Neoepitope-based therapies hold great promise for cancer immunotherapy because they target tumor-specific mutations and elicit potent anti-tumor T-cell responses. However, their clinical implementation remains limited by the complexity of neoepitope discovery and uncertainty regarding presentation by tumor cells. A potential alternative is the generation of immunogenic neoepitopes directly within cancer cells through programmable RNA editing. Here, we develop Short Precise-Encodable ADAR Recruiting (SPEAR) gRNAs that harness endogenous ADAR1 to direct precise adenosine-to-inosine (A-to-I) editing at selected transcript sites. Using these gRNAs, we demonstrate the generation of immunogenic neoepitopes through RNA editing at the transcript level, termed editopes. In a proof-of-concept model based on the melanoma antigen MART-1, SPEAR-mediated RNA editing restored antigen-specific T cell recognition and enabled tumor control in vivo. Finally, we developed a computational pipeline to identify candidate tumor-selective neoepitopes across multiple cancer types amenable to guided RNA editing. Our findings establish programmable RNA editing as a strategy for engineering immunogenic editopes and provide a framework for neoepitope-directed cancer immunotherapy. Clinical implementation of neoepitope-based cancer immunotherapy remains limited by challenges with neoepitope identification and presentation by tumor cells. This study develops Short Precise-Encodable ADAR Recruiting (SPEAR) gRNAs, a programmable RNA editing platform that harnesses endogenous ADAR1 to generate immunogenic neoepitopes at the transcript level (“editopes”), and uses them to enable antigen-specific T cell recognition in vitro and tumor control in vivo. The new RNA editing platform enables recruitment of endogenous ADAR1 to generate immunogenic neoepitopes at the transcript level (“editopes”).

Immunotherapies have substantially advanced cancer treatment; however, their efficacy in gliomas remains limited. This observation cannot be fully explained by tumour-intrinsic factors and may rather be linked to the distinct relationship between the central nervous system (CNS) and the immune system, commonly described as CNS immune privilege. CNS immune privilege is maintained by specialized brain barriers that divide the CNS into compartments with distinct accessibility to immune mediators and immune cells. Although maintaining homeostasis of the CNS parenchyma, these brain barriers direct CNS immune surveillance to the subarachnoid and the perivascular spaces at the CNS borders. Consequently, tumours arising in the CNS parenchyma are shielded from effective immune detection, limiting the efficacy of immunotherapies such as immune checkpoint inhibitors, cancer vaccines and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) transgenic T cells by restricting their access. Importantly, emerging evidence also indicates that gliomas actively remodel brain barrier functions to reinforce immune evasion. Failure to adequately consider brain barrier function in the context of immunotherapy strategies and clinical trial design therefore represents a major gap in the field. Understanding the orchestrated function of the brain barriers as neuroimmunological interfaces is essential for enhancing immune surveillance and improving immunotherapy responses in patients with brain tumours.

Classification of tumors in neuro-oncology today relies on molecular patterns (mostly DNA methylation) and their machine learning-supported interpretation. Understanding the process of algorithmic interpretation is essential for safe application in clinical routine. This is paradigmatically true for the most common primary intracranial tumor in adults, meningioma. Here, by applying multiomic profiling and multiple lines of orthogonal computational evaluation in multiple independent datasets, we found that not only tumor cell characteristics but also incremental changes in the tumor microenvironment (TME) have impact on epigenetic meningioma classification and clinical outcome. Besides revealing the decisive role of non-neoplastic cells in the CNS methylation classifier, this challenges the model of distinct meningioma subgroups toward a TME-determined risk continuum. This refines current controversies in molecular meningioma subtyping. In addition, we apply these learnings to devise and validate a simple diagnostic approach for increased clinical prediction accuracy based on immunohistochemistry, which is also applicable in resource-limited settings.

