Glioma Therapy Research Articles

Chemical Information Network and Molecular Docking Inspire the Novel Indole Discovery Against Glioma from Tabernaemontana corymbosa.

The alkaloidingredients were considered to be responsible forthe diverse pharmacological activitiesof the medicinalplant Tabernaemontana corymbosa(Roxb. ex Wall.). In the current finding, the systematic phytochemical investigation onT.corymbosahave been achieved. One new indole alkaloidtabercorympyline A(1) along with sevenknown indoles (2-8) wereisolated from T.corymobsa. Their structures were elucidated by means of spectroscopic techniquesand quantum chemical calculations. Tabercorympyline A(1) possessedthe indoleskeleton with rare N-containing nine membered ring.Chemical informationnetwork was used to comprehensively discover the cluesfor the glioma therapeutic leadsfromT.corymbosaalkaloids (TA). Inspired by chemical information networkanalysis, all the isolated compoundshave been furthervalidated theiranti glioma activities in glioma cell line U251.Interestingly, the compounds2, 3,5, and6exhibited significantinhibitory effects on gliomacellsin vitro.Molecular docking was ultimately used to indicatepossible binding performance and mechanism between active compounds(2-3) andthe core targets.This study sequentially assembled chemical informationand networkanalysis, phytochemistry, molecular docking, and in vitroactivity validation to comprehensively explore the effective compounds, related targets, and potential mechanisms of TA therapy for glioma.

IMMU-40. INVESTIGATING THE ROLE OF MUTATIONAL BURDEN IN TUMOR IMMUNOGENICITY USING A PRE-CLINICALMLH1-DEFICIENT GLIOBLASTOMA MODEL

Abstract BACKGROUND Although there is an established correlation between tumor mutational burden (TMB) and response to immune checkpoint inhibition (ICI) in many cancers, such an association has not been definitively shown in high-grade gliomas. Most studies of ICI therapy in gliomas, including glioblastoma (GBM), have failed to demonstrate efficacy, with the exception of hypermutated cases resulting from rare inherited defects in mismatch repair (MMR) genes. We sought to investigate the association of TMB to immune response using a syngeneic murine model with a spectrum of mutational burdens. METHODS We used CRISPR-Cas9 to knockout the MMR gene Mlh1 in the murine glioma model SB28, an ICI-resistant cell line with a very low mutational burden (108 non-synonymous mutations). RESULTS Single-cell sorted Mlh1 knockout SB28 clones revealed a two- to six-fold increase in TMB. Importantly, loss of Mlh1 also brought about global changes in immune- and inflammatory-related gene expression in vitro, without correlation to increasing TMB. While all clones had the same rate of in vitro proliferation, flank injection of a high TMB vs a low TMB SB28 Mlh1 knockout clone resulted in similar survival benefits compared to Mlh1 wildtype SB28. CONCLUSIONS These preliminary results suggest that, although disruption of the MMR system may result in heightened tumor immunogenicity, elevated TMB may not be the sole significant determinant. We are currently investigating tumor proliferation after flank injection in immunocompromised mice to confirm that slowed growth is immune-related, as well as clone-specific response to ICI treatment. We are also exploring the role of specific cytokines/chemokines in conferring this survival advantage and potential immune response. By generating a GBM model of varied mutational burdens and immune profiles and comparing to the baseline SB28 cell line, we can interrogate the relative significance of TMB in tumor immunogenicity and ICI response.

