Enhancement of the Proapoptotic Properties of Newcastle Disease Virus Promotes Tumor Remission in Syngeneic Murine Cancer Models

Abstract

Newcastle disease virus (NDV) is considered a promising agent for cancer therapy due to its oncolytic properties. These include preferential replication in transformed cells, induction of innate and adaptive immune responses within tumors and cytopathic effects in infected tumor cells due to the activation of apoptosis. In order to enhance the latter and thus possibly enhance the overall oncolytic activity of NDV, we generated a recombinant NDV encoding the human TNF receptor Fas (rNDV-B1/Fas). rNDV-B1/Fas replicates to similar titers as its wild type (rNDV-B1) counterpart, however overexpression of Fas in infected cells leads to higher levels of cytotoxicity correlated with faster and increased apoptosis responses in which both the intrinsic and extrinsic pathways are activated earlier. Furthermore, in vivo studies in syngeneic murine melanoma model show an enhancement of the oncolytic properties of rNDV-B1/Fas, with major improvements in survival and tumor remission. Altogether, our data suggest that up-regulation of the pro-apoptotic function of NDV is a viable approach to enhance its anti-tumor properties, and adds to the currently known, rationally-based strategies to design optimized therapeutic viral vectors for the treatment of cancer.

The therapeutic effect of death: Newcastle disease virus and its antitumor potential

“…Fas receptor, one of the most important tumor necrosis factor receptors involved on extrinsic pathway signaling, has not being described as an active cellular component involved in the apoptosis program displayed by NDV infected cells, neither did its physiological ligand, Fas-L (Ravindra et al, 2009a; Balogh et al, 2014). Our research group has investigated the implications of adding Fas receptor as a pro-apototic new player into the already known NDV-induced apoptosis scenario (Cuadrado-Castano et al, 2015). A newly generated lentogenic rNDV-B1/Fas virus expressing Fas receptor has demonstrated an enhanced oncolytic capacity in different in vitro and in vivo models correlated with up-regulation of Fas signaling during rNDV-B1/Fas infection.…”

“…Confocal microscopy images of HeLa cells infected with the recombinant rNDV-B1/Fas virus (Cuadrado-Castano et al, 2015). Left: composite Z-stack of six optical slices showing Hela-infected cells undergoing apoptosis; highlighted are different stages of the apoptosis response observed among the cell population identified accordingly to the morphological changes observed during the progression of apoptosis cell death: pre-apoptosis stage (lack of morphological changes); active apoptosis (A) showing cellular shrinkage and DNA fragmentation.…”

Newcastle disease virus mediates pancreatic tumor rejection via NK cell activation and prevents cancer relapse by prompting adaptive immunity

“…Indeed, contrasting the former thought of the immune system as an impediment for virotherapy, the combination of both direct oncolysis and the induction of an adaptive antitumor immune response might lead to an even more efficient attack of tumors . Because early preclinical studies were often implemented in immunocompromised animals in order to use human cancer cells, NDV‐stimulated immune cell response against the tumor was not assessable . Subcutaneous inoculation of tumor cells also distorts observed NDV‐mediated effects against the tumor due to an unnatural tumor microenvironment .…”

“…[16][17][18] Because early preclinical studies were often implemented in immunocompromised animals in order to use human cancer cells, NDV-stimulated immune cell response against the tumor was not assessable. 19,20 Subcutaneous inoculation of tumor cells also distorts observed NDV-mediated effects against the tumor due to an unnatural tumor microenvironment. 20,21 In this study, we took advantage of a syngeneic orthotopic murine model of pancreatic cancer to characterize the immune response upon infection with a field isolate of NDV, strain R75/98, regarding tumor progression and a possible antitumor immune response in immunocompetent mice in vivo.…”

Reverse Genetics of Newcastle Disease Virus

“…NDV reverse genetics has made possible the development of a valuable recombinant vaccine system, enabling expression of its own mutated proteins or foreign proteins, thus opening opportunities to investigate its applications as recombinant vaccines, as a multivalent vaccine candidate for poultry, and as a vaccine vector for other animal species and humans [14,[17][18][19][20][21][22][23][24][25][26][27][28][29][30]. NDVs modified by reverse genetics have also become valuable candidates for anticancer therapy in humans [31][32][33][34][35].…”