BiTE-armed oncolytic measles viruses for cancer immunovirotherapy

Abstract

Attenuated measles virus (MV) vaccine strains preferentially infect, replicate in and thus destruct cancerous cells. In recent years, it has become evident that therapeutic success of oncolytic virotherapy largely depends on the modulation of the immune system. MV-mediated oncolysis induces an immunogenic cell death (ICD), which provides the basis to enhance or reinitiate a sustained antitumor immune response. In clinical testing, salvage therapy with oncolytic MV has led to complete tumor resolutions, demonstrating its therapeutic potential. However, extensive therapeutic efficacy is limited to a minority of patients. Thus, efforts are put into preclinical research to generate more potent MV vectors. Many strategies in cancer immunotherapy aim to augment T cell responses against tumor cells. Bispecific T cell engagers (BiTEs) simultaneously engage T cells and tumor cells. BiTEmediated T cell engagement activates the engaged T cell and specifically directs its cytotoxic potential towards the crosslinked tumor cell. BiTE therapy has achieved compelling clinical success in the treatment of B cell malignancies. However, BiTEs have failed to demonstrate efficacy against solid tumors so far. Moreover, short terminal half-life of BiTEs requires continuous intravenous infusion and systemic administration of BiTEs can cause severe or even fatal side effects. We hypothesize that tumor-targeted expression of BiTEs by oncolytic MV enhances therapeutic efficacy, as compared to either monotherapy alone. Furthermore, we hypothesize that tumorrestricted BiTE-expression reduces systemic exposure to BiTEs and thus increases safety of BiTE therapy. To test these hypotheses, MVs encoding BiTEs were generated (MV-BiTE). MV-BiTE vectors were characterized in vitro in terms of replication kinetics, oncolytic activity and BiTE expression. BiTEs produced by MV-BiTE-infected cells were purified to evaluate binding specificity and BiTE-mediated T cell cytotoxicity in vitro. Therapeutic efficacy of MVBiTE in terms of survival was demonstrated using syngeneic and xenogeneic tumor models. For all studies, no signs of MV-BiTE-related toxicities were observed and BiTE plasma levels of MV-BiTE-treated mice remained below detection limit. Conclusively, tumor-targeted expression of BiTEs by oncolytic MV is feasible and prevented systemic exposure to BiTEs. Moreover, MV-BiTE treatment demonstrated therapeutic efficacy in different models of solid tumors in vivo. The MV-BiTE constructs constitute a modular vector platform that can be adapted to target any tumor antigen of choice. Thus, MV-BiTE therapy represents a promising approach for individualized cancer immunovirotherapy.