INNV-13. OPHTHALMOLOGICAL COMPLICATIONS IN NF-1 PATIENTS RECEIVING MEK INHIBITORS: MD ANDERSON CANCER CENTER EXPERIENCE

Abstract BACKGROUND MEK inhibitors (MEKi) are a novel therapy for plexiform neurofibromas and optic gliomas in Neurofibromatosis type 1 (NF1). Potential ophthalmic complications are MEKi-induced retinopathy (MEKAR) requiring regular ophthalmologic assessments. We assess the importance of screening and ocular adverse events (OAE) in pediatric NF1 patients receiving MEKi. METHODS We reviewed 45 NF1 patients with baseline and follow-up examinations before and post MEKi treatment initiation. Evaluations included comprehensive eye examination, visual acuity, dilated fundoscopic examination, optical coherence tomography (OCT) of the macula and nerve fiber layer, and Humphrey visual field testing. RESULTS Twenty-six (62% male) of 45 patients were included. Median age at treatment was 15 (range 2-23) years. Plexiform neurofibromas were the most common indication for MEKi (n=22). Selumetinib was the most common MEKi (n=19, 77%), then trametinib (n=6, 23%), and mirdametinib (n=1, 4%). Only two patients had to switch to different MEKi. Patients were followed for a mean of 413-days after treatment initiation (range 103-1122 days) for an average of 3.85 ophthalmology exams per patient. No retinopathy was observed at each of the 3–6 month follow-ups. Around 15% of patients experienced dry eye symptoms with none requiring artificial tears for management. Seven patients had pre-existing optic neuropathy. No dose adjustments were needed due to OAEs. One patient’s visual acuity decreased temporarily but returned to baseline and the patient remains on MEKi. CONCLUSIONS Regular ophthalmologic assessments are crucial for NF1 patients undergoing MEKi treatment. Consensus guidelines on frequency of ophthalmologic screening during MEKi treatment are not well reported. In our cohort no patients had MEKAR at regular 3–6 month follow ups. In addition to baseline screening, future larger cohort studies are needed to confirm if decreasing the frequency of retinal exams is safe while on MEKi to inform future clinical screening guidelines for NF1 patients on MEKi.

IMMU-18. IL-7 MEDIATED UPREGULATION OF VLA-4 INCREASES ACCUMULATION OF ADOPTIVELY TRANSFERRED T LYMPHOCYTES IN MURINE GLIOMA

Abstract We have previously described the development of a novel brain bi-specific T cell engager (BRiTE) targeting EGFRvIII in Glioma. Despite BRiTEs impressive potency, efficacy in solid tumors is dependent on tumor-infiltrating lymphocytes (TILs). We evaluated if peripheral adoptive lymphocyte transfer (ALT) increases TILs in immunocompetent mice, even during glioma-induced sequestration. C57/Bl6 mice were implanted with 3 x 10^4 cells syngeneic glioma (CT-2AvIII) and treated with 1 x 10^7 IV CD45.1+ ALT on Day 15. The brain was divided into tumor and non-tumor bearing hemispheres and analyzed each day for exogenous (CD45.1+) CD3/4/8 counts. We observed that IL-7-expanded ALT accumulated at a higher rate within tumor versus IL-2 ALT (72-hours IL-7 median 26.66x vs IL-2 median 4.291x, p=0.0159*). Exogenous T cell entry into tumor-bearing CNS overwhelmingly consisted of CD8+ T cells, and CD45.1+ IL-7 ALT cells made up ~20% of the CD3+ population in tumor 72-hours following administration (mean 19.4%, SD ±4.53%, n=5). Survival experiments used combination ALT and anti-4-1BB therapy in the same model. Mice were treated with IV ALT on Day 5, along with 200µg of IP anti-4-1BB. IP mAb Injections were given every 3 days for 4 total cycles (D5, D8, D11 & D14). Evaluation at these time points was selected as this correlated with peak sequestration of immune cells as evidenced by splenic involution. For survival studies, only combination ALT and anti-4-1BB produced significantly increased survival benefit in our CT-2AvIII model compared to ALT alone (median survival 45.5 days for combination versus 25 days in ALT only group, p=0.0134, chi-square test). These findings demonstrate the feasibility of combination ALT/antibody-based therapy in pre-clinical glioma, as well as outlining a novel approach for delivering both immune cells and antibody-based immunotherapy. Combination therapy with BRiTE and ALT will be explored in an upcoming clinical trial (NCT04903795).

