Oncolytic Newcastle disease virus for cancer therapy: old challenges and new directions

Abstract

Newcastle disease virus (NDV) is an avian paramyxovirus, which has been demonstrated to possess significant oncolytic activity against mammalian cancers. This review summarizes the research leading to the elucidation of the mechanisms of NDV-mediated oncolysis, as well as the development of novel oncolytic agents through the use of genetic engineering. Clinical trials utilizing NDV strains and NDV-based autologous tumor cell vaccines will expand our knowledge of these novel anticancer strategies and will ultimately result in the successful use of the virus in the clinical setting.

Figure 1. Mechanisms of NDV-mediated anti-tumor effects

Cytolytic activity of NDV in cancer cells proceeds through direct and indirect mechanisms. The direct mechanisms include formation of multinucleated syncytia, activation of the extrinsic apoptotic pathway, activation of the intrinsic apoptotic pathway, activation of ER stress pathway, and involvement of MAPK pathways. The indirect mechanisms include secretion of proinflammatory cytokines and chemokines, which recruit mediators of both innate and adaptive immune responses such as NK cells, lymphocytes, and macrophages. Anti-tumor immune responses are further facilitated by the enhanced adhesion of leukocytes through binding to the viral glycoproteins expressed on the surface of infected cells, by upregulation of MHC and cell adhesion molecules, which serve to activate tumor-specific lymphocytes, and by activation of macrophages. MHC: major histocompatibility complex, LFA-3: lymphocyte function-associated antigen-3, ICAM-1: intercellular adhesion molecule-1, IFNβ: interferon β, RANTES: regulated upon activation, normal T cell expressed and secreted, IP-10: interferon gamma-induced protein-10, ADA: adenosine deaminase, iNOS: inducible nitric oxide synthase, TNFα: tumor necrosis factor α, TRAIL: TNF-related apoptosis-inducing ligand.

Figure 2. Strategies employed to enhance anti-tumor activity of NDV via genetic engineering

Several approaches have been demonstrated to improve anti-tumor activity of NDV. Those include enhancement of intrinsic cytolytic properties of NDV via 1) increased fusogenicity; 2) inhibition of innate immune responses; and 3) expression of proapoptotic proteins; as well as enhancement of immune-mediated anti-tumor effects via 1) expression of tumor-associated antigens (TAA), leading to activation and expansion of tumor-specific lymphocytes; 2) expression of tumor-directed antibodies with activation of antibody-dependent cell-mediated cytotoxicity (ADCC); and 3) expression of immunostimulatory cytokines, leading to activation and recruitment of lymphocytes and dendritic cells (DC).