Abstract 4058: TheraT - a highly versatile arenavirus based vector platform for intravenous and intratumoral cancer immunotherapy

Abstract

The unprecedented success of checkpoint blockade therapies clearly demonstrates the power of the immune system to fight cancer. Yet, only a minority of cancer patients respond with long-term control of the tumor or even cure, necessitating the development of other treatment modalities. Hookipa Pharma developed a novel attenuated, replication-competent viral vector platform (TheraT) that induces powerful cytotoxic T lymphocyte responses against foreign and self-antigens. In a preclinical model for human papilloma virus 16 (HPV16) associated cancer (TC-1), we evaluated immunogenicity and efficacy upon systemic and intratumoral application of TheraT vectors based on the arenaviruses lymphocytic choriomeningitis virus (LCMV) and pichinde virus (PICV). Both HB-201 (LCMV) and HB-202 (PICV) product candidates encode a non-oncogenic but highly antigenic E6/E7 fusion protein from HPV16. Independent of the route of administration, single administration of HB-201 or HB-202 induced potent peripheral E7-specific CD8+ T cell responses and led to efficient tumor growth control. Survival of TheraT treated animals was significantly longer compared to buffer treated animals. Similarly, single systemic as well as intratumoral application of HB-201 or HB-202 induced major infiltration of CD8+ T cells into the tumor microenvironment. Combination of intravenous HB-201 and anti-PD1 was well tolerated but did not further enhance efficacy in this model, implicating the presence of other immune evasion factors. In conclusion, replication-attenuated TheraT is safe, highly immunogenic and shows excellent therapeutic efficacy after single intravenous and intratumoral application. These data underline the potential and versatility of this novel vector platform. Mechanistic studies in various mouse tumor models are underway. Phase 1/2 clinical trial initiation of HB-201 monotherapy is planned for end of 2019 and preparations for an IND filing for a combination trial of HB-201 and HB-202 in H1 2020 have been initiated. Citation Format: Josipa Raguz, Sarah Schmidt, Theresa Kleisner, Manuel Zerbs, Goran Bekic, Sonja Feher, Daniel Oeler, Felix Stemeseder, Ursula Berka, Bettina Kiefmann, Sophie Schulha, Igor Matushansky, Henning Lauterbach, Klaus Orlinger. TheraT - a highly versatile arenavirus based vector platform for intravenous and intratumoral cancer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4058.

Immunotherapy in HPV-Related Oropharyngeal Cancers

“…Finally, another exciting ongoing study is a randomized phase I/II trial of TheraT® vectors expressing HPV 16 specific antigens in combination with neoadjuvant chemotherapy followed by transoral robotic surgery (TORS) or concurrent chemoradiotherapy for locoregional HPV-positive OPSCC. TheraT® is based on live-attenuated lymphocytic choriomeningitis virus (artLCMV) and works by delivering tumor-associated antigen-specific immunization with the release of IL-33 [ 30 •]. IL-33 is an important driver of CD8+ cytotoxic effector T-cell function.…”

Clinical, morphologic and molecular heterogeneity of HPV-associated oropharyngeal cancer

“…Since HPV E6 and E7 are constitutively expressed in HPV + OPSCC, they are attractive targets for therapeutic vaccines [ 57 ]. These therapeutic vaccines have yielded promising results in several Phase I and II clinical trials in locally advanced or recurrent and metastatic HPV + HNSCC, especially in conjunction with PD-L1/PD-1 therapy [ 58 – 60 ]. Further validation from prospective Phase III trials is needed for implementation into clinical routine.…”