EPCO-31. THE GERMLINE POLYMORPHISM RS55705857 IS ASSOCIATED WITH A POOR SURVIVAL IN ASTROCYTOMA, IDH-MUTANT, GRADE 2

Abstract Histologic features, presence of CDKN2A/B homozygous deletion and methylation subtype are strong determinants of outcome and of therapy in IDH-mutant gliomas. We were interested in learning if there are additional markers of outcome in these tumors. To address this question, we assembled a cohort of 963 IDH-mutant gliomas with overall survival data (median follow-up alive 2.7 years, median follow-up deceased 3.9 years). Array-based copy number data, targeted NGS, germline genotyping data and Illumina EPIC array methylation data were available on 872, 226, 542, and 401 patients, respectively. Morphologic type (oligodendroglioma versus astrocytoma, grade (2/3 vs 4) and methylation subtype (A_IDH_LG vs A_IDH_HG) were all significantly associated with survival (p <0.001). There was no significant difference in survival between grade 2 vs 3 IDH-mutant astrocytomas (p=0.53 adjusting for age and sex). However, subjects with the risk allele (G) for rs55705857 had a better overall survival than subjects with the non-risk allele (A) in IDH-mutant oligodendroglioma (AG/GG vs AA, median overall survival 21.6 vs 15.7 years, p=0.048 after adjusting for grade, age, and sex). Conversely, rs55705857 was associated with a markedly worse survival in grade 2 IDH-mutant astrocytomas (AG/GG vs AA, median overall survival 8.6 vs 19.6 years, p=0.007 after adjusting for age and sex). Despite similar sample sizes and number of deaths, there was no significant difference in overall survival by rs55705857 genotype in grade 3 or 4 IDH-mutant astrocytomas. Upon further functional analyses, TLX1 and GALNT17 were found to be differentially methylated in IDH1-mutant astrocytomas and oligodendrogliomas, respectively, when stratified by rs55705857 risk allele. This is the first observation of a germline characteristic (e.g. rs55705857) predicting survival in low-grade IDH-mutant astrocytoma. While this observation requires validation, it suggests that germline genotype may be practice changing and inform results of trials such as CATNON and CODEL.

INNV-26. FEASIBILITY EVALUATION OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR BRAINSTEM GLIOMAS

Abstract BACKGROUND Tumor Treating Fields (TTFields) therapy is a novel anti-mitotic therapy that is FDA-approved for use in patients with newly diagnosed and recurrent glioblastoma (GBM). However, TTFields therapy is currently only approved for supratentorial GBM, and the feasibility of TTFields therapy for treating infratentorial GBM remains unknown. TTFields values of average local minimum power density (LMiPD) >1.15 mW/cm3 and local minimum field intensity (LMiFI) >1.06 V/cm, were associated with improved OS and PFS based on a posthoc analysis of the EF-14 study. This is a dosimetric planning evaluation of the feasibility of TTFields therapy for brainstem gliomas. METHODS MRIs of patients with brainstem gliomas were used for this dosimetric evaluation, with planning conducted using MAXPOINT (Novocure, Switzerland). Gross tumor volume (GTV) for TTFields planning was defined as enhancing tumor on T1 post contrast MRI. Clinical target volume (CTV) was defined as GTV expanded by a 3 mm margin around sum total of resection cavity, necrotic core, and enhancing tumor. LMiPD and LMiFI to the GTV and CTV were evaluated. RESULTS A total of 5 patients with brainstem gliomas were included in this study. The median GTV volume was 8.2 cc (range: 3.8 – 13.5 cc), and median CTV volume was 18.6 cc (range: 9.1 – 23.4 cc). The median LMiPD for GTV and CTV were 1.9 (range: 1.1 – 2) and 1.9 (range: 1-2.1) mW/cm3, respectively. The median LMiFI for GTV and CTV were 1.3 (range: 1.1-1.6) and 1.2 (range: 1.1-1.6) V/cm, respectively. CONCLUSION LMiPD and LMiFI values for brainstem gliomas achieved levels that are consistent with those associated with improved OS and PFS in posthoc analyses in supratentorial GBM. This dosimetric planning study suggests feasibility and theoretical benefit of TTFields for brainstem gliomas. Further clinical evaluation is warranted to validate its efficacy.