BACKGROUND:Isocitrate dehydrogenase (IDH)-wildtype Glioblastoma (GB) is the most prevalent primary malignant central nervous system (CNS) tumour in adults. The standard treatment regimen involves radiotherapy, which can cause radionecrotic (postactinic) changes as a late-onset treatment complication. While radiation is thought to mainly affect resident brain tissue, progressive GB and radionecrotic changes can be challenging to differentiate, as they may present with similar symptoms and appear alike on Magnetic Resonance Imaging (MRI). Therefore, histopathological examination remains the gold standard of diagnostics. METHODS:The cohort comprised ten samples from 9 patients diagnosed with GB, all of whom underwent first-line standard of care treatment including surgery, radio- and chemotherapy with temozolomide. Subsequent radiological examination identified tumour progression in all patients, thus necessitating a second surgery. Following histopathological examination of the material collected from the second surgery, 4 patients were histologically diagnosed with tumour recurrence, 4 exhibited no evidence of recurrence but manifested with radionecrotic changes, and 1 patient demonstrated both. The spatial single cell transcriptomic profiling of the samples was conducted using the Xenium platform. RESULTS:We generated a comprehensive spatial single cell transcriptomic atlas of progressive GB and brain tissue with radionecrotic changes. Tumour cells were detected in samples from both groups. The employment of the dataset revealed that progressive GB samples contained oligodendrocyte progenitor (OPC), and neural progenitor (NPC)-like and proliferating tumour cells with high epidermal growth factor receptor (EGFR) expression. Conversely, in samples with radionecrotic changes, tumour cells downregulated their EGFR expression even in the presence of gene amplification and did not show proliferation markers. Additionally, border-associated macrophages infiltrated the tissue and might have promoted gliosis in samples with radionecrotic changes. CONCLUSIONS:This study delineates a complex spatial architecture of brain tissue with post-treatment changes and its discrepancies from progressive GB, thus facilitating future research into novel treatment strategies.

Plasticity is a hallmark of aggressive tumors, including glioblastoma (GBM), enabling tumor cells and the tumor microenvironment (TME) to adapt to diverse niches and evade treatment. Here, we discuss how innate and adaptive immune players cooperate in time and space to create an immunosuppressive TME that supports GBM growth and confers resistance to conventional treatments and immunotherapies. We highlight how therapeutic interventions reshape the TME, underscoring the need for targeted approaches to overcome resistance. We introduce the concepts of local TME priming and TME rewiring as necessary foundations for achieving more effective and durable clinical responses in the future. In this Review, Golebiewska and colleagues summarize the main features of the immunosuppressive microenvironment in glioblastoma (GBM) and discuss how different therapeutic approaches reshape GBM immunity.

H3 K27-altered diffuse midline glioma (DMG) is a molecularly defined, highly aggressive tumor entity since the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). It has been most extensively characterized in children and adolescents and continues to pose significant challenges to treating physicians due to its growth along the midline structures of the brain and its ability to progress distantly leading to poor prognosis. Clinical and molecular determinants of distant progression and its impact on patient survival particularly in adults have not been thoroughly characterized. This retrospective multicenter cohort study of 52 adult patients with DMG was analyzed for clinical and molecular predictors of distant tumor progression using gene panel sequencing and genome-wide DNA methylation arrays. Distant progression including leptomeningeal disease occurred in 10 out of 52 adult patients (19

Leptomeningeal metastatic disease (LMD) of solid tumors represents a cancer stage with high unmet therapeutic need. Here we report results from the dose escalation part of a multicenter phase 1 trial investigating intraventricular nivolumab, now continuing in the expansion part. Eligible participants had LMD from tumors with an approval for intraveneous PD1/PDL1 therapy or high tumor mutational burden. The primary endpoint was safety across four dose levels (20, 30, 40 and 50 mg) with each cohort reviewed by an independent data safety monitoring board before escalation. The secondary endpoint was overall survival. Exploratory endpoints included participant-reported outcome measures. Of 30 enrolled participants, 24 received at least one dose (intention-to-treat population) and 18 completed predefined safety evaluations (per-protocol population). One dose-limiting toxicity occurred at 40 mg. The primary endpoint was met and the recommended fixed dose for the ongoing expansion part is 50 mg. Median overall survival (OS) was 6.6 months. The 6-month, 12-month and 18-month OS rates were 55.0% (95% confidence interval (CI): 37.5-80.6%), 33.3% (95% CI: 17.8-62.4%) and 16.7% (95% CI 6.03-46.1%), respectively. Participant-reported quality of life remained stable. Intraventricular nivolumab has demonstrated safety and feasibility (ClinicalTrials.gov: NCT05112549 ).

