Current prophylactic human papillomavirus (HPV) vaccines prevent infection but have limited therapeutic benefit in established HPV-driven malignancies. To address this unmet need, we developed VTX-067, a modular self-assembling therapeutic cancer vaccine consisting of a recombinant Mycobacterium tuberculosis heat shock protein 70-avidin fusion (MAV) noncovalently bound to biotinylated HPV E6/E7 MHC class I- and II-restricted peptide concatemers. MAV is produced in CHO cells with minimal endotoxin. Assembled VTX-067 is designed to elicit both CD4⁺ and CD8⁺ T-cell responses against HPV-associated tumors. In multiple tumor models expressing HPV E6/E7, intradermal vaccination with VTX-067 induced potent and dose-dependent HPV E6/E7-specific CD8⁺ and CD4⁺ T-cell responses without evidence of local reactogenicity. Therapeutic vaccination significantly delayed subcutaneous tumor progression, extended survival, and provided durable protection against tumor rechallenge. VTX-067 treatment increased intratumoral CD8⁺ T-cell infiltration, elevated the CD8:Treg ratio, and upregulated a Th1/cytotoxic transcriptional program including Ifnγ, Tbx21, Stat1, and Gzmb. Depletion of CD8⁺ T cells eliminated vaccine efficacy, while adoptive transfer of VTX-067-primed CD8⁺ T cells conferred tumor protection in recipient mice. In a cervicovaginal orthotopic model, both intradermal and intramucosal administration generated systemic E6/E7-specific effector responses and sustained control of mucosal tumors. Notably, combining a suboptimal VTX-067 dose with the immunomodulatory agent lenalidomide further enhanced tumor control and survival, demonstrating a potential dose-sparing strategy. These findings establish VTX-067 as a safe, highly immunogenic therapeutic vaccine with CD8⁺ T-cell-dependent antitumor activity, and support its clinical development alone or in combination with immune-modulating agents for HPV-associated cancers.
Y. Gemechu, Sonia Mukherjee, J. Gelfand et al.· Molecular Cancer Therapeutic...· 0 citations
Despite their promise, lipid nanoparticle gene delivery systems have repeatedly failed clinical trials and struggle to achieve efficient, localized transfection in target tissues. The majority of endocytosed nanoparticles are degraded before nucleic acid release, and an inability to track particle distribution in vivo prevents validation of successful delivery. Alternatively, nanobubbles (NBs) are lipid-shelled, gas-core preclinical ultrasound contrast agents and stimuli-responsive drug delivery vehicles. Under varying acoustic pressures, NBs expand, contract, and burst, releasing cargo in an externally controlled, site-specific manner while scattering unique echoes for simultaneous ultrasound visualization. Here, we introduce a cationic nanobubble (CNB) formulation with a +42.3 mV zeta potential, 265 nm diameter, and 2.43×10 11 NBs/mL concentration. CNBs produce stable ultrasound contrast, electrostatically load plasmid DNA onto their surface, and internalize into >99% of human prostate cancer cells within 15 minutes in vitro . CNBs remain brightly echogenic intracellularly and induce sonication-dependent expression of green fluorescent protein (GFP). In vivo , CNBs generate contrast in mouse livers for 50 minutes after intravenous administration. Therapeutic ultrasound stimulation over the liver causes a sharp reduction in ultrasound contrast, visualizing localized cavitation in the target organ and inducing a 2.5-fold increase in anti-GFP mean fluorescence intensity relative to the untransfected control. Importantly, no GFP expression is observed without ultrasound stimulation, supporting a mechanism for selective and site-specific gene delivery. This study presents a highly stable CNB capable of efficient DNA loading and ultrasound-dependent gene expression. These results provide a foundation for the future development of CNB platforms to advance image-guided, ultrasound-triggered gene therapy.
Laura E. Chen, Pinunta Nittayacharn, Aayushi Laliwala et al.· bioRxiv· 0 citations
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