bims-malgli 2025-10-05 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–10–05
sixteen papers selected by
Oltea Sampetrean, Keio University

YBX1&YBX3 as novel targets to potentiate immune checkpoint blockade response in gliomas.
White matter injury fuels early progression of glioblastoma.
Inhibition of ICAM1 diminishes stemness and enhances antitumor immunity in glioblastoma via β-catenin/PD-L1 signaling.
Differential migration mechanics and immune responses of glioblastoma subtypes.
Post-resection delivery of a TLR7/8 agonist from a biodegradable scaffold achieves immune-mediated glioblastoma clearance and protection against tumor challenge in mice.
Characterization of MAIT cells in glioblastoma reveals a potential immunosuppressive role through a MAIT-neutrophil axis.
BLVRA promotes glioblastoma progression by regulating fatty acid metabolism.
Convection-enhanced delivery of dexamethasone in glioma suppresses myeloid inflammation while avoiding systemic toxicities.
Defining heterogeneity in core regulatory circuitry reveals HOXB3 condensation as a potential target in glioblastoma.
Deciphering glioma susceptibility.
Alkaline loading of extracellular vesicles produced from human neural stem cell-derived neurospheres enables CNS drug delivery.
Uncertainty-aware ensemble of foundation models differentiates glioblastoma from its mimics.
Adoptive macrophages suppress glioblastoma growth by reversing immunosuppressive microenvironment through programmed phenotype repolarization.
Cracking glioblastoma core regulatory codes.
IL-7-mediated expansion of autologous lymphocytes increases CD8 + VLA-4 expression and accumulation in glioblastoma models.
Final Results from a First-in-Human Phase 1 Study of the Dual Isocitrate Dehydrogenase (IDH) 1/2 Inhibitor, LY3410738, in Advanced Solid Tumors Harboring IDH1 or IDH2 Mutations.

Neuro Oncol. 2025 Sep 30. pii: noaf227. [Epub ahead of print]

YBX1&YBX3 as novel targets to potentiate immune checkpoint blockade response in gliomas.

Heba Ali, Ningjia Zhou, Li Chen, Levi van Hijfte, Rima Tulaiha, Vivekanudeep Karri, Yalu Zhou, Karl Habashy, Victor A Arrieta, Kwang-Soo Kim, Joseph Duffy, Ragini Yeeravalli, Deanna M Tiek, Xiao Song, Snehasis Mishra, Craig Horbinski, Catalina Lee-Chang, Atique Ahmed, Lu Wang, Dieter Henrik Heiland, Adam M Sonabend, Crismita Dmello.

   BACKGROUND: Glioblastoma (GBM) exhibits profound resistance to CD8⁺ T cell-mediated killing, yet the tumor-intrinsic mechanisms driving this immune evasion remain poorly defined. Our earlier study revealed Checkpoint Kinase 2 (Chek2) as the driver of CD8+ T cell resistance. This study investigates the immunomodulatory program exerted by the CHK2-YBX1&YBX3 regulatory hub.
METHODS: Protein-protein interactions were investigated through immunoprecipitation (IP) followed by mass spectrometry (MS) and phosphoproteomics. Single gene knockout of CHEK2, Y-box-binding protein 1 (YBX1), and Y-box-binding protein 3 (YBX3) were generated in human and mouse glioma cells. Transcriptomic and epigenetic alterations were characterized by bulk RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq). Single-cell RNA sequencing and spatial transcriptomics analysis were performed to evaluate CHK2-YBX1&YBX3 related phenotype in human GBM tumors. In vivo survival studies were conducted to assess the therapeutic potential of CHK2-YBX1&YBX3 degradation and immune checkpoint blockade (ICB).
RESULTS: CHK2, YBX1, and YBX3 exhibited reciprocal positive regulation and depletion of any of these genes resulted in derepression of pro-inflammatory gene expression. Pharmacological inhibition with the drug targeting YBX1 led to degradation of the CHK2-YBX1&YBX3 hub accompanied by enhanced antigen presentation and antigen-specific CD8⁺ T cell proliferation. Combination therapy targeting CHK2-YBX1&YBX3 hub and ICB significantly improved survival in preclinical glioma models.
CONCLUSIONS: These findings define a novel glioma-intrinsic immunosuppressive program and proposes targeting the CHK2-YBX1&YBX3 hub to potentiate response to ICB in glioma.

