Ntx-0250, a multimodal mrna-based immunotherapy, eradicates large established tumors in a stringent mouse model of hpv16driven cancer
Regular and Young Investigator Award Abstracts(2022)
Abstract
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.
References
https://www.who.int/health-topics/cervical-cancer#tab=tab_1 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.
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Key words
immunotherapy,cancer,mrna-based
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