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Raquel Yokoda,1 Bolni M Nagalo,1 Mansi Arora,1 Jan B Egan,1 James M Bogenberger,1 Thomas T DeLeon,1 Yumei Zhou,1 Daniel H Ahn,1 Mitesh J Borad1–3 1Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, 2Department of Molecular Medicine, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 3Department of Oncology, Mayo Clinic Cancer Center, Phoenix, AZ, USA Abstract: Upper gastrointestinal tract malignancies are among the most challenging cancers with regard to response to treatment and prognosis. Cancers of the esophagus, stomach, pancreas, liver, and biliary tree have dismal 5-year survival, and very modest improvements in this rate have been made in recent times. Oncolytic viruses are being developed to address these malignancies, with a focus on high safety profiles and low off-target toxicities. Each viral platform has evolved to enhance oncolytic potency and the clinical response to either single-agent viral therapy or combined viral treatment with radiotherapy and chemotherapy. A panel of genomic alterations, chimeric proteins, and pseudotyped capsids are the breakthroughs for vector success. This article revisits developments for each viral platform to each tumor type, in an attempt to achieve maximum tumor selectivity. From the bench to clinical trials, the scope of this review is to highlight the beginnings of translational oncolytic virotherapy research in upper gastrointestinal tract malignancies and provide a bioengineering perspective of the most promising platforms. Keywords: oncolytic viruses, hepatopancreatobiliary, gastric cancer, pancreatic cancer, liver cancer, biliary cancer

Raquel Yokoda,1 Bolni M Nagalo,1 Brent Vernon,2 Rahmi Oklu,3 Hassan Albadawi,3 Thomas T DeLeon,1 Yumei Zhou,1 Jan B Egan,1 Dan G Duda,4 Mitesh J Borad1 1Division of Hematology Oncology, Department of Medicine, Mayo Clinic, Scottsdale, 2Department of Biomedical Engineering, Arizona State University, Tempe, 3Division of Vascular and Interventional Radiology, Department of Radiology, Mayo Clinic, Scottsdale, AZ, 4Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA Abstract: With the advancement of a growing number of oncolytic viruses (OVs) to clinical development, drug delivery is becoming an important barrier to overcome for optimal therapeutic benefits. Host immunity, tumor microenvironment and abnormal vascularity contribute to inefficient vector delivery. A number of novel approaches for enhanced OV delivery are under evaluation, including use of nanoparticles, immunomodulatory agents and complex viral–particle ligands along with manipulations of the tumor microenvironment. This field of OV delivery has quickly evolved to bioengineering of complex nanoparticles that could be deposited within the tumor using minimal invasive image-guided delivery. Some of the strategies include ultrasound (US)-mediated cavitation-enhanced extravasation, magnetic viral complexes delivery, image-guided infusions with focused US and targeting photodynamic virotherapy. In addition, strategies that modulate tumor microenvironment to decrease extracellular matrix deposition and increase viral propagation are being used to improve tumor penetration by OVs. Some involve modification of the viral genome to enhance their tumoral penetration potential. Here, we highlight the barriers to oncolytic viral delivery, and discuss the challenges to improving it and the perspectives of establishing new modes of active delivery to achieve enhanced oncolytic effects. Keywords: oncolytic viruses, oncolytic virotherapy, drug delivery systems, tumor microenvironment&nbsp

Hani M Babiker,1 Irbaz Bin Riaz,2 Muhammad Husnain,2 Mitesh J Borad3,4 1University of Arizona Cancer Center, 2Department of Internal Medicine, University of Arizona, Tucson, 3Division of Hematology-Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ, 4Department of Molecular Medicine, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA Abstract: The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients. This is certainly a burgeoning time in immunotherapy drug development, and the aforementioned efforts along with the recent US Food and Drug Administration approval of talimogene laherparepvec (T-VEC), a recombinant oncolytic herpes virus, have paved the way to exploring the role of additional oncolytic viruses, such as the echovirus Rigvir, as new and innovative treatment modalities in patients with melanoma. Herein, we discuss the current standard of care treatment in melanoma with an emphasis on immunotherapy and oncolytic viruses in development. Keywords: melanoma, virotherapy, Rigvir

Babiker HM, Riaz IB, Husnain M, Borad MJ. Oncolytic Virother. 2017;6:11–18.On page 16, left column, line 19 from the bottom, our publication indicates: “However, the data should be interpreted with caution, given the retrospective nature of the study, lack of control arm or randomization and other biases inherent with studies that are not prospective in nature”. However, the trial did have 52 malignant melanoma patients (post-surgical resection stages IB, IIA, IIB, and IIC) who did receive Rigvir, and 27 patients who were observed and treated per the standard guidelines (control group). Hence, there was a control group as in indicated in Figure 1 in the Doniņa et al paper.1On page 16, left column, line 16 from the bottom, our publication indicates: “From a safety perspective, it was reported that there were no severe treatment-related toxicities. However, detailed data supporting this were not provided in the study publication, making it difficult to interpret objectively”. The authors would like to indicate regarding publication by Doniņa et al,1 Melanoma Research 2015, that Table 4 detailed the serum chemistry parameters of the patients. While no details of clinical adverse events, serious adverse events, or treatment related adverse events were highlighted, the authors do indicate on the paper that “In this retrospective study, however, that there was no record of any untoward side effect from Rigvir treatmentor its discontinuation” (page 423 line 7 from the bottom,Doniņa et al1).Read the original article&nbsp