IMMU-11. GUARDIANS OF INNATE IMMUNE ACTIVATION: CRUCIAL ROLES OF NONO AND CGAMP IN GLIOMA VIROTHERAPY

Abstract Despite aggressive therapeutic interventions, glioblastoma patients face a median survival of seven months after tumor recurrence. Alarmingly, there has been no improvement to the standard of care for two decades, and patients still receive toxic doses of radiation and chemotherapy, rendering many unable to perform daily functions. An emerging approach, oncolytic virotherapy (OV) using Delta-24-RGD, is gaining traction due to recent clinical trials (NCT00805376, NCT03178032, and NCT02798406) exhibiting robust responses in subsets of patients. While these studies demonstrated the therapeutic potential of OV, findings also indicate the early clearance of the virus, hindering the establishment of an effective anti-tumor immune response in most patients. We propose that mitigating the innate immune response against the therapeutic virus should result in improved intratumoral persistence, increasing the window of opportunity for developing an anti-tumor immune response. RNA-sequencing identified the non-POU domain containing octamer-binding (NONO) pathway as highly upregulated in syngenic glioma models and further amplified by OV treatment. In-vitro RNA sequencing and comparative analysis complemented these results to define a unique transcriptomic profile induced by adenovirus infection. LC-MS/MS identified host cGAS and adenoviral capsid proteins as candidate binding partners of NONO, which were validated using co-immunoprecipitation. Although the type I interferon cluster is deleted in most gliomas, tumor cells have a profound influence on their microenvironment through the secretion of the second messenger cGAMP. We show that NONO is required for cGAMP production, providing a mechanism to modulate antiviral responses in the tumor microenvironment during OV. Our findings underscore the significance of cGAMP shed from tumor cells in response to OV, and how NONO interacts with cGAS in the nucleus to sensor adenovirus infection. These findings uncover novel innate immunity mechanisms in gliomas and will inform the design of more efficacious oncolytic adenoviruses for glioma therapy.

Deciphering the topological landscape of glioma using a network theory framework

Glioma stem cells have been recognized as key players in glioma recurrence and therapeutic resistance, presenting a promising target for novel treatments. However, the limited understanding of the role glioma stem cells play in the glioma hierarchy has drawn controversy and hindered research translation into therapies. Despite significant advances in our understanding of gene regulatory networks, the dynamics of these networks and their implications for glioma remain elusive. This study employs a systemic theoretical perspective to integrate experimental knowledge into a core endogenous network model for glioma, thereby elucidating its energy landscape through network dynamics computation. The model identifies two stable states corresponding to astrocytic-like and oligodendrocytic-like tumor cells, connected by a transition state with the feature of high stemness, which serves as one of the energy barriers between astrocytic-like and oligodendrocytic-like states, indicating the instability of glioma stem cells in vivo. We also obtained various stable states further supporting glioma’s multicellular origins and uncovered a group of transition states that could potentially induce tumor heterogeneity and therapeutic resistance. This research proposes that the transition states linking both glioma stable states are central to glioma heterogeneity and therapy resistance. Our approach may contribute to the advancement of glioma therapy by offering a novel perspective on the complex landscape of glioma biology.

Advancements in nanotheranostics for glioma therapy.

