Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA360272 | ENA |
REPOSITORIES: ENA
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Project description:HPV-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced stage disease. Despite improved outcomes with PD-1 targeted therapies, treatment resistance and modest response rates highlight a significant unmet need to develop novel therapies for these patients. PDS0101 (designated HPV vaccine) is a liposomal nanoparticle HPV16-specific therapeutic vaccine that has been shown to generate strong HPV-specific responses in pre-clinical and clinical studies. Here we assess the efficacy of this HPV vaccine in combination with the tumor-targeting immunocytokine NHS-IL12 (PDS01ADC), plus either aPD-1 or the class I histone deacetylase (HDAC) inhibitor Entinostat. Mice bearing HPV16+, aPD-1 refractory TC-1 and mEER tumors were treated with HPV vaccine, NHS-IL12, and either aPD-1 or Entinostat to determine anti-tumor efficacy and survival benefits. A comprehensive analysis of the tumor microenvironment was performed using flow cytometry, multiplex immunofluorescence, chemokine and cytokine assessment, and scRNAseq with TCR enrichment. Combination of HPV vaccine and NHS-IL12 with either Entinostat or aPD-1 yields significant anti-tumor activity and prolonged survival in aPD-1 refractory models of HPV16+ cancer, with superior activity employing Entinostat versus aPD-1 combination. Entinostat triple therapy increased overall and HPV16-specific tumor CD8+ T cell infiltration with heightened cytotoxicity. TCR sequencing revealed a CD8+ T cell clone unique to vaccine-treated cohorts, which displayed an enriched cytotoxic transcriptional profile with triple therapy. These effects were parallelled by strong differentiation of tumor-associated macrophages (TAMs) towards proinflammatory, anti-tumor M1-like cell states. Single-cell transcriptomic analysis indicated all three agents were required for highest modulation of both CD8+ T cells and TAMs conducive to tumor control. A biomarker signature reflecting the pre-clinical findings was found to be associated with improved survival in patients with HPV-associated malignancies. Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies.
2025-05-07 | GSE295238 | GEO
Project description:Nanostring gene expression profiling of 24 BALB/c mice bearing EMT-6 tumors under avelumab and NHS-muIL12 mono and combination therapies.
2017-12-20 | GSE93192 | GEO
Project description:Clinical benefit remains elusive for most patients with poorly inflamed carcinomas treated with immune checkpoint blockade. Alternative therapies able to convert the tumor microenvironment (TME) into a functionally inflamed immune hub may increase clinical benefit. Using comprehensive TME single-cell transcriptome, proteome, and immune cell analysis, we demonstrated that entinostat, a class I HDAC inhibitor, facilitates tumor deposition of the necrosis-targeted immunocytokine NHS-IL12 to promote potent anti-tumor efficacy against established MC38 and CT26 colon carcinoma models, with complete eradication of poorly immunogenic EMT6 breast tumors. Combination therapy reprogrammed the tumor innate and adaptive immunome to an inflamed landscape, where the concerted action of highly functional CD8+ T cells and activated neutrophils drove a dramatic macrophage M1-like polarization leading to complete tumor eradication. A biomarker signature of the mechanism involved in these studies is associated with patients’ overall survival in multiple tumor types. Collectively, these findings provide a rationale for combining NHS-IL12 with entinostat in the clinical setting.
2021-06-14 | GSE171273 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive stroma rich in tumor-associated macrophages (TAMs) that limit the therapeutic efficacy. We introduce a TAM-targeted nanotherapy platform that selectively delivers either a CSF1R inhibitor or the STING agonist cGAMP to immunosuppressive TAMs. While CSF1R inhibitor–loaded nanoparticles efficiently depleted TAMs and produced moderate antitumor effects, TAM-targeted cGAMP nanoparticles reprogrammed TAMs into immune-stimulating effectors. This reprogramming normalized aberrant vasculature, alleviated desmoplasia, and enhanced infiltration and activation of cytotoxic immune cells. In combination with gemcitabine, PD-1 checkpoint blockade, or CAR-NK cell therapy, TAM-targeted STING activation provided an in situ immunostimulatory signal that markedly improved antitumor efficacy in preclinical PDAC models. Ex vivo efficacy in human PDAC tissues and a favorable safety profile show the translational potential of this TAM-targeted nanotherapy to overcome the immune desert of PDAC.
2025-12-01 | GSE310136 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive stroma rich in tumor-associated macrophages (TAMs) that limit the therapeutic efficacy. We introduce a TAM-targeted nanotherapy platform that selectively delivers either a CSF1R inhibitor or the STING agonist cGAMP to immunosuppressive TAMs. While CSF1R inhibitor–loaded nanoparticles efficiently depleted TAMs and produced moderate antitumor effects, TAM-targeted cGAMP nanoparticles reprogrammed TAMs into immune-stimulating effectors. This reprogramming normalized aberrant vasculature, alleviated desmoplasia, and enhanced infiltration and activation of cytotoxic immune cells. In combination with gemcitabine, PD-1 checkpoint blockade, or CAR-NK cell therapy, TAM-targeted STING activation provided an in situ immunostimulatory signal that markedly improved antitumor efficacy in preclinical PDAC models. Ex vivo efficacy in human PDAC tissues and a favorable safety profile show the translational potential of this TAM-targeted nanotherapy to overcome the immune desert of PDAC.
2025-12-18 | GSE313718 | GEO
Project description:E7386 enhances lenvatinib’s antitumor activity in preclinical models and human hepatocellular carcinoma.
| PRJNA1273097 | ENA
Project description:Glioblastoma (GBM) is the most frequent and aggressive primary brain cancer. Our studies have shown that the Src inhibitor, TAT-Cx43266-283, exerts antitumor effects in different preclinical models of GBM, including fresh specimens from GBM patients, and enhances survival in glioma-bearing mice. Because addressing TAT-Cx43266-283 mechanism of action is essential to translate these results to a clinical setting, in this study we carried out an unbiased proteomic approach in human glioblastoma stem cells (GSCs). Data-independent acquisition mass spectrometry proteomics allowed the identification and quantification of 6,561 proteins, of which 190 were modified by TAT-Cx43266-283. Our results are consistent with the inhibition of Src as the mechanism of action of TAT-Cx43266-283 and unveils additional crucial proteins. Altogether, this study expands the knowledge about the mechanism of action of TAT-Cx43266-283, providing a rationale for therapy combination and supporting its use in GBM clinical trials.
2024-06-22 | PXD045883 | Pride
Project description:Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti–PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti–PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the molecular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.
2024-01-14 | GSE252960 | GEO
Project description:Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl-transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti-PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the mole-cular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.
2023-11-04 | GSE246837 | GEO
Project description:Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti–PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti–PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the molecular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.
2024-01-06 | GSE252537 | GEO