Keywords:  Glioma; Immunotherapy; YBX1&YBX3

DOI:  https://doi.org/10.1093/neuonc/noaf227
Cancer Res. 2025 Oct 01.

White matter injury fuels early progression of glioblastoma.

Keon Woo Kim, Hyun Jin Choi, Jeong Ho Lee.

Glioblastoma (GBM) is the most aggressive and devastating primary brain cancer in adults. Most GBMs are diagnosed at an advanced stage with therapy resistance, posing a major obstacle to understanding the tumor microenvironment (TME) at the earliest stages of disease development. A precise characterization of early-stage GBM and its TME could provide critical insights into tumor progression and inform new therapeutic strategies. In a recent issue of Nature, Clements and colleagues demonstrated that white matter (WM) injury, induced by early tumor cells, constitutes a key TME factor driving GBM progression. Using somatic mouse models, patient-derived xenografts (PDXs), and human tissues, they showed that early glioma cells preferentially infiltrate WM tracts, inducing SARM1-mediated Wallerian degeneration (WD) that propagates into distal WM regions. Remarkably, WM injury induced by axonal transection significantly accelerated GBM progression at distal sites, whereas this effect was abolished by Sarm1 knockout, confirming that axonal injury followed by WD drives distal tumor progression. Collectively, these findings reveal a previously unrecognized evolutionary process in GBM development and highlight potential targets for therapeutic intervention.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4362
Nat Commun. 2025 Sep 30. 16(1): 8642

Inhibition of ICAM1 diminishes stemness and enhances antitumor immunity in glioblastoma via β-catenin/PD-L1 signaling.

Meixia Guo, Zheng Yuan, Xiong Jin, Xinyu Li, Yilin Deng, Shuchang Zhou, Rui Niu, Joonbeom Bae, Jong Bae Park, Bingyang Shi, Jinlong Yin.

Glioblastoma (GBM) stem cells (GSCs) are pivotal in tumor initiation, recurrence, and therapeutic resistance, underscoring their critical role in the complex pathology of GBM. Despite their recognized importance, the mechanisms by which GSCs facilitate immune evasion, especially in emerging immunotherapies, remain incompletely understood. Here, we identify intercellular adhesion molecule 1 (ICAM1) as a key regulator of GSC stemness and tumorigenicity, promoting an immunosuppressive microenvironment via β-catenin/PD-L1 signaling. Mechanistically, ICAM1 interacts with ZNRF3, leading to its autoubiquitination and clearance, stabilizing LRP6, and activating β-catenin signaling, which upregulates PD-L1 expression. Combined treatment with anti-ICAM1 and anti-PD-1 antibodies results in the most effective tumor inhibition and significantly extends survival in ICAM1-overexpressing GBM models. CyTOF and flow cytometry analyses reveal that ICAM1 overexpression reduces cytotoxic CD8+ T cell populations via PD-L1/PD-1 interactions, reversible by PD-1 blockade. Our findings highlight the co-targeting of ICAM1 and PD-1 as a promising strategy against immune evasion in GBM.

DOI: https://doi.org/10.1038/s41467-025-63796-2
bioRxiv. 2025 Sep 22. pii: 2022.06.26.497270. [Epub ahead of print]

Differential migration mechanics and immune responses of glioblastoma subtypes.

Ghaidan A Shamsan, Chao J Liu, Brooke C Braman, Ruyi Li, Susan K Rathe, Aaron L Sarver, Nima Ghaderi, Mariah M McMahon, Rebecca L Klank, Barbara R Tschida, S Joey McFarren, Pamela C Rosato, David Masopust, Jann N Sarkaria, H Brent Clark, Steven S Rosenfeld, David A Largaespada, David J Odde.