Gliomas are brain tumors mainly derived from glial cells that are difficult to treat and cause high mortality. Radiation, chemotherapy, and surgical excision are the conventionaltreatments for gliomas. Patients who have surgery or have undergone chemotherapy for glioma treatment have poor prognosis with tumor recurrence. In particular, for glioblastoma,the 5-year averagesurvival rateis 4-7%, and the median survival is 12-18months. Anumber of issues hinder effective treatmentsuch as, poor surgical resection, tumor heterogeneity, insufficient drug penetration across the blood-brain barrier, multidrug resistance, and difficulties with drug specificity. Nanotheranostic-mediated drug delivery is becoming a well-researched consideration, and an efficient non-invasive method for delivering chemotherapeutic drugs to the target area. Theranostic nanomedicines, which incorporate therapeutic drugs and imaging agents forpersonalized therapies, can be used for preventing overdose of non-responders. Through the identification of massive and complicated information from next-generation sequencing, machine learning enables for precise prediction of therapeutic outcomes and post-treatment management for patients with cancer. This article gives a thorough overview of nanocarrier-mediated drug delivery with a brief introduction to drug delivery challenges. In addition, this assessment offers a current summary of preclinical and clinical research on nanomedicines for gliomas. In the future, nanotheranostics will provide personalized treatment for gliomas and other treatable cancers.

Integrated analysis of bulk and single-cell RNA sequencing reveals the impact of nicotinamide and tryptophan metabolism on glioma prognosis and immunotherapy sensitivity

BackgroundNicotinamide and tryptophan metabolism play important roles in regulating tumor synthesis metabolism and signal transduction functions. However, their comprehensive impact on the prognosis and the tumor immune microenvironment of glioma is still unclear. The purpose of this study was to investigate the association of nicotinamide and tryptophan metabolism with prognosis and immune status of gliomas and to develop relevant models for predicting prognosis and sensitivity to immunotherapy in gliomas.MethodsBulk and single-cell transcriptome data from TCGA, CGGA and GSE159416 were obtained for this study. Gliomas were classified based on nicotinamide and tryptophan metabolism, and PPI network associated with differentially expressed genes was established. The core genes were identified and the risk model was established by machine learning techniques, including univariate Cox regression and LASSO regression. Then the risk model was validated with data from the CGGA. Finally, the effects of genes in the risk model on the biological behavior of gliomas were verified by in vitro experiments.ResultsThe high nicotinamide and tryptophan metabolism is associated with poor prognosis and high levels of immune cell infiltration in glioma. Seven of the core genes related to nicotinamide and tryptophan metabolism were used to construct a risk model, and the model has good predictive ability for prognosis, immune microenvironment, and response to immune checkpoint therapy of glioma. We also confirmed that high expression of TGFBI can lead to an increased level of migration, invasion, and EMT of glioma cells, and the aforementioned effect of TGFBI can be reduced by FAK inhibitor PF-573,228.ConclusionsOur study evaluated the effects of nicotinamide and tryptophan metabolism on the prognosis and tumor immune microenvironment of glioma, which can help predict the prognosis and sensitivity to immunotherapy of glioma.

Machine learning-based new classification for immune infiltration of gliomas.

