mRNA‐HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV‐mediated cancers via subcutaneous immunization

Abstract

The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA‐HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell‐mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor‐implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV‐treated mice. Furthermore, tumor expansion was significantly reduced upon TC‐1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV‐related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

Immunogenicity and effectiveness of an mRNA therapeutic vaccine for HPV-related malignancies

“…Different from the ionizable lipid SM-102 in mHTV-02, DLin-MC3-DMA or other similar self-developed ionizable lipids were used in gDE7 (36) and HPV mRNA-LNP (37) targeting HPV16 E7. Although SM-102 delivery system was also chosen in the mHTV vaccine reported by Lee et al (38), the lipid composition was SM-102/6,69-trehalose dioleate/ DOPE/butyl lithocholate/DMG-PEG2000 (molar ratio of 25:25:10: 38.5:1.5). The different properties in LNP-mediated RNA delivery may contribute to distinct features of these vaccines, such as mRNA transfection efficiency, biodistribution, and administration route.…”

Recent progress in mRNA cancer vaccines

“… 1 For example, a recent study showed that a messenger RNA-HPV therapeutic vaccine (mHTV) exhibited strong immunogenicity and anti-tumor effects in mice and non-human primates, positioning mHTV as a promising therapeutic and prophylactic vaccine for HPV. 98 …”

Preclinical Immunogenicity and Efficacy Studies for Therapeutic Vaccines for Human Papillomavirus-Type-16-Associated Cancer

“…HPV-16 oncoprotein-expressing vaccines based on DNA [ 12 ], mRNA [ 13 ], viral vectors [ 14 , 15 ], proteins [ 16 ], or other platforms [ 17 ] have shown efficacy in mouse models. Treatment with checkpoint inhibitors such as antibodies to PD-1 or therapeutic vaccines also achieved tumor regression or partial responses in humans with respiratory papillomatosis due to chronic airway infection by HPV-6 or -11 [ 18 ], moderate to advanced cervical intraepithelial neoplasia, and HPV + head and neck cancers [ 19 , 20 ].…”