Identification of Genetically Modified Maraba Virus as an Oncolytic Rhabdovirus

Abstract

To expand our current array of safe and potent oncolytic viruses, we screened a variety of wild-type (WT) rhabdoviruses against a panel of tumor cell lines. Our screen identified a number of viruses with varying degrees of killing activity. Maraba virus was the most potent of these strains. We built a recombinant system for the Maraba virus platform, engineered a series of attenuating mutations to expand its therapeutic index, and tested their potency in vitro and in vivo. A double mutant (MG1) strain containing both G protein (Q242R) and M protein (L123W) mutations attenuated Maraba virus in normal diploid cell lines, yet appeared to be hypervirulent in cancer cells. This selective attenuation was mediated through interferon (IFN)-dependent and -independent mechanisms. Finally, the Maraba MG1 strain had a 100-fold greater maximum tolerable dose (MTD) than WT Maraba in vivo and resulted in durable cures when systemically administered in syngeneic and xenograft models. In summary, we report a potent new oncolytic rhabdovirus platform with unique tumor-selective attenuating mutations.

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials

“…This is consistent with the premise that the attenuated Maraba MG1 virus is extremely sensitive to type I IFN and selectively replicates in tumor cells that have defective type I responses but not in normal cells. 25 Non-human primates are considered to be ideal models for the assessment of potential neurotoxicity resulting from live viral vaccines 41 thus instilling confidence in the preclinical safety profile established here.…”

“…So, the impact of functional oncolysis on the safety and immunogenicity has not been extended beyond previously published murine data. 14,20,23–25 Toxicity has been associated with acute, massive cytokine release in some immunotherapeutics, such as CAR T-cells. 49 Cytokines were not monitored in this study as their importance in a tumor-free animal is questionable.…”

“…The therapeutic activity of oncolytic Maraba MG1 results from multimodal mechanisms: i) systemic administration delivers MG1 to the tumor bed resulting in selective direct oncolysis; 14,20,23–27 ii) infection of tumors by MG1 reprograms the tumor microenvironment (TME) rendering it susceptible to the recruitment and activation of innate and adaptive mediators of antitumor immunity 14,28–30 and iii) circulating MG1 accesses secondary lymphoid organs and rapidly engages the central memory compartment thereby boosting Ad-primed adaptive antitumor immunity. 31 Maraba MG1 has a well-established safety profile within rodents and demonstrates broad oncolytic activity against multiple human and murine cancer cell lines, 14,20,23–25,32,33 primary tumor biopsies, 14,23,28 as well as xenograft and syngeneic tumor models in mice. 23–25,28,29 When administered as an oncolytic vaccine, MG1 exerts remarkable efficacy with complete regressions achieved in aggressive immunocompetent models of melanoma and HPV-positive cancer.…”

“…31 Maraba MG1 has a well-established safety profile within rodents and demonstrates broad oncolytic activity against multiple human and murine cancer cell lines, 14,20,23–25,32,33 primary tumor biopsies, 14,23,28 as well as xenograft and syngeneic tumor models in mice. 23–25,28,29 When administered as an oncolytic vaccine, MG1 exerts remarkable efficacy with complete regressions achieved in aggressive immunocompetent models of melanoma and HPV-positive cancer. 14,20 The present work enabled appraisal of the safety and immunogenicity of oncolytic vaccination in an outbred population of cynomolgus macaques ( Macaca fascicularis ), with increased biologic relevance to humans, enabling the translation of this treatment into a first-in-man clinical trial.…”

Stratégies génétiques, immunologiques et pharmacologiques au service d’une nouvelle génération de virus anticancéreux

“…SYNTHÈSE REVUES MG-1, par substitution de deux acides aminés en position 242 de la protéine G et en position 123 de la protéine M. La dose maximale tolé-rable de MG-1 est plus de 100 fois supérieure à celle de la souche sauvage chez la souris. Son administration par voie intraveineuse a permis de guérir différents modèles murins de cancer [12]. De plus, MG-1 présente une activité antitumorale supérieure à la version oncolytique de VSV de première génération, VSVΔM51 [9,12].…”