Glioma is a highly heterogeneous and poorly immunogenic malignant tumor, with limited efficacy of immunotherapy. The characteristics of the immunosuppressive tumor microenvironment (TME) are one of the important factors hindering the effectiveness of immunotherapy. Therefore, this study aims to reveal the immune microenvironment (IME) characteristics of glioma and predict different immune subtypes using machine learning methods, providing guidance for immune therapy in glioma. We first performed unsupervised cluster analysis on the genes and arrays of 693 gliomas in CGGA database and 702 gliomas in TCGA database. Then establish and verify the classification model through Machine Learning (ML). Then, use DAVID to perform functional enrichment analysis for different immune subtypes. Next step, analyze the immune cell distribution, stemness maintenance, mesenchymal phenotype, neuronal phenotype, tumorigenic cytokines, molecular and clinical characteristics of different immune subtypes of gliomas. Firstly, we divide the IME of gliomas in the CGGA database into four different subtypes, namely IM1, IM2, IM3, and IM4; similarly, the IME of gliomas in the TCGA database can also be divided into four different subtypes (IMA, IMB, IMC, and IMD). Next, based on ML, we developed a highly reliable model for predicting different immune subtypes of glioma. Then, we found that Monocytic lineage, Myeloid dendritic cells, NK cells and CD8 T cells had the highest enrichment in the IM1/IMD subtypes. Cytotoxic lymphocytes were highest expressed in the IM4/IMA subtypes. Next step, Enrichment analysis revealed that the IM1-IMD subtypes were mainly closely related to the production and secretion of IL-8 and TNF signaling pathway. The IM2-IMB subtypes were strongly associated with leukocyte activation and NK cell mediated cytotoxicity. The IM3-IMC subtypes were closely related to mitotic nuclear division and mitotic cell cycle process. The IM4-IMA subtypes were strongly associated with Central Nervous System (CNS) development and striated muscle tissue development. Afterwards, Single sample gene set enrichment analysis (ssGSEA) showed that stemness maintenance phenotypes were mainly enriched in the IM4/IMA subtypes; Neuronal phenotypes were closely associated with the IM2/IMB subtypes; and mesenchymal phenotypes and tumorigenic cytokines were highly correlated with the IM2 /IMB subtypes. Finally, we found that compared with patients in the IM2/IMB and IM4/IMA subtypes, the IM1/IMD and IM3/IMC subtypes have the highest proportion of GBM patients, the shortest average overall survival of patients and the lowest proportion of patients with IDH mutation and 1p36/19q13 co-deletion. We developed a highly reliable model for predicting different immune subtypes of glioma by ML. Then, we comprehensively analyzed the immune infiltration, molecular and clinical features of different immune subtypes of gliomas and defined gliomas into four subtypes: immunogenic subtype, adaptive immune resistance subtype, mesenchymal subtype, and immune tolerance subtype, which represent different TMEs and different stages of tumor development.

Chimeric antigen receptor T-cell therapy in patients with malignant glioma-From neuroimmunology to clinical trial design considerations.

Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner.

Modulation of the Immune Environment in Glioblastoma by the Gut Microbiota

Studies increasingly support the role of the gut microbiota in glioma development and treatment, although the exact mechanisms remain unclear. Research indicates that the gut microbiota can influence glioma progression, response to therapies, and the effectiveness of treatments like immunotherapy, with certain microbial compositions being linked to better outcomes. Additionally, the gut microbiota impacts the tumor microenvironment, affecting both tumor growth and the response to treatment. This review will explore glioma, the gut microbiota, and how their interaction shapes glioma development and therapy responses. Additionally, this review examines the influence of gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and tryptophan, on glioma development and treatment. It also explores gut microbiome signaling via pattern recognition receptors, and the role of molecular mimicry between microbial and tumor antigens in glioblastoma, and if these interactions affect glioma development and treatment.

Oxime Linked Doxorubicin Glycoconjugates Improve the Specific Targeting of Glioblastoma in High-Grade Glioma Therapy

Oxime Linked Doxorubicin Glycoconjugates Improve the Specific Targeting of Glioblastoma in High-Grade Glioma Therapy

Enhancing glioblastoma cytotoxicity through encapsulating O6-benzylguanine and temozolomide in PEGylated liposomal nanocarrier: an in vitro study

Glioblastoma (GBM) (grade IV glioma) is the most fatal brain tumor, with a median survival of just 14 months despite current treatments. Temozolomide (TMZ), an alkylating agent used with radiation, faces challenges such as systemic toxicity, poor absorption, and drug resistance. To enhance TMZ effectiveness, we developed poly(ethylene glycol) (PEG) liposomes co-loaded with TMZ and O6-benzylguanine (O6-BG) for targeted glioma therapy. These liposomes, prepared using the thin-layer hydration method, had an average size of 146.33 ± 6.75 nm and a negative zeta potential (−49.6 ± 3.1 mV). Drug release was slower at physiological pH, with 66.84 ± 4.62% of TMZ and 69.70 ± 2.88% of O6-BG released, indicating stability at physiological conditions. The liposomes showed significantly higher cellular uptake (p < 0.05) than the free dye. The dual drug-loaded liposomes exhibited superior cytotoxicity against U87 glioma cells, with a lower IC50 value (3.99µg/mL) than the free drug combination, demonstrating enhanced anticancer efficacy. The liposome formulation induced higher apoptosis (19.42 ± 3.5%) by causing sub-G0/G1 cell cycle arrest. The novelty of our study lies in co-encapsulating TMZ and O6-BG within PEGylated liposomes, effectively overcoming drug resistance and improving targeted delivery for glioma treatment.

