The mRNA-Based Therapeutic Vaccine NTX250 Induces Potent Antitumor Immunity in HPV-Driven Cancers.

Human papillomavirus (HPV) plays a pivotal role in various malignancies, including cervical, anogenital, head, and neck cancers. Despite the availability of highly effective prophylactic vaccines, many individuals remain susceptible to HPV-driven cancers due to barriers such as limited vaccine access, lack of awareness, or personal preferences. Current treatments primarily target lesions without eradicating persistent HPV infections, leading to an increased risk of subsequent HPV-associated cancers. This scenario underscores an urgent need for innovative treatment modalities aimed at eliminating persistent HPV infections. Here, we developed NTX250, an mRNA-based therapeutic platform engineered to deliver HPV type 16 (HPV16) E6 and E7 antigens, in conjunction with the immunomodulators IL-12 and LIGHT. A lipid and ionizable peptoid nanoparticle system facilitated precise intralesional delivery of NTX250. Localized NTX250 administration in HPV16-transformed tumor-bearing models led to complete tumor regression and established durable, antigen-specific immune memory. Replacing the HPV antigens with a construct comprising colorectal cancer cell specific neoepitopes enabled stimulated antitumor immunity and suppressed tumor growth, supporting the generalizability of the approach. Overall, NTX250 represents a promising non-surgical immunotherapy platform that is capable of eliciting robust and targeted anti-tumor immune responses across diverse malignancies. This adaptable mRNA nanoparticle approach enables the co-delivery of tumor-specific antigens and immunomodulators, with the potential to target tumor-associated antigens beyond HPV.