INTRODUCTION:Radiation necrosis (RN) complicates neuro-oncological care, mimicking tumor recurrence and lacking high-level evidence for standardized management. METHODS:A European Association for Neuro-Oncology (EANO) expert panel utilized a three-round Delphi process to create a comprehensive expert opinion document based on the available current scientific evidence. A series of statements, derived from the published literature were created by the experts in each field. Consensus was defined as ≥ 80% agreement using a 5-point Likert scale. RESULTS:After three rounds among 20 experts that included adaptation of statements, the Delphi process reached a consensus (≥80% agreement) on 53 statements out of 57. RN occurs in 4% to 30% of patients, typically appearing 6 to 24 months after radiotherapy for primary (glial) or metastatic brain tumors. Experts identified perfusion MRI and amino acid PET as the most suitable imaging modalities for differentiation from tumor recurrence. While histopathology remains the gold standard, identifying viable tumor cells in irradiated gliomas is challenging due to overlapping cytological features with reactive glia. For symptomatic management, corticosteroids may be tried, and bevacizumab is recommended for corticosteroid-refractory cases, with evidence suggesting profound efficacy even at low doses. Surgery is considered effective for rapid symptom relief and definitive diagnosis in accessible lesions. Laser Interstitial Thermal Therapy (LITT) can be considered an additional treatment option for symptomatic RN. CONCLUSIONS:Despite the absence of Level 1 evidence, these Delphi-survey-formulated recommendations provide actionable guidance for clinical practice. There is a need for prospective randomized trials focusing on symptomatic RN.

Personalized cell therapies engineer millions of a patient’s T cells to recognize and kill cancer cells using a patient derived cancer-targeting T cell receptor (TCR). The results can be impressive: in an early trial a patient with late stage metastatic breast cancer refractory to chemotherapy was completely cured of cancer 1. Unfortunately the process of identifying a suitable cancer-targeting TCR for a patient is labor intensive, slow and thus expensive, taking 3-6 months in a commercial setting 2. While pipelines utilizing cancer genome sequencing identify high quality, neoepitope-specific TCRs, the long turnaround time is too slow to be of clinical utility for many patients, and too expensive for widescale use. We used >100,000 TCRs to train the ‘predicTCR’ machine learning classifier to identify tumor-reactive TCR clonotypes form single-cell sequenced tumor infiltrating lymphocytes (TILs) samples. predicTCR is over 85% accurate at detecting tumor-reactive TCRs across diverse tumor types and sequencing technologies 3. predicTCR is antigen agnostic, recognizing tumor-reactive T cells clonotypes in minutes. We then developed makeTCR: a rapid, modular TCR cloning platform to manufacture candidate tumor-reactive TCRs in as little as 24 hours 4. Using makeTCR, candidate TCRs’ tumor killing capacity is validated and TCRs prioritized using autologous T cells and either patient cancer cells or individualized patient-derived tumor organoids (IPTOs) 5. We have combined these platforms to generate the 2T2T pipeline, enabling a 2 week turnaround to patient-specific TCR therapy using experimentally validated TCRs. Our tools are available to the scientific community at https://predictcr.com and https://maketcr.com. 1. Zacharakis et al (Nature Medicine 2018). Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer 2. Foy et al (Nature 2023). Non-viral precision T cell receptor replacement for personalized cell therapy. 3. Tan et al (Nature Biotechnology 2024). Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy. 4. Hamberger et al (biorxiv 2025). makeTCR: A Modular Platform for Rapid, Flexible, Scalable, Single-Step T Cell Receptor Synthesis. 5. Peng et al (Cell Stem Cell 2025). Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy. Chin Leng Tan, Tamara Boschert, Marie-Therese Neuhoff, Moritz Hamberger, Amelie C. Dietsch, Katherina Lindner, Claudia Maldonado-Torres, Alina Errerd, Isabel Poschke, John M. Lindner, Hai-Kun Liu, Lukas Bunse, Michael Platten, Edward W. Green. 2T2T: 2 week turnaround to personalised TCR therapy: Rapid identification, validation and prioritization of patient-specific, cancer-targeting TCRs [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B006.