Bioinformatics investigation of the prognostic value and mechanistic role of CD9 in glioma

In recent years, CD9 has been extensively studied as a potential biomarker for cancer. However, the biological role of CD9 in gliomas remains unclear. This study investigates the function of CD9 in gliomas and its molecular mechanisms. Utilizing pan-cancer analysis with TCGA, CGGA, and GEO databases, differential expression of CD9 was observed in 11 tumor types within the TCGA cohort, and it was associated with patient survival rates. Analysis of the CGGA glioma database revealed that patients with high CD9 expression had lower survival rates. The area under the ROC curve (AUC) for GSE16011 was greater than 0.7, indicating a high discriminative ability. Through gene set enrichment analysis (GSEA), immune-related analysis, and CD9 mutation detection, CD9 was found to have the strongest correlation with neutrophil involvement (cor = 0.30, P < 0.05), and the high CD9 expression group exhibited higher rejection responses and TIDE scores, suggesting a lower likelihood of successful immunotherapy. The high CD9 expression group was more sensitive to 81 drugs, indicating potential therapeutic effects for gliomas. Furthermore, overexpression of CD9 in gliomas may be associated with gene mutations. Down-regulation or up-regulation of CD9 expression in the glioblastoma cell line LN229 showed that CD9 could positively regulate the migratory ability of LN229 cells. Further, several marker genes, such as VEGFR-2, TGF-β1, CASP1 and PI3K, were down regulated in CD9 knockdown cell lines and up regulated in CD9 overexpression cell lines, compared with control cell line. This study preliminarily explores the role of CD9 in gliomas and its prognostic value, providing new insights for personalized treatment strategies in glioma therapy.

Overcoming multiple barriers to deliver photo-gene system for glioma-targeted combined therapy

Overcoming multiple barriers to deliver macromolecular drugs is an urgent challenge for glioma treatment. Herein, a strategy of protein corona-regulation synergizing with photoactivation based on T10 peptide-modified and indocyanine green (ICG)-loaded dendrigraft poly-L-lysines was proposed to augment prime editing therapy of glioma. First, the modified T10 peptide could escape the interference barrier of protein crown in blood via its specific binding with endogenous transferrin, thus crossing the blood-brain barrier (BBB) and achieving the targeting recognition of glioma cells. Next, the loaded ICG could weaken the tumor stromal barrier, decrease the cell membrane barrier and escape the lysosomal degradation/autophagy barrier via its photothermal and photodynamic effects. Subsequently, a therapeutic gene that could downregulate p-ERK1/2 for tumor growth inhibition and immunoregulation could be effectively delivered into the glioma cells. The glioma-targeted photo-gene combined immunotherapy effectively inhibit the glioma growth, especially co-dosing with the PD-1 antibody.

Nanoplatelets modified with RVG for targeted delivery of miR-375 and temozolomide to enhance gliomas therapy

