**Bharat Burman 1,2, Giulio Pesci 1,2 and Dmitriy Zamarin 1,2,3,4,\***


Received: 30 October 2020; Accepted: 24 November 2020; Published: 28 November 2020

**Simple Summary:** Newcastle disease virus (NDV) is an RNA virus belonging to the Paramyxoviridae family. In nature, NDV primarily infects birds, but poses no threat to human health. Multiple studies have demonstrated that NDV caries oncolytic potential due to its predilection for infection and replication in human cancer cells while sparing normal cells. In addition to its direct lytic effects, the virus triggers both innate and adaptive immune responses. In animal models, NDV injection into a tumor has been demonstrated to result in local inflammation and the recruitment of tumor-specific T cells, an effect that can be further potentiated through the use of viruses encoding immunomodulatory ligands and through combinations with immune checkpoint blockade. Initial clinical trials with naturally occurring NDV administered intravenously demonstrated durable responses across a number of cancer types. Clinical studies utilizing recombinant NDV in combination with immune checkpoint inhibitors are ongoing.

**Abstract:** Preclinical and clinical studies dating back to the 1950s have demonstrated that Newcastle disease virus (NDV) has oncolytic properties and can potently stimulate antitumor immune responses. NDV selectively infects, replicates within, and lyses cancer cells by exploiting defective antiviral defenses in cancer cells. Inflammation within the tumor microenvironment in response to NDV leads to the recruitment of innate and adaptive immune effector cells, presentation of tumor antigens, and induction of immune checkpoints. In animal models, intratumoral injection of NDV results in T cell infiltration of both local and distant non-injected tumors, demonstrating the potential of NDV to activate systemic adaptive antitumor immunity. The combination of intratumoral NDV with systemic immune checkpoint blockade leads to regression of both injected and distant tumors, an effect further potentiated by introduction of immunomodulatory transgenes into the viral genome. Clinical trials with naturally occurring NDV administered intravenously demonstrated durable responses across numerous cancer types. Based on these studies, further exploration of NDV is warranted, and clinical studies using recombinant NDV in combination with immune checkpoint blockade have been initiated.

**Keywords:** oncolytic virus; newcastle disease virus; NDV; cancer; immunotherapy; immune checkpoint inhibitor; PD-1; PD-L1; CTLA-4; type I interferon
