with findings suggestive of acute cholecystitis, especially those receiving TPN, early use of HIDA scan may be considered over ultrasound.

PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer.

The programmed death 1 (PD-1) pathway is an immune checkpoint that has been implicated in tumoral immune escape, and has emerged as a major focus of immunotherapy in non-small cell lung cancer (NSCLC). Multiple agents have progressed through clinical development in recent years, including antibodies targeting both PD-1 and its key ligand, programmed death ligand 1 (PD-L1). This article reviews PD-1/PD-L1 blockade in NSCLC, including completed clinical trials, ongoing studies, future directions, and challenges.

Exploiting Iron Metabolism as a Therapeutic Vulnerability in Glioblastoma.

In this CCR Translations, we discuss pharmacologic ascorbate as a novel therapeutic for glioblastoma (GBM). Aberrant iron metabolism in GBM can be assessed noninvasively by MRI and exploited to potentially improve the efficacy of chemoradiotherapy. We contextualize the study's results and discuss the next steps to further develop this paradigm. See related article by Petronek et al., p. 283.

An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma.

Cancer immunity is subjected to spatiotemporal regulation by leukocyte interaction with neoplastic and stromal cells, contributing to immune evasion and immunotherapy resistance. Here, we identify a distinct mesenchymal-like population of endothelial cells (ECs) that form an immunosuppressive vascular niche in glioblastoma (GBM). We reveal a spatially restricted, Twist1/SATB1-mediated sequential transcriptional activation mechanism, through which tumor ECs produce osteopontin to promote immunosuppressive macrophage (Mφ) phenotypes. Genetic or pharmacological ablation of Twist1 reverses Mφ-mediated immunosuppression and enhances T cell infiltration and activation, leading to reduced GBM growth and extended mouse survival, and sensitizing tumor to chimeric antigen receptor T immunotherapy. Thus, these findings uncover a spatially restricted mechanism controlling tumor immunity and suggest that targeting endothelial Twist1 may offer attractive opportunities for optimizing cancer immunotherapy.

Systematic Review of Cerebrospinal Fluid Biomarker Discovery in Neuro-Oncology: A Roadmap to Standardization and Clinical Application.

Effective diagnosis, prognostication, and management of CNS malignancies traditionally involves invasive brain biopsies that pose significant risk to the patient. Sampling and molecular profiling of cerebrospinal fluid (CSF) is a safer, rapid, and noninvasive alternative that offers a snapshot of the intracranial milieu while overcoming the challenge of sampling error that plagues conventional brain biopsy. Although numerous biomarkers have been identified, translational challenges remain, and standardization of protocols is necessary. Here, we systematically reviewed 141 studies (Medline, SCOPUS, and Biosis databases; between January 2000 and September 29, 2022) that molecularly profiled CSF from adults with brain malignancies including glioma, brain metastasis, and primary and secondary CNS lymphomas. We provide an overview of promising CSF biomarkers, propose CSF reporting guidelines, and discuss the various considerations that go into biomarker discovery, including the influence of blood-brain barrier disruption, cell of origin, and site of CSF acquisition (eg, lumbar and ventricular). We also performed a meta-analysis of proteomic data sets, identifying biomarkers in CNS malignancies and establishing a resource for the research community.

Integrating imaging and genomic data for the discovery of distinct glioblastoma subtypes: a joint learning approach.