Gliomas are one of the most frequent primary brain tumors and pose a serious threat to people’s lives and health. Platelets, a crucial component of blood, have been applied as drug delivery carriers for disease diagnosis and treatment. In this study, we designed engineered nanoplatelets for targeted delivery of therapeutic miR-375 and temozolomide (TMZ, a first-line glioma treatment agent) to enhance glioma therapy. Nanoplatelets were prepared through mild ultrasound, TMZ and miR-375 were co-loaded through ultrasound and electrostatic interactions, respectively, to combine chemotherapy with gene therapy against glioma. To improve the blood brain barrier (BBB) crossing efficiency and glioma targeting ability, the nanoplatelets were modified with central nervous system-specific rabies viral glycoprotein peptide (RVG) through thiol-maleimide click reaction. The RVG modified nanoplatelets co-loaded TMZ and miR-375 (NR/TMZ/miR-375) not only inherited the good stability and remarkable biocompatibility of platelets, but also promoted the cellular uptake and penetration of glioma tissues, and effectively induced cell apoptosis to enhance the therapeutic effect of drugs. In vivo studies showed that NR/TMZ/miR-375 significantly increased the circulation time of TMZ, and exhibited superior combined antitumor effects. In summary, this multifunctional ‘natural’ nanodrug delivery system provides a potent, scalable, and safety approach for platelet-based combined cancer chemotherapy and gene therapy.

Role of Contrast Perfusion Weighted Magnetic Resonance Imaging in Grading of Brain Tumors with Histopathological Correlation

Background: Traditional MRI sequences provide precise anatomical information about brain tumors. But these sequences can’t quantitatively evaluate vascular physiology, or capture tumor biology at the molecular level; which is important for tumor grading, therapeutic assessment, and prognostication. Furthermore, non-enhancing parts of the tumor affected brain, which generally indicates peri-tumoral brain edema with infiltrative tumor cells, is not visible on conventional MRI sequences. Perfusion weighted Magnetic Resonance Imaging (PW-MRI) techniques such as Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) and Dynamic Susceptibility Contrast Magnetic Resonance Imaging (DSC-MRI) have shown promise as imaging biomarkers for glioma therapy, since these new sequences can also provide information about vascular hemodynamics. Our study was first prospective study from Himalayan belt of India, wherein we tried to assess the role of PW-MRI in the grading of brain tumors, with histopathological correlation. Aim and Objective: To compare tumor perfusion and histopathological tumor grading, in evaluation of brain tumor especially gliomas. Material and Method: 40 patients who were referred to Department of Radiodiagnosis for evaluation of brain tumor, and who gave informed consent, were included in this prospective study, done over a period of 18 months. All patients underwent MRI, followed by surgical resection. Observation and Result: In our study, diagnostic accuracy was 90% for mean rCBV (lesion) (cut off: 7 by ROC), mean rCBF (lesion) (cut off: 13.9 by ROC), and rCBF ratio (cut off: 2.9 by ROC); for differentiating benign versus malignant brain tumor. rCBF ratio was found to be best diagnostic parameter with sensitivity of 96%, specificity of 80%, positive predictive value of 89%, negative predictive value of 92%, diagnostic accuracy of 90%, area under ROC curve=0.909, and p value&lt;0.001. Conclusion: We come to conclusion that high grade brain tumor display higher CBF, than do low grade brain tumor. Three parameters showed good diagnostic accuracy, which includes rCBF ratio, mean rCBF (lesion), and mean rCBV (lesion). These parameters can be used to predict the grade of the brain tumor, with good diagnostic accuracy.

CAR T-cell therapy for gliomas.

To review the landscape of chimeric antigen receptor T-cell (CAR T) therapy for gliomas as seen in recently published trials and discuss on-going challenges with new cancer immunotherapy treatments. Given how CAR T therapy has revolutionized the treatment of several hematologic malignancies, there has been increasing interest in using immunotherapy, and particularly CAR T therapy for gliomas. Within the past decade, several first in human trials have published early patient experiences showing treatment is generally well tolerated but with limited efficacy, which may be improving with newer evolutions in CAR T design to overcome known resistance mechanisms in glioma treatment. CAR T therapy is a promising avenue of treatment for high-grade gliomas, which have a universally poor prognosis as well as limited therapeutics. There are a growing number of CAR T clinical trials for CNS tumors and thus, an understanding of their treatment strategies, toxicity management, and overcoming resistance mechanisms will be important for both clinical practice and to identify areas for future research.