Development and applications of oncolytic Maraba virus vaccines

Abstract

Oncolytic activity of the MG1 strain of the Maraba vesiculovirus has proven efficacy in numerous preclinical cancer models, and relied not only on a direct cytotoxicity but also on the induction of both innate and adaptive antitumor immunity. To further expand tumor-specific T-cell effector and long-lasting memory compartments, we introduced the MG1 virus in a prime-boost cancer vaccine strategy. To this aim, a replication-incompetent adenoviral [Ad] vector together with the oncolytic MG1 have each been armed with a transgene expressing a same tumor antigen. Immune priming with the Ad vaccine subsequently boosted with the MG1 vaccine mounted tumor-specific responses of remarkable magnitude, which significantly prolonged survival in various murine cancer models. Based on these promising results, we validated the safety profile of the Ad:MG1 oncolytic vaccination strategy in nonhuman primates and initiated clinical investigations in cancer patients. Two clinical trials are currently under way (NCT02285816; NCT02879760). The present review will recapitulate the discoveries that led to the development of MG1 oncolytic vaccines from bench to bedside.

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

“…Though not effective as a priming vector, Maraba viruses encoding tumor antigens have been shown to efficiently boost CTL-mediated anti-tumor immunity by infection of splenic follicular B cells [29,65]. Thus, Maraba virus is currently applied in heterologous prime-boost settings with replication-deficient adenoviral vectors [64]. Previous work by Mühlebach and colleagues [31] and the present data support the notion that measles vaccines can be used for priming in oncolytic vaccination regimens.…”

“…The present study suggests that measles vaccines can also be designed to promote CTL responses against specific tumor antigens by encoding the antigens or their immunodominant epitopes in the viral vector. Other oncolytic virus platforms, such as VSV and Maraba virus, have been used for this purpose [24][25][26][27][28]30,64]. Though not effective as a priming vector, Maraba viruses encoding tumor antigens have been shown to efficiently boost CTL-mediated anti-tumor immunity by infection of splenic follicular B cells [29,65].…”

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice

“…adoptive T cell therapies, cancer vaccines). [53][54][55][56][57][58][59] Notwithstanding the aforementioned limitations, our results delineate a strategy for tumor treatment that involves a therapy consisting in the administration of three drug classes: (i) ICD inducers exemplified by MTX and OXA, (ii) CRMs exemplified by HC and Spd and substitutable for fasting (if the nutritional status of the patient allows it) and (iii) ICIs targeting the PD-1/PD-L1 interaction. As shown here, such a triple combination has the potential to cure the majority of mice bearing established fibrosarcomas.…”

Effective Treatment of Glioblastoma Multiforme With Oncolytic Virotherapy: A Case-Series

“…While mixtures of OV strains may convey additive clinical effects, systematic assessment in controlled clinical trials with multiple OVs remains challenging. To date, combinations of OVs in clinical trials have been limited to one oncolytic Maraba vesiculovirus component combined with an adenoviral vaccine vector (32). Preclinically, a few studies have addressed potential synergy of OV combinations, such as adenovirus and vaccinia (33), mumps and measles virus (34), and Newcastle disease virus (NDV) with reovirus and parvovirus (35).…”