Glioblastoma is a highly heterogeneous disease, with variations observed at both phenotypical and molecular levels. Personalized therapies would be facilitated by non-invasive in vivo approaches for characterizing this heterogeneity. In this study, we developed unsupervised joint machine learning between radiomic and genomic data, thereby identifying distinct glioblastoma subtypes. A retrospective cohort of 571 IDH-wildtype glioblastoma patients were included in the study, and pre-operative multi-parametric MRI scans and targeted next-generation sequencing (NGS) data were collected. L21-norm minimization was used to select a subset of 12 radiomic features from the MRI scans, and 13 key driver genes from the five main signal pathways most affected in glioblastoma were selected from the genomic data. Subtypes were identified using a joint learning approach called Anchor-based Partial Multi-modal Clustering on both radiomic and genomic modalities. Kaplan-Meier analysis identified three distinct glioblastoma subtypes: high-risk, medium-risk, and low-risk, based on overall survival outcome (p < 0.05, log-rank test; Hazard Ratio = 1.64, 95% CI 1.17-2.31, Cox proportional hazard model on high-risk and low-risk subtypes). The three subtypes displayed different phenotypical and molecular characteristics in terms of imaging histogram, co-occurrence of genes, and correlation between the two modalities. Our findings demonstrate the synergistic value of integrated radiomic signatures and molecular characteristics for glioblastoma subtyping. Joint learning on both modalities can aid in better understanding the molecular basis of phenotypical signatures of glioblastoma, and provide insights into the biological underpinnings of tumor formation and progression.

Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results.

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .

Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial.

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII+ glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9-6.0 months) and median overall survival (11.8 months; 90% CI, 9.2-14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4 + T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

Optimizing CAR-T Therapy for Glioblastoma.

Chimeric antigen receptor T-cell therapies have transformed the management of hematologic malignancies but have not yet demonstrated consistent efficacy in solid tumors. Glioblastoma is the most common primary malignant brain tumor in adults and remains a major unmet medical need. Attempts at harnessing the potential of chimeric antigen receptor T-cell therapy for glioblastoma have resulted in glimpses of promise but have been met with substantial challenges. In this focused review, we discuss current and future strategies being developed to optimize chimeric antigen receptor T cells for efficacy in patients with glioblastoma, including the identification and characterization of new target antigens, reversal of T-cell dysfunction with novel chimeric antigen receptor constructs, regulatable platforms, and gene knockout strategies, and the use of combination therapies to overcome the immune-hostile microenvironment.

Small-molecule toosendanin reverses macrophage-mediated immunosuppression to overcome glioblastoma resistance to immunotherapy.

T cell-based immunotherapy holds promise for treating solid tumors, but its therapeutic efficacy is limited by intratumoral immune suppression. This immune suppressive tumor microenvironment is largely driven by tumor-associated myeloid cells, including macrophages. Here, we report that toosendanin (TSN), a small-molecule compound, reprograms macrophages to enforce antitumor immunity in glioblastoma (GBM) in mouse models. Our functional screen of genetically probed macrophages with a chemical library identifies that TSN reverses macrophage-mediated tumor immunosuppression, leading to enhanced T cell infiltration, activation, and reduced exhaustion. Chemoproteomic and structural analyses revealed that TSN interacts with Hck and Lyn to abrogate suppressive macrophage immunity. In addition, a combination of immune checkpoint blockade and TSN therapy induced regression of syngeneic GBM tumors in mice. Furthermore, TSN treatment sensitized GBM to Egfrviii chimeric antigen receptor (CAR) T cell therapy. These findings suggest that TSN may serve as a therapeutic compound that blocks tumor immunosuppression and circumvents tumor resistance to T cell-based immunotherapy in GBM and other solid tumors that warrants further investigation.

RNA fusion transcript panel identifies diverse repertoire of fusions in adult glioma patients with therapeutic implications.

Background: Recurrent gliomas are therapeutically challenging diseases with few treatment options available. One area of potential therapeutic vulnerability is the presence of targetable oncogenic fusion proteins. Methods: To better understand the clinical benefit of routinely testing for fusion proteins in adult glioma patients, we performed a retrospective review of 647 adult patients with glioma who underwent surgical resection at our center between August 2017 and May 2021 and whose tumors were analyzed with an in-house fusion transcript panel. Results: Fifty-two patients (8%) were found to harbor a potentially targetable fusion with 11 (21%) of these patients receiving treatment with a fusion-targeted inhibitor. The targetable genes found to be involved in a fusion included FGFR3, MET, EGFR, NTRK1, NTRK2, BRAF, ROS1, and PIK3CA. Conclusions: This analysis demonstrates that routine clinical testing for gene fusions identifies a diverse repertoire of potential therapeutic targets in adult patients with glioma and can offer rational therapeutic options for patients with recurrent disease.