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Published on: February 16, 2015
Multimodal glioma immunotherapy combining TLR9-targeted STAT3 antisense oligodeoxynucleotides with PD1 immune
Chia-Yang Hung1, Elaine Y Kang1, Karol Jacek2
1Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
Background:
Therapeutic 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.
Methods:
Here, 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.
Results:
CpG-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.
Conclusions:
Our 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.
Insights
A novel STAT3 antisense oligonucleotide (CpG-STAT3dsASO) targets glioma cells and myeloid cells, enhancing immunotherapy. Combination therapy with anti-PD1 promotes T-cell responses and regression of glioblastoma.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Oligonucleotide Therapeutics
Background:
- Glioblastoma (GBM) exhibits therapeutic resistance due to heterogeneity, immune privilege, and a tolerogenic microenvironment.
- Signal transducer and activator of transcription 3 (STAT3) is crucial for glioma cell survival and immune evasion, contributing to GBM resistance.
Purpose of the Study:
- To develop and evaluate a novel cell-selective, double-stranded STAT3 antisense oligonucleotide (CpG-STAT3dsASO) for targeting glioma cells and glioma-associated myeloid cells (GAMs).
- To assess the safety and efficacy of CpG-STAT3dsASO in orthotopic GBM models.
Main Methods:
- Development of a cell-selective, double-stranded STAT3 antisense oligonucleotide (CpG-STAT3dsASO).
- Assessment of oligonucleotide safety and efficacy in immunocompetent and immunodeficient mice with orthotopic GBM.
- Evaluation of CpG-STAT3dsASO monotherapy and combination therapy with PD1 inhibition.
Main Results:
- CpG-STAT3dsASO was well-tolerated, reduced GBM progression, and did not induce neurotoxicity in immunocompetent mice.
- CpG-STAT3dsASO activated intratumoral GAMs, increased CD4+ Th1 cells, and decreased TREGs.
- Combination therapy (CpG-STAT3dsASO/anti-PD1) induced significant glioma regression and long-term survival by enhancing CD8+ T-cell activity and intratumoral immune cell interactions.
Conclusions:
- CpG-STAT3dsASO disrupts GAM-mediated immune evasion in GBM.
- This approach restores sensitivity to PD1-blockade, facilitating T-cell-mediated antitumor responses.
- CpG-STAT3dsASO represents a promising strategy for enhancing GBM immunotherapy.
