Evidence map›Paper›PMID 40214214›Full record

ArticleNeuro-oncology2025

Multimodal glioma immunotherapy combining TLR9-targeted STAT3 antisense oligodeoxynucleotides with PD1 immune checkpoint blockade.

Chia-Yang Hung, Elaine Y Kang, Karol Jacek, Chunsong Yu, Xiaowei Zhang, Yicheng Zhu, Maryam Aftabizadeh, Robyn A Wong, Benham Badie, Piotr Świderski and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuro-oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Chia-Yang HungDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Elaine Y KangDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Karol JacekLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
Chunsong YuDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Xiaowei ZhangDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Yicheng ZhuDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Maryam AftabizadehDepartment of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Robyn A WongDepartment of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Benham BadieDivision of Neurosurgery, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Piotr ŚwiderskiDNA/RNA Synthesis Core Facility, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Bożena KamińskaLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
Darya AlizadehDepartment of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Amy B HeimbergerDepartment of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.ORCID 0000-0002-9970-8695
Christine E BrownDepartment of Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Marcin KortylewskiDepartment of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.ORCID 0000-0002-6003-1816

Funding

Transgenic Mouse FacilityP30CA033572 · NCI · CITY OF HOPE/BECKMAN RESEARCH INSTITUTE · PI John Charles Williams · 1985 to 2026
$86.3M
The impact of interstitial fluid flow on CAR T cell trafficking, distribution, and efficacyR01NS115971 · NINDS · VIRGINIA POLYTECHNIC INST AND ST UNIV · PI BROWN, CHRISTINE, MUNSON, JENNIFER M · 2021 to 2025
$3.3M
Clinical evaluation of IL13Ra2-targeted CAR T cell therapy in combination with nivolumab in patients with recurrent malignant gliomaR01CA236500 · NCI · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · PI BADIE, BEHNAM, BROWN, CHRISTINE · 2019 to 2024
$3.3M
Cell-Selective CpG-STAT3 Inhibitors for Radioimmunotherapy of Malignant GliomaR01CA215183 · NCI · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · PI KORTYLEWSKI, MARCIN · 2018 to 2022
$2.3M
NCI NIH HHS P30 CA033572NCI NIH HHS R01 CA215183NCI NIH HHS R01CA215183NCI NIH HHS R01 CA236500NCI NIH HHS R01CA236500NCI NIH HHS R01NS115971NIH HHS P30CA033572NINDS NIH HHS R01 NS115971
6 · The paper itself

Abstract

backgroundTherapeutic resistance in glioblastoma (GBM) is multifactorial and results from genetic heterogeneity, the immunoprivileged localization, and the potently tolerogenic microenvironment. Signal transducer and activator of transcription 3 (STAT3) plays a key role in both glioma cell survival and immune evasion, reinforcing GBM resistance.

methodsHere, we describe a new cell-selective and double-stranded STAT3 antisense oligonucleotide (CpG-STAT3dsASO) for targeting human/mouse glioma cells and GAMs but not T cells. The oligonucleotide safety and efficacy against orthotopic GBM was assessed in immunocompetent or immunodeficient mice.

resultsCpG-STAT3dsASO injected intracranially/intratumorally was well-tolerated and reduced progression of human U251 GBM xenotransplants and mouse GL261 or neural cell-derived QPP8 gliomas. Unlike the single-stranded oligonucleotide, local CpG-STAT3dsASO administration did not trigger type-I IFN-dependent neurotoxicities in immunocompetent mice within the therapeutic dose range. CpG-STAT3dsASO activated intratumoral GAMs, such as dendritic cells, macrophages and microglia, thereby expanding CD4+ Th1 cells while reducing TREG numbers. CpG-STAT3dsASO monotherapy did not have curative effects as it led to recruitment of only limited numbers of mostly exhausted effector CD8+ T cells. However, when combined with systemic PD1 inhibition, CpG-STAT3dsASO/anti-PD1 treatments caused regression of GL261 as well as immunotherapy-resistant QPP8 gliomas and resulted in long-term survival of the majority of mice. The combination treatment boosted CD8+ effector T-cell activity, while promoting their intratumoral interaction with activated CD4+ Th1 cells and activated macrophages as indicated by spatial transcriptomics.

conclusionsOur results suggest rationale for GBM immunotherapy using CpG-STAT3dsASO to disrupt GAMs-dependent immune evasion, thereby restoring sensitivity to PD1 blockade and facilitating T-cell-mediated antitumor immune responses.

Indexed as

Brain NeoplasmsGliomaImmune Checkpoint InhibitorsImmunotherapyOligodeoxyribonucleotidesOligonucleotides, AntisenseProgrammed Cell Death 1 ReceptorSTAT3 Transcription FactorToll-Like Receptor 9AnimalsCombined Modality TherapyHumansMiceMice, Inbred C57BLTumor Cells, CulturedTumor MicroenvironmentImmune Checkpoint InhibitorsOligodeoxyribonucleotidesOligonucleotides, AntisensePDCD1 protein, humanProgrammed Cell Death 1 ReceptorSTAT3 protein, humanSTAT3 Transcription FactorTLR9 protein, humanToll-Like Receptor 9antisense oligonucleotideglioblastomaPD1STAT3TLR9

Identifiers

PMID40214214
PMCPMC12526143

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.