Glioblastoma remains a deadly cancer driven in part by invasion of tumor cells into the brain. Transcriptomic analyses have identified distinct molecular subtypes, but mechanistic differences that account for clinical differences are not clear. Here, we show that, as predicted by the motor-clutch model of cell migration, mesenchymal glioma cells are more spread, generate larger traction forces, and migrate faster in brain tissue compared to proneural cells. Despite their rapid migration and comparable proliferation rates in vitro, mice with mesenchymal tumors survive longer than those with proneural tumors. This improved survival correlated with an immune response in the mesenchymal tumors, including T cell-mediated. Consistently, inducing mesenchymal tumors in immunodeficient mice resulted in shorter survival supporting a protective immune role in mesenchymal tumors. Thus, mesenchymal tumors have aggressive migration, but are immunologically hot which suppresses net proliferation. These two features counteract each other and may explain the lack of a strong survival difference between subtypes clinically, while also opening up new opportunities for subtype-specific therapies.

DOI: https://doi.org/10.1101/2022.06.26.497270
Nat Commun. 2025 Sep 29. 16(1): 8603

Post-resection delivery of a TLR7/8 agonist from a biodegradable scaffold achieves immune-mediated glioblastoma clearance and protection against tumor challenge in mice.

Elizabeth G Graham-Gurysh, Ryan N Woodring, Sean R Simpson, Sophie E Mendell, Nicole Rose Lukesh, Erik S Pena, Kathryn M Moore, Luis A Ontiveros-Padilla, Aaron T Hendricksen, Alexandra M Lopez, Grace L Williamson, Connor T Murphy, Christopher J Genito, Kaitlyn A Hipp, Garima Singh, William C Zamboni, Shawn D Hingtgen, Peter E Fecci, Eric M Bachelder, Kristy M Ainslie.

Glioblastoma is an aggressive brain cancer with a dismal prognosis despite current therapeutic interventions. Surgical tumor resection, standard-of-care for glioblastoma, not only results in the reduction of tumor burden, but also has profound immunostimulatory effects, offering a unique opportunity to break local immune tolerance and mount an effective anti-tumor immune response. Here, we explore the effect of local controlled release of resiquimod, a TLR7/8 agonist, from a biodegradable polymer scaffold implanted at the time of tumor resection. We find that treatment leads to the clearance of residual post-resection tumor, improved survival, and subsequent protection from tumor challenges in orthotopic mouse models of glioma. In addition, the controlled release of resiquimod from the scaffold boosts the resection-mediated disruption to the tumor microenvironment, leading to an early inflammatory innate immune response both in the brain and cervical lymph node, followed by an influx of lymphocytes. Thus, we show that sustained local TLR7/8 agonism at the time of tumor resection represents a promising approach for the treatment of glioblastoma.

DOI: https://doi.org/10.1038/s41467-025-63692-9
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf173

Characterization of MAIT cells in glioblastoma reveals a potential immunosuppressive role through a MAIT-neutrophil axis.

Seketoulie Keretsu, Taijun Hana, Alexander Lee, Noemi Kedei, Nargis Malik, Hye Kim, Jo Spurgeon, Guzal Khayrullina, Benjamin Ruf, Ayaka Hara, Morgan Coombs, Matthew B Watowich, Ananth Hari, Michael K B Ford, S Cenk Sahinalp, Masashi Watanabe, George Zaki, Mark R Gilbert, Patrick J Cimino, Robert Prins, Masaki Terabe.