Combination therapies involving vascular targeting drugs have shown promise in overcoming resistance to immunotherapy. However, the prerequisite for vascular modulation to evoke an effective antitumor T-cell response remains elusive. Tracing the transcriptional response of liver metastasis-associated peritumoral and tumor endothelial cells (TEC) to T-cell intervention, we discovered an immunomodulatory TEC subpopulation that highly expressed lipoprotein lipase (LPL). LPL+ TECs facilitated intratumoral homing of activated antitumor CD8+ T cells driving liver metastatic regression. Mechanistically, LPL enhanced MHC-I-dependent cross-presentation of tumor antigens on TECs for T-cell trafficking. Consequently, LPL+ TECs were recognized and targeted by T cells, further aiding antitumor response. Corresponding analyses of human liver metastasis samples identified a significant correlation between the presence of intratumoral LPL+ blood vessels and the accumulation of T cells. Altogether, the study identifies a decisive role of TECs in orchestrating an effective T-cell response by overcoming tumor's intrinsic insufficient antigen presentation. SIGNIFICANCE:The study identifies LPL+ TECs as orchestrators of activated CD8+ T-cell homing into immunologically cold tumors with low baseline MHC-I expression. Enhancing tumor antigen exposure by MHC-I cross-presentation in TECs presents a promising approach to compensate the intrinsic inability of tumor cells and boost antitumor immunotherapy.

Abstract Background and aims Intravenous thrombolysis (IVT) is a highly time-sensitive and effective acute ischemic stroke (AIS) treatment. To minimize door-to-needle-times (DNT), we implemented an optimized stroke pathway based on the Helsinki Stroke model, including EMS pre-notification, AI-assisted real-time CT analysis, and bolus administration before CT angiography. This study aimed to characterize patient-related aspects associated with different DNT intervals. Ultrafast thrombolysis was defined as DNT ≤20 min. Methods We retrospectively analyzed IVT-treated AIS patients treated 2021-2024 excluding those undergoing additional thrombectomy. Patients were stratified by DNT; groups were compared regarding demographics, admission characteristics, and in-hospital outcomes. Results Among 669 patients, DNT was ≤20 min in 30.8%, 21-30 min in 44.9%, 31-60 min in 14.8%, and >60 min in 9.6%. In the ultrafast group, mean DNT was 15.7 min (SD 3.49). Baseline NIHSS differed significantly across groups, with patients in the ultrafast group presenting with slightly higher NIHSS scores (medians [IQR]: 5 [3-8], 5 [2-8], 5 [2-7], 4 [1-7]; p=0.026). Discharge mRS (1-5) varied across groups, with the fastest-treated group showing the most favorable functional status (medians [IQR]: 3 [0-4], 2 [1-4], 3 [1-4), 3 [1-4.75]; p=0.030). Early neurological improvement, measured by median NIHSS change, declined stepwise with longer DNT (median delta NIHSS [IQR]: 3 [1-5], 2 [1-4.75], 1 [0-3], 1 [0-4]; p<0.001). Conclusions Patients receiving ultrafast thrombolysis under 20 minutes presented with slightly more severe strokes but achieved greater early neurological improvement. These results highlight the clinical benefit of systematic process optimization in acute stroke care. Conflict of interest All authors: nothing to disclose. Figure 1 - belongs to Conclusions

