Multiple Administration Routes, Including Intramuscular Injection, of Oncolytic Tanapoxvirus Variants Significantly Regress Human Melanoma Xenografts in BALB/c Nude Mice Reconstituted with Splenocytes from Normal BALB/c Donors.

Human melanoma is the most aggressive form of skin cancer and is responsible for the most deaths of all skin cancers. Localized tumors, and those which have limited spread, have 5-year survival rates of over 90%, with those numbers steadily rising over the past decade. However, metastatic melanomas have a sharp decrease in 5-year survival rates and are still an area of need for new, successful therapies. Immuno-oncolytic viruses (OVs) have emerged as a promising class of immunovirotherapy that can potentially address this disease. The Food and Drug Administration in the United States has approved one oncolytic herpes simplex virus expressing granulocyte-macrophage colony-stimulating factor (Talimogene Laherparepvec) for the treatment of metastatic melanoma, and others could soon follow for this and other cancers. In previous studies, Tanapoxvirus (TPV) recombinants expressing mouse interleukin-2 (mIL-2) and another expressing bacterial flagellin from Salmonella typhimurium (FliC) have demonstrated anti-tumor efficacy in nude mouse models. TPV replicates only in humans and monkeys, including tumor cells, which makes the use of syngeneic tumor models impossible for the study of this OV in a standard immunocompetent system. In this study, TPV/Δ66R/mIL-2 and TPV/Δ2L/Δ66R/FliC were tested for their ability to treat human melanoma xenografts (SK-MEL3) in a BALB/c nude mouse model reconstituted with splenocytes from genetically compatible, normal BALB/c donor mice. Two SK-MEL3 tumors were transplanted into each flank of BALB/c nude mice, and the larger tumor was treated intratumorally (IT) with virus or mock injection. In one set of animals, mice received adoptive transfers of splenocytes from BALB/c mice on day 4 to reconstitute their immune systems and allow for adaptive immune responses