   Background: Glioblastoma (GBM) is the most aggressive primary brain cancer in adults and remains incurable. Mucosal-associated invariant T (MAIT) cells are unconventional T cells with a semi-invariant T cell receptor and have been shown to regulate immune responses. However, the role of MAIT cells in glioblastoma (GBM) has not been well characterized.
Methods: We used flow cytometry, bulk RNA-seq and scRNA-seq, and multiplexed tissue imaging to investigate the role of MAIT cells in GBM.
Results: Flow cytometry analysis of peripheral blood samples of GBM patients showed a significant reduction of MAIT cell frequency and the ability to produce Th1 cytokines. In bulk RNA sequencing data analysis of GBM tissues, the MAIT cell gene signature significantly correlated with poor patient survival. A scRNA-seq of CD45+ cells from 20 GBM tissue samples showed 12 (60%) were positive for MAIT cells and the enrichment of RORC-expressing MAIT17. The MAIT cell signature significantly correlated with tumor-associated neutrophil (TAN) activities. Multiple immune suppressive genes known to be used by TANs were upregulated in MAIT-positive tumors. Spatial imaging analysis of GBM tissues showed that all specimens were positive for both MAIT cells and TANs, and localized enrichment of TANs.
Conclusion: These findings revealed an immunosuppressive role of MAIT cells in GBM and highlighted the MAIT-TAN axis as a potential novel therapeutic target to modulate GBM's immunosuppressive tumor microenvironment.

Keywords:  MAIT cell; glioblastoma; myeloid cells; neutrophil

DOI:  https://doi.org/10.1093/noajnl/vdaf173
Sci Rep. 2025 Sep 29. 15(1): 33708

BLVRA promotes glioblastoma progression by regulating fatty acid metabolism.

Lang Li, Jia-Hao Yao, Jing Feng, Qi Zhan, Meng-Si Zhan, Hong-Bo San, Xue-Feng Wang.

  Fatty acid metabolism is critically involved in glioblastoma (GBM) pathogenesis; however, its regulatory mechanisms remain incompletely understood. In this study, we identified biliverdin reductase A (BLVRA) as a novel metabolic driver and prognostic biomarker in GBM by integrating bulk and single-cell RNA sequencing with in vitro functional validation. Using ten machine learning algorithms, we developed a fatty acid metabolism-related gene prognostic index (FAMRGPI), which demonstrated strong prognostic value and highlighted the importance of metabolic reprogramming and immune modulation in GBM. Among FAMRGPI components, BLVRA emerged as an independent prognostic factor, with elevated expression associated with poor clinical outcomes. Single-cell transcriptomic analysis revealed that BLVRA expression correlated with tumor heterogeneity and differentiation potential. Experimental validation confirmed that BLVRA was markedly upregulated in GBM tissues and cell lines. Functional assays showed that BLVRA knockdown suppressed GBM cell proliferation and colony formation, disrupted lipid homeostasis (decreased carnitine and triglyceride levels, increased CPT1A and coenzyme A), and induced oxidative stress and DNA damage. Mechanistically, BLVRA depletion increased ROS accumulation, upregulated γ-H2AX, p53, and cleaved caspase-3 expression, and led to downregulation of key cell cycle regulators including CDK2, CDK4, CDK6, Cyclin D1, and c-MYC, thereby promoting cell cycle arrest and apoptosis. This study is the first to establish BLVRA as a critical regulator of fatty acid metabolism in GBM, revealing its dual role in maintaining metabolic homeostasis and supporting tumor growth. These findings uncover a novel metabolic vulnerability in GBM and suggest that BLVRA may serve as a potential therapeutic target for metabolic intervention.

Keywords:  Apoptosis; BLVRA; Fatty acid metabolism; Glioblastoma; Oxidative stress; Therapeutic target

DOI:  https://doi.org/10.1038/s41598-025-19026-2
bioRxiv. 2025 Sep 26. pii: 2025.09.24.677899. [Epub ahead of print]

Convection-enhanced delivery of dexamethasone in glioma suppresses myeloid inflammation while avoiding systemic toxicities.

Nathaniel W Rolfe, Nicholas B Dadario, Liang Lei, Damian E Teasley, Misha Amini, Peter Chabot, Nkechime Ifediora, Nathan J Winans, Nina Yoh, Anthony Tang, Nadine Khoury, Julia Furnari, Corina Kotidis, Clara H Stucke, Nivia M Urena, Yanping Sun, Pavan Upadhyayula, Michael G Argenziano, Colin P Sperring, Abby Brand, Ashwin Viswanathan, Nelson Humala, Peter A Sims, Brian J Gill, Peter Canoll, Jeffrey N Bruce.

Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration via convection-enhanced delivery (CED) to maximize intratumoral anti-inflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In a syngeneic glioma mouse model, continuous intraparenchymal infusion of dexamethasone was well tolerated and associated with a modest but significant survival benefit versus vehicle. Single-nucleus RNA sequencing (snRNA-seq) and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell (iPSC)-derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves steroid-sparing control of inflammation without the systemic adverse effects associated with standard therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.

DOI: https://doi.org/10.1101/2025.09.24.677899
Nat Cell Biol. 2025 Sep 30.

Defining heterogeneity in core regulatory circuitry reveals HOXB3 condensation as a potential target in glioblastoma.

Chuanxia Zhang, Yijing He, Xiudan Zhan, Jiaming Yu, Shao Xu, Qinkai Zhang, Ru Qiu, Xinyue Wang, Zhuoxing Gao, Meng Huang, Wenyong Long, Qing Liu, Wei Zhao.

Glioblastoma (GBM) exhibits marked heterogeneity, yet therapeutic strategies effectively targeting this variability remain inadequately developed. Here we employed single-cell CUT&Tag analysis to investigate H3K27ac modifications, uncovering pronounced heterogeneity within the core regulatory circuitry (CRC) of GBM. Notably, we observed heterogeneous condensation states of CRC factors, particularly HOXB3, which are shaped by its intrinsically disordered regions and interactions with RUNX1, driving the phenotypic manifestations. Leveraging these findings, we synthesized the peptide P621-R9, which effectively disrupted HOXB3 condensation, altered chromatin structure and reduced transcription at super-enhancer-associated oncogenic sites in GBM cells exhibiting HOXB3 condensation. Treatment with P621-R9 selectively diminished tumourigenic potential in GBM patient-derived xenograft models characterized by HOXB3 condensates, but showed no efficacy in the models lacking these condensates. These results highlight the critical role of CRC condensation in GBM heterogeneity and suggest that peptide-based targeting of distinct GBM subpopulations could represent an avenue for therapeutic exploration.

DOI: https://doi.org/10.1038/s41556-025-01758-y
Nat Cell Biol. 2025 Oct 03.

Deciphering glioma susceptibility.

Andrea Fratton, Boyan Bonev.

DOI: https://doi.org/10.1038/s41556-025-01782-y
Res Sq. 2025 Sep 23. pii: rs.3.rs-7622911. [Epub ahead of print]

Alkaline loading of extracellular vesicles produced from human neural stem cell-derived neurospheres enables CNS drug delivery.

Amar M Singh, Charles M White, Adeline Phillips, Logan P Crowe, Robert Marti, Morgan C Finnerty, Martonio Ponte Viana, William Antoniades, Michael G Bartlett, Viviana Martinez, Raymond Swetenburg, Steven L Stice.

The blood brain barrier and blood tumor barrier (BBB and BTB, respectively) represent significant obstacles for the delivery of drugs to treat diseases of the central nervous system, such as brain cancers and neurodegenerative diseases. Extracellular vesicles (EVs) or exosomes have emerged as a new drug delivery vehicle for CNS diseases as they may penetrate the BBB/BTB and are less immunogenic than liposomal carriers. EVs derived from human neural stem cells (hNSC) provide additional benefits over other EV sources due to their increased homing capability to neural cells and demonstrated efficacy for treating stroke and traumatic brain injury in rodent models. However, the utilization of EVs from hNSC for drug delivery remains largely unexplored, due in part to difficulties in manufacturing capacity compared to traditional cell lines. Here, we report the development of a hNSC suspension neurosphere system for EV production and drug delivery. As proof of concept, doxorubicin was loaded into hNSC-EV, using a novel, high-efficiency alkaline passive loading method, and shown to be effective at inducing cytotoxicity in glioma cells in vitro and exhibiting higher BBB penetrance than doxorubicin-alone in vivo . These studies demonstrate the potential for hNSC-EV loaded doxorubicin as a therapeutic treatment for brain cancers such as glioblastoma, while also establishing hNSC-EVs as a drug-delivery vehicle for CNS diseases.

