Abstract B131: Live-attenuated LCMV-based vector for active immunotherapy of HPV16+ cancer

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 head and neck cancer. It encodes a non-oncogenic version of the human papilloma virus 16 (HPV16) oncoproteins E7 and E6 (TheraT®-E7E6). 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 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 TC-1 tumors, a syngeneic mouse 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. Furthermore, the efficacy of TheraT®-E7E6 can be potentiated in combination therapies, e.g., with PD-1 checkpoint inhibitors. 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. Citation Format: Sarah Schmidt, Ahmed ElGazzar, Weldy V. Bonilla, Mindaugas Pauzuolis, Andrea Reiter, Theresa Kleissner, Daniel Oeler, Felix Stemeseder, Ursula Berka, Bettina Kiefmann, Sophie Schulha, Igor Matushansky, Doron Merkler, Daniel Pinschewer, Klaus Orlinger. Live-attenuated LCMV-based vector for active immunotherapy of HPV16+ cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B131.