Live-Attenuated Lcmv-Based Vector For Active Immunotherapy Of Hpv16+Cancer.

e14303 Background: Active immunization against cancer requires the induction of exquisitely potent tumor-specific CD8+ T cell (CTL) responses, which can be repeatedly boosted and reactivated. Hookipa Pharma engineered a replication-attenuated viral vector platform (TheraT) based on the arenavirus lymphocytic choriomeningitis virus (LCMV), which meets these aforementioned criteria. Here, we present a preclinical data package of Hookipa´s lead immunotherapy product HB-201, targeting HPV16-driven cancer. Methods: TheraT-E7E6 encodes a highly immunogenic, non-oncogenic version of the human papilloma virus 16 (HPV16) oncoproteins E7 and E6. Results: Attenuation and safety of TheraT-E7E6 were demonstrated by i) rapid viral clearance after systemic administration of the vector and ii) reduced neurovirulence in mice.TheraT-E7E6 can be administered intravenously as systemic therapy or intratumorally as local therapy with an abscopal-like effect. Treatment was shown to induce substantial CD8+ T cell expansion and high frequencies of E7- and E6-specific CTL responses with a balanced effector / central memory profile. These responses were boosted and reactivated upon TheraT-E7E6 re-administration. TheraT-E7E6 eradicated palpable tumors in a syngeneic mouse TC-1 tumor model of HPV-driven cancer. Even in mice with large tumors (~300mm3) TheraT-E7E6 afforded significant tumor control and improved survival, with high frequencies of E7-specific CTLs persisting for several weeks. Animals which cleared the tumor after TheraT therapy were long term protected from tumor re-challenge. Furthermore, TheraT is efficacious in checkpoint inhibitory refractory models and can also synergize in combination with checkpoint inhibitors (CPIs). Conclusions: In conclusion, replication-attenuated TheraT-E7E6 is safe, highly immunogenic and shows excellent therapeutic efficacy as mono- or combination therapy in a preclinical model of HPV-induced cancer. Clinical trials for the treatment of HPV16+ cancers will be initiated in 2019.