DOI: https://doi.org/10.21203/rs.3.rs-7622911/v1
Nat Commun. 2025 Sep 29. 16(1): 8341

Uncertainty-aware ensemble of foundation models differentiates glioblastoma from its mimics.

Junhan Zhao, Shih-Yen Lin, Raphaël Attias, Liza Mathews, Christian Engel, Guillaume Larghero, Dmytro Vremenko, Ting-Wan Kao, Tsung-Hua Lee, Yu-Hsuan Wang, Cheng Che Tsai, Eliana Marostica, Ying-Chun Lo, David Meredith, Keith L Ligon, Omar Arnaout, Thomas Roetzer-Pejrimovsky, Shih-Chieh Lin, Natalie Nc Shih, Nipon Chaisuriya, David J Cook, Jung-Hsien Chiang, Chia-Jen Liu, Adelheid Woehrer, Jeffrey A Golden, MacLean P Nasrallah, Kun-Hsing Yu.

Accurate pathological diagnosis is crucial in guiding personalized treatments for patients with central nervous system cancers. Distinguishing glioblastoma and primary central nervous system lymphoma is particularly challenging due to their overlapping pathology features, despite the distinct treatments required. To address this challenge, we establish the Pathology Image Characterization Tool with Uncertainty-aware Rapid Evaluations (PICTURE) system using 2141 pathology slides collected worldwide. PICTURE employs Bayesian inference, deep ensemble, and normalizing flow to account for the uncertainties in its predictions and training set labels. PICTURE accurately diagnoses glioblastoma and primary central nervous system lymphoma with an area under the receiver operating characteristic curve (AUROC) of 0.989, with the results validated in five independent cohorts (AUROC = 0.924-0.996). In addition, PICTURE identifies samples belonging to 67 types of rare central nervous system cancers that are neither gliomas nor lymphomas. Our approaches provide a generalizable framework for differentiating pathological mimics and enable rapid diagnoses for central nervous system cancer patients.

DOI: https://doi.org/10.1038/s41467-025-64249-6
Cell Rep. 2025 Sep 26. pii: S2211-1247(25)01121-0. [Epub ahead of print]44(10): 116350

Adoptive macrophages suppress glioblastoma growth by reversing immunosuppressive microenvironment through programmed phenotype repolarization.

Yang Fan, Hang Yin, Jing Zhao, Bolin Yao, Guangli Cheng, Yaqi Yang, Minghao Yang, Luo Chen, Jian Chen, Ji Zhou, Ren Li, Botao Zhao, Xiao-Yong Zhang, Cong Wang, Xihui Gao, Cong Li.

  Glioblastoma (GBM) is a highly lethal brain tumor resistant to immunotherapy due to poor brain drug delivery and an immunosuppressive microenvironment. This study introduces a macrophage-based adoptive cell therapy that reprograms the tumor immune landscape to suppress GBM growth. We reveal that macrophage homing to GBM is phenotype-dependent, with anti-inflammatory macrophages more efficiently navigating the brain vasculature and targeting tumors. Based on this observation, we developed engineered M2-like macrophages (eM2-Mφs) capable of programmable polarization. These adoptive cells maintain an anti-inflammatory phenotype during early circulation, allowing deep tumor infiltration, and subsequently switch to a proinflammatory state within the tumor to trigger immune activation. Treatment with eM2-Mφs alone, or combined with low-dose irradiation and/or checkpoint inhibitor, remarkably suppressed tumor growth and extended survival in mouse models. This approach offers a promising strategy to overcome GBM's immunosuppressive barriers and enhance immunotherapy efficacy.

