The concept of tumor vaccination is based on the induction of robust immune responses against tumor-associated antigens (TAA) selectively expressed within the tumor. Whereas in the case of foreign antigens an immune response can be induced quite easily, induction of appropriate immunity against self-antigens needs potent antigen presentation to break immune tolerance.
Tumor vaccines may be further improved by utilizing the properties of oncolytic viruses (OVs), that selectively replicate within and destroy tumor tissue and may further enhance the vaccination effects by supplying danger signals in situ and stimulating the immune system. Immunogenic OVs additionally delivering a specific TAA by in situ antigen presentation can break immmune tolerance, induce a specifically redirected immune response, and thereby may increase therapeutic efficacy.
Attenuated measles virus (MV) derived from a vaccine strain is currently tested as oncolytic virotherapeutic in clinical trials. Recombinant MVs additionally reveal excellent vaccine characteristics per se, inducing potent and long lasting immune responses against endogenous and foreign antigens, if the latter are additionally expressed by the recombinant virus. Therefore, we develop and aim to validate novel prototypic replicating MV for simultaneous oncolysis and in situ tumor vaccination. For that purpose, a well characterized tumor-confined TAA of the claudin family is used as vaccination target antigen (GNTP01). Different antigen formats or epitopes of GNTP01 were cloned into the MV genome and recombinant viruses were generated, which express those epitopes in different amounts as expected due to positional effects of the additional transcription units either behind the P (post P) or the H (post H) gene cassettes of Moraten vaccine strain-derived MVvac2 genome, presented on in situ produced particles or not. Based on these data, selected viruses expressing different antigen formats have been chosen for further characterization. The selected viruses were amplified, and unimpaired growth and genetic stability of the inserted TAA were demonstrated. To test their immunogenic properties, MV-susceptible IFNAR-/--CD46Ge mice have been immunized with the different viruses, and humoral as well as cellular immune responses are currently analyzed.
In parallel, an immune competent, syngeneic tumor model has been established by employment of transgenic C57/BL6-derived tumor cell lines expressing the target antigen as well as MV-receptors. For three different transgenic tumor cell lines antigen expression and tumorigenicity in MV-susceptible animals has been confirmed. Such tumor-bearing animals will be used for analysis of induced immune responses, anti-tumoral activity, and therapeutic efficacy after immunization with selected viruses that have been shown to induce significant humoral or cellular immune responses.
Once the proof-of-concept has been established this innovative oncolytic virus-based approach holds the potential for a novel therapeutic technology platform that synergistically combines the direct tumor-lytic properties of recombinant MVs with the therapeutic induction of potent immune responses depending on the patient´s TAA expression profile.
Citation Format: Stefan Hutzler, Stephanie Erbar, Robert A. Jabulowsky, Tim Beissert, Jan Hanauer, Oezlem Tuereci, Rita Mitnacht-Kraus, Sebastian Kreiter, Mustafa Diken, Cedrik M. Britten, Ugur Sahin, Michael D. Muehlebach. Oncolytic measles virus for tumor vaccination. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B040.
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