Avian Paramyxovirus 4 Antitumor Activity Leads to Complete Remissions and Long-term Protective Memory in Preclinical Melanoma and Colon Carcinoma Models

Abstract

Avulaviruses represent a diverse subfamily of nonsegmented negative-strand RNA viruses infecting avian species worldwide. To date, 22 different serotypes have been identified in a variety of avian hosts, including wild and domestic birds. APMV-1 (Avian Paramyxovirus 1), also known as Newcastle disease virus (NDV), is the only avulavirus that has been extensively characterized because of its relevance for the poultry industry and, more recently, its inherent oncolytic activity and potential as a cancer therapeutic. An array of both naturally occurring and recombinant APMV-1 strains has been tested in different preclinical models and clinical trials, highlighting NDV as a promising viral agent for human cancer therapy. To date, the oncolytic potential of other closely related avulaviruses remains unknown. Here, we have examined the in vivo antitumor capability of prototype strains of APMV serotypes -2, -3, -4, -6, -7, -8, and -9 in syngeneic murine colon carcinoma and melanoma tumor models. Our studies have identified APMV-4 Duck/Hong Kong/D3/1975 virus as a novel oncolytic agent with greater therapeutic potential than one of the NDV clinical candidate strains, La Sota. Intratumoral administration of the naturally occurring APMV-4 virus significantly extends survival, promotes complete remission, and confers protection against rechallenge in both murine colon carcinoma and melanoma tumor models. Furthermore, we have designed a plasmid rescue strategy that allows us to develop recombinant APMV-4–based viruses. The infectious clone rAPMV-4 preserves the extraordinary antitumor capacity of its natural counterpart, paving the way to a promising next generation of viral therapeutics. Significance: Discovery of the oncolytic properties of APMV-4 Duck/Hong Kong/D3/1975: a novel cancer therapeutic with natural capacity to exert complete remission and long-term antitumor protection in syngeneic mouse cancer models.