Keywords:  CP: Cancer; CP: Immunology; adoptive macrophage; glioblastoma; immunotherapy; phenotype polarization; tumor immune-microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.116350
Nat Cell Biol. 2025 Sep 30.

Cracking glioblastoma core regulatory codes.

Yonglong Dang, Yuk Kit Lor, Gonçalo Castelo-Branco.

DOI: https://doi.org/10.1038/s41556-025-01780-0
bioRxiv. 2025 Apr 14. pii: 2024.04.01.587634. [Epub ahead of print]

IL-7-mediated expansion of autologous lymphocytes increases CD8 + VLA-4 expression and accumulation in glioblastoma models.

Kirit Singh, Kelly M Hotchkiss, Sarah L Cook, Pamy Noldner, Ying Zhou, Eliese M Moelker, Chelsea O Railton, Emily E Blandford, Bhairavy J Puviindran, Shannon E Wallace, Pamela K Norberg, Gary E Archer, Beth H Shaz, Katayoun Ayasoufi, John H Sampson, Mustafa Khasraw, Peter E Fecci.

The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. We observed that non-specific autologous CD8 + ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8 + T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression ( CD9) . We also observed that IL-7 increases S1PR1 transcription in human CD8 + T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors, and that pre-treatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pre-treatment can be combined with T cell-activating therapies.
Brief Summary: T cell immunotherapies are limited by few T cells in glioma. Adoptively transferred lymphocytes expanded with IL-7 exhibit increased VLA-4 expression and accumulate in tumors.

DOI: https://doi.org/10.1101/2024.04.01.587634
Clin Cancer Res. 2025 Sep 30.

Final Results from a First-in-Human Phase 1 Study of the Dual Isocitrate Dehydrogenase (IDH) 1/2 Inhibitor, LY3410738, in Advanced Solid Tumors Harboring IDH1 or IDH2 Mutations.

James J Harding, Do-Youn Oh, Teresa Macarulla Mercade, Lipika Goyal, Andreas Varkaris, Lola Jade Palmieri, Masafumi Ikeda, Shunsuke Kondo, Li-Yuan Bai, Makoto Ueno, Li-Tzong Chen, Kyriakos P Papadopoulos, Rachna T Shroff, Sani H Kizilbash, Antoine Hollebecque, Jorge Adeva, Rasha Cosman, Tomoya Yokota, Joon Oh Park, Anita Turk, Chih-Yi Liao, Taroh Satoh, Mitesh J Borad, Anthony El-Khoueiry, Nilofer Azad, Kurt A Jaeckle, Herbert H Loong, Wei-Peng Yong, Mark H Bender, Sunoj Chacko Varughese, Deepa Sachdeva, David B Radtke, Ivelina Gueorguieva, Anna M Szpurka, Hsiao-Rong Chen, Hui Liu, Xiaojian Xu, Jordi Rodon.

BACKGROUND: Isocitrate dehydrogenase (IDH) 1/2-isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated (mIDH1/mIDH2) neoplasms. However, primary and secondary resistance limits their therapeutic potential. LY3410738, an oral, brain penetrant, dual mIDH1/mIDH2 isoform-selective inhibitor was designed to overcome resistance.
METHODS: This global, multicenter, open-label, phase 1 study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose-escalation) for advanced solid tumors in combination with cisplatin-gemcitabine for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose-expansion) (NCT04521686). Primary objectives were the maximum tolerated dose (MTD), recommended phase 2 dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and circulating tumor DNA (ctDNA) were assessed.
RESULTS: Overall, 119 patients received LY3410738 alone (N=94) or in combination with cisplatin-gemcitabine (N=19) or durvalumab (N=6). No dose-limiting toxicities (DLTs) were observed; the MTD was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1%, and disease control rates of 56.9% and 63.0%, were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one DLT in the durvalumab cohort. LY3410738 plus cisplatin-gemcitabine demonstrated a response rate of 42.1%, median DOR of 8.1 months, median PFS of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma.
CONCLUSIONS: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus cisplatin-gemcitabine exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0174