Targeting TGFβ and Over-Expressing GM-CSF in the Tumor with Oncolytic Adenovirus Inhibits Tumor Growth/Metastases and Augments Immune Checkpoint Inhibitor Response in a Triple Negative Breast Cancer Mouse Model

Deleted Journal, Год журнала: 2025, Номер 33(1), С. 200936 - 200936

Опубликована: Янв. 18, 2025

Despite therapeutic advancements, metastatic triple-negative breast cancer (TNBC) remains mostly incurable and is a frequent cause of cancer-related deaths. We tested the hypothesis that inhibiting suppressive signals sustained by transforming growth factor (TGF)-β concurrently stimulating recruitment inflammatory cells with granulocyte-macrophage colony-stimulating (GM-CSF) oncolytic viruses would result in improved anti-tumor responses. Thus, we developed new adenovirus rAd.sT.GM (AMUN-003) expresses both sTGFβRIIFc (a TGF-β decoy), GM-CSF it mouse TNBC (4T1) subcutaneous model. was safe to use more effective controlling tumor progression lung metastasis following intratumoral injections when compared control adenoviruses without modifications. In same model, combinations immune checkpoint inhibitor (ICI) therapy resulted better inhibition metastasis. Furthermore, examined key response prognosis biomarkers sera, lungs, spleens, tumors evaluate treatment efficacy. found several Th1 cytokines such as interleukin (IL)-2, IL-4, interferon-γ, were stimulated combination either systemically or both, well Granzyme B perforin. These results support advancement clinical testing ICIs for patients.

Язык: Английский

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Engineering an oncolytic adenoviral platform for precise delivery of antisense peptide nucleic acid to modulate PD-L1 overexpression in cancer cells

International Journal of Pharmaceutics, Год журнала: 2024, Номер 668, С. 124941 - 124941

Опубликована: Ноя. 10, 2024

Cancer immunotherapy is focused on stimulating the immune system against cancer cells by exploiting checkpoint mechanisms. PD-1/PD-L1 one of most known checkpoints due to widespread upregulation Programmed Death Ligand 1 (PD-L1) transmembrane protein in tissues. Accordingly, taking advantage ability oncolytic adenoviruses (OAd) specifically infect and kill tumor over healthy ones, here, we developed a targeted delivery platform based OAd selectively deliver an antisense peptide nucleic acid (PNA) targeting PD-L1 mRNA. The PNA was modified with six-lysine tail improve water solubility binding affinity polyanionic surface carrier. Dynamic light scattering measurements confirmed effective cargo OAd. Flow cytometry analysis evaluated impact expression A549 SK-OV3 cell lines post-incubation OAd/PNA system. Statistically significant downregulation observed treated OAd-delivered PNA, surpassing effect free PNA. Confocal microscopy showed cytoplasmic localization supporting proposed mechanism for downregulation. This holds potential enhancing effectiveness immunotherapy.

Язык: Английский

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Leveraging oncovirus-derived antigen against the viral malignancies in adoptive cell therapies

Biomarker Research, Год журнала: 2024, Номер 12(1)

Опубликована: Июль 29, 2024

Adoptive cell therapies (ACTs) have revolutionized cancer immunotherapy, prompting exploration into their application against oncoviruses. Oncoviruses such as human papillomavirus (HPV), hepatitis B virus (HBV), C (HCV), and Epstein-Barr (EBV) contribute significantly (12-25%) to malignancies through direct or indirect oncogenic mechanisms. These viruses persistently latently infect cells, disrupt cellular homeostasis pathways, challenging current antiviral treatment paradigms. Moreover, viral infections pose additional risks in the setting of long-term therapy lead morbidity mortality. Virally encoded oncoproteins, which are tumor-restricted, immunologically foreign, even uniformly expressed, represent promising targets for patient-tailored ACTs. This review elucidates rationale leveraging antigen-specific ACTs combating viral-associated malignancies. On this basis, ongoing preclinical studies consolidate our understanding harnessing malignancies, underscoring potential eradicate implicated progression. Furthermore, we scrutinize landscape clinical trials focusing on virus-specific discuss implications therapeutic advancement.

Язык: Английский

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Beginning at the ends: telomere and telomere-based cancer therapeutics

Molecular Genetics and Genomics, Год журнала: 2024, Номер 300(1)

Опубликована: Дек. 6, 2024

Язык: Английский

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