Background Human papillomavirus (HPV) is a contagious cause of anogenital and oropharyngeal cancers developing from persistently infected and subsequently transformed basal keratinocytes of mucosal epithelium. More than 90% of cervical cancers and pre-cancerous cervical intraepithelial neoplasia (CIN) are linked to infections with high-risk HPV, with more than 50% of cancers linked to HPV16.1,2 At least 25% of women with high-grade CIN lesions progress to in situ or invasive cancer, if untreated.3 Current treatments for high-grade CIN can remove abnormal tissue but do not address underlying HPV infection, and 15% of women treated develop residual or recurrent high-grade CIN or cervical cancer.4 Long-term efficacy may require induction of tumor-specific T cell responses combined with alleviated local immune suppression and increased tumor immune cell infiltration. Multimodal mRNA-based immunotherapies that deliver both antigens and immunomodulators in a single drug product represent a promising new approach for treatment of CIN and cervical cancer that can address current disease as well as the underlying cause (HPV infection). Here we report on pre-clinical efficacy of NTX-0250, a nanoparticle-formulated, multi-component mRNA drug that co-delivers a novel HPV16 antigen design with two potent immunomodulators.
Methods To test efficacy, we utilized the well-established, clinically relevant, C3.43 tumor model (5). C3.43 is a progressive subclone of C3, HPV16-transformed B6 mouse embryo cell line that expresses HPV16 E6 and E7 antigens under the natural promoter.5 Therapeutic efficacy of NTX-0250 was assessed in mice with large (>120mm3) C3.43 tumors. HPV16-specific T cells were assessed by flow cytometry on peripheral blood mononuclear cells (PBMCs). Mechanistic studies were performed by post-treatment tumor microenvironment characterization. To assess translational potency of NTX-0250, induction of HPV-specific T cell responses in cynomolgus monkeys was measured by flow cytometry and IFNg ELISpot on PBMCs
Results In tumor challenged mice, administration of NTX-0250 induces complete regression of large tumors resulting in long-term, tumor-free survival of 100% of treated animals (figure 1A). Complete responses are accompanied by strong tumor immune infiltration of CD8+, CD4+ APCs and NK cells and upregulation of IFNγ in the tumor microenvironment (figure 1B). In cynomolgus monkeys, administration of NTX-0250 induces strong HPV16-specific responses (figure 2).
Conclusions Here we report for the first time robust pre-clinical efficacy of a multimodal, mRNA-based therapeutic combining antigen- and immunomodulator-encoding mRNAs in a novel nanoparticle formulation. NTX-0250 treatment resulted in complete regression of large established murine tumors and robust induction of HPV-specific T cell responses in non-human primates.
da Silva RL, da Silva Batista Z, Bastos GR, et al. Role of HPV 16 variants among cervical carcinoma samples from Northeastern Brazil. BMC Women’s Health 2020;20:162.
Tao L, Han L, Li X, et al. Prevalence and risk factors for cervical neoplasia: a cervical cancer screening program in Beijing. BMC Public Health 2014;14:1185.
Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Mariëlle Kocken 1, Theo J M Helmerhorst, Johannes Berkhof, Jacqueline A Louwers, Mariëlle A E Nobbenhuis, Aagje G Bais, Cornelis J A Hogewoning, Afra Zaal, René H M Verheijen, Peter J F Snijders, Chris J L M Meijer. Lancet Oncol 2011;12(5):441–50
Feltkamp MC, Smits HL, Vierboom MP, et al. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur J Immunol 1993;23:2242–9.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.