Background & Aims Recurrent glioblastoma (GB) still carries a dismal prognosis with few established treatment options. In the multicenter CAR2BRAIN phase I first-in-human clinical trial, we investigated repetitive local adoptive transfer of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2 alone and in combination with the anti-PD-1 checkpoint inhibitor ezabenlimab in patients with recurrent HER2-positive GB. Methodology After establishing the dose of 1×108 irradiated CAR-NK cells as safe for intracerebral injection in the dose-escalation cohort in 9 patients, 6 patients were treated with repetitive doses of CAR-NK cells in the expansion cohort. In the subsequent CAR2BRAIN-Check cohort, 12 patients received a combination therapy with the anti-PD-1 checkpoint inhibitor ezabenlimab. CAR-NK cells were injected into the margins of the surgical cavity during relapse surgery, and repeatedly via an implanted reservoir into the resection cavity. Where feasible, we adhered to a biopsy-treat-resect-treat strategy, initiating study treatment before planned tumor resection. An in-depth analysis of tissue, cerebrospinal fluid (CSF) and blood samples before and after immunotherapy was performed to assess treatment-induced modulation of the tumor immune microenvironment. Results Repetitive intracranial injection of CAR-NK cells was feasible and safe and none of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Combination immunotherapy induced a local immune response with elevated pro-inflammatory cytokines and cell counts measured in CSF sampled from the resection cavity. We observed an increase of CD4+ and CD8+ T cells, and a decrease of regulatory CD4+FoxP3+ T cells. Median progression-free survival of the patients treated in the dose-escalation cohort was 7 weeks, compared to 10.5 and 14.5 weeks, respectively, for the patients of the expansion cohort and the CAR2BRAIN-Check chort. Median overall survival of the patients in the dose escalation cohort was 31 weeks and 44.5 weeks for both the expansion and CAR2BRAIN-Check cohort. Conclusion Immunotherapy with repetitive intracranial injection of HER2-targeted CAR-NK cells is feasible and safe both as monotherapy and in combination with the systemic checkpoint inhibitor ezabenlimab, and favorably modulates the intratumoral immune microenvironment. Given the highly promising results obtained so far, further trials are warranted to confirm the potential clinical benefit of this strategy.

Immune checkpoint molecules are essential regulators of immune homeostasis, maintaining the balance between activation and tolerance. In cancer, tumours exploit checkpoint pathways to suppress antitumour immunity and promote progression. The advent of immune checkpoint inhibitors, particularly those that target the clinically validated PDL1-PD1 and CTLA4 axes, has transformed cancer therapy, and the LAG3 axis has recently entered clinical practice, yet most patients experience limited or transient benefit, often because the checkpoint molecules become dysregulated. Here, we examine how multilayered regulatory mechanisms operating at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational levels collectively shape checkpoint abundance and function in tumour and immune cells. We further connect these regulatory processes to immune evasion and therapeutic resistance and highlight how this knowledge informs biomarker development and mechanism-guided strategies to improve immunotherapy outcomes.

Background:Despite recent advances, survival in patients with glioblastoma remains poor. Outside clinical trials, lomustine is commonly considered standard of care in recurrent disease. However, comparative data between lomustine and other chemotherapy regimens are limited. Methods:We performed a retrospective multicenter cohort study including patients from seven certified neuro-oncology centers in Germany to compare lomustine monotherapy with combination therapy using lomustine and procarbazine in first recurrence of glioblastoma. Propensity score matching was applied to obtain comparable groups based on sex, age, extent of resection at primary diagnosis, Karnofsky performance status at the start of recurrence therapy, and MGMT promoter methylation status. Post-recurrence survival (PRS) and progression-free survival (PFS) were analyzed using Kaplan-Meier estimation and multivariable Cox regression analysis. Results:Seventy-seven patients were matched in each treatment group. PRS was comparable, with a median of 11.6 months for lomustine monotherapy and 10.0 months for lomustine plus procarbazine (log-rank test, P = .120). Multivariable Cox regression showed no significant difference (HR 1.33, 95% CI, 0.93-1.90, P = .123). PFS was shorter in patients receiving combination therapy compared to monotherapy (3.7 vs. 5.1 months, log-rank test, P = .042). Multivariable Cox regression did not reveal significant differences (HR 1.31, 95% CI, 0.90-1.90, P = .166). Conclusions:Our data indicates that potential additive toxicity by intensified combination chemotherapy should be avoided due to lack of efficacy compared to lomustine monotherapy.

Abstract Amyloid beta (Aβ) plaque deposition in the central nervous system (CNS) is a hallmark of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), triggering robust innate immune responses. However, the role of the adaptive immune system remains less well understood. Here we show the immune microenvironment dynamics in APP23 transgenic (APP23-tg) mice modelling CNS amyloid pathology, using single-cell transcriptomics. We observed a marked increase in T-cell populations during late disease stages, particularly CD8⁺ T-cells that clustered around Aβ plaques, suggesting a targeted immune response. Among these, we identified an Aβ plaque-associated subset of CD8⁺ T cells expressing interferon-stimulated genes (ISGs), which promoted Type-I interferon signaling. This subset also produced CXCL10, facilitating the recruitment of non-ISG T cells through the CXCL10-CXCR3 axis. Importantly, similar Type-I interferon responses were detected near plaques in human CNS amyloid pathology. Together, these findings highlight a shift from microglia-driven to T-cell-mediated neuroinflammation as amyloid pathology progresses, with implications for time-resolved therapy development.

Central nervous system (CNS) involvement in adult acute myeloid leukemia (AML) is uncommon and more frequently observed at relapse than at initial presentation. Typically, CNS relapse coincides with systemic disease, evidenced by detectable blasts in the bone marrow (BM) and/or peripheral blood. We describe a rare case of an 82-year-old patient with a history of AML, diagnosed three and a half years earlier, who developed an isolated CNS relapse while receiving palliative chemotherapy-without concurrent BM involvement or molecular evidence of systemic progression. Cerebrospinal fluid (CSF) analysis revealed blast cells harboring an FLT3 internal tandem duplication (FLT3-ITD). Targeted therapy with an FLT3 tyrosine kinase inhibitor (TKI) achieved complete remission, with clearance of FLT3-ITD from the CSF.

ABSTRACT:Immunodeficiency-associated primary central nervous system lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted a retrospective multicenter study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL cases, diagnosed at 23 participating sites in 7 countries. Preexisting immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%) and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab and methotrexate-based chemotherapy was associated with the highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable, with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment; hazard ratio [HR], 1.05 (95% confidence interval [CI], 1.02-1.07); P< .001), Karnofsky performance status (KPS) <70 (HR, 3.10; 95% CI, 1.67-5.87; P< .001), and EBV positivity (HR, 3.26; 95% CI, 1.47-7.33; P = .004) as prognostic factors for overall survival. A prognostic score was developed based on the sum of these adverse variables (age >60 years, KPS <70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to 1, 2, and 3 unfavorable markers (P< .0001). It allowed improved prognostic stratification of ID-PCNSL as compared with the Memorial Sloan Kettering Cancer Center and International Extranodal Lymphoma Study Group models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiological features of ID-PCNSL and introduces a prognostic system with potential to guide future management.

BACKGROUND:Replication-repair-deficiency is associated with increased risk of developing malignant gliomas. The aim of this study was to investigate primary mismatch repair deficient gliomas (PMMRDGs), a group of IDH-wildtype and H3-wildtype gliomas that is enriched among patients with CMMRD and Lynch syndrome. METHODS:We investigated how PMMRDGs differ from other gliomas with respect to DNA methylation profile, genomic alterations, histopathology, and clinical outcomes. RESULTS:PMMRDGs occur in pediatric, adolescents and the elderly, falling in two related methylation clusters and are characterized by a high frequency of replication repair deficiency. Histology showed multinucleated giant cells, and immunohistochemistry demonstrated loss of MMR protein expression. Survival analysis revealed long-term survival in patients with high mutational burden (>50 mut/Mb) and an intact chromosome 9p region, which was validated in an independent reference cohort. CONCLUSIONS:Overall, our findings indicate that PMMRDGs represent a distinct type of IDH-wildtype gliomas with potential for long-term survival likely driven by immune activation.

Abstract Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTBhigh) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 (p = 0.009; p = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT.

Both the nervous system and cancer-intrinsic neural features can govern cancer initiation, growth, progression, metastasis, and treatment resistance, while cancer can likewise influence the nervous system, promoting neural reprogramming and neuropsychiatric symptoms that worsen patient outcomes. The field of cancer neuroscience seeks to unravel this complex neuro-cancer crosstalk and holds the promise to develop neuroscience-instructed cancer therapies that improve disease control and quality of life. Here, we summarize the key discoveries of neuro-cancer crosstalk to date, including neuron-to-cancer synapses and paracrine and neuro-immuno-oncological interactions, and then explore emerging topics such as downstream effects on cancer cell pathophysiology, circadian influences, brain-body-cancer communication, and neural regulation of the metastatic cascade and the tumor microenvironment. Finally, we distill overarching principles, highlight relevant ongoing research, and outline conclusions to guide the development of cancer neuroscience, proposing hypotheses for future experimental validation.