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• W4308406961 abstract "<h3>Background</h3> 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. <h3>Methods</h3> 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 <h3>Results</h3> 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). <h3>Conclusions</h3> 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. <h3>References</h3> https://www.who.int/health-topics/cervical-cancer#tab=tab_1 da Silva RL, da Silva Batista Z, Bastos GR, <i>et al</i>. Role of HPV 16 variants among cervical carcinoma samples from Northeastern Brazil. <i>BMC Women’s Health</i> 2020;<b>20</b>:162. Tao L, Han L, Li X, <i>et al</i>. Prevalence and risk factors for cervical neoplasia: a cervical cancer screening program in Beijing. <i>BMC Public Health</i> 2014;<b>14</b>: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. <i>Lancet Oncol</i> 2011;<b>12</b>(5):441–50 Feltkamp MC, Smits HL, Vierboom MP, <i>et al.</i> Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. <i>Eur J Immunol</i> 1993;<b>23</b>:2242–9." @default.
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• W4308406961 date "2022-11-01" @default.
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• W4308406961 title "1084 NTX-0250, a multimodal mRNA-based immunotherapy, eradicates large established tumors in a stringent mouse model of HPV16-driven cancer" @default.
• W4308406961 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1084" @default.
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