**6. Conclusions**

Over the past 60 years, NDV has repeatedly demonstrated its therapeutic potential, both as an oncolytic agent and an immunotherapeutic agent. With intravenous administration, NDV is one of the few viruses that has demonstrated an ability to result in partial and even complete responses as a single agent. Durability of these responses further highlights that the therapeutic effect of the virus is likely not solely dependent on direct oncolysis, but rather on the ability of the virus to induce durable immunity. While the use of mesogenic and velogenic (and thus most lytic) strains for antitumor therapy is limited due to their pathogenic potential in birds, data with fewer lytic strains nevertheless highlights their potential to incite antitumor immunity, with the recent data indicating their ability to potentiate the efficacy of systemic immune checkpoint inhibitors. Furthermore, with the advent of genetic engineering, it has become possible to modify NDV to further enhance its immunogenic potential, with introduction of transgenes targeting both innate and adaptive immune pathways. As with other oncolytic viruses, many questions surrounding therapy with NDV remain unanswered, including optimal route of administration, ideal strategies for genetic engineering, therapeutic sequencing with immune checkpoint inhibitors, and best combination partners. While preclinical syngeneic models have provided some answers to these questions, most, if not all, models fail to capture the heterogeneity of human cancers and are thus not sufficient for guiding therapy. It is thus imperative that within the context of clinical trials we collect as much information as possible, with translational endpoints being prioritized as essential elements of any study. Understanding of the evolution of immune response to the virus and the tumor, even in a trial with no clinical benefit, should be a key priority for any clinical trial utilizing oncolytic viruses, as it is the only way to guide the further development of these agents and move the field forward.

**Author Contributions:** B.B., G.P., and D.Z. all contributed to manuscript composition and editing. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded in part through the NIH/NCI Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748. D.Z. is a member of the Parker Institute for Cancer Immunotherapy at MSKCC. D.Z. is supported by the Ovarian Cancer Research Foundation Liz Tilberis Award and the Department of Defense Ovarian Cancer Research Academy (OC150111). B.B. is supported by the NIH T32 Investigational Cancer Therapeutics Training Program Grant (T32-CA009207) and the ASCO Conquer Cancer Foundation Young Investigator Award.

**Conflicts of Interest:** D.Z. is an inventor on two patents related to use of NDV for cancer therapy. D.Z. reports personal/consultancy fees from Merck, Synlogic Therapeutics, Biomed Valley Discoveries, Trieza Therapeutics, Tesaro, and Agenus of the scope of this work. D.Z. reports institutional research support from Astra Zeneca, Plexxikon, and Genentech, outside of the scope of this work. B.B. and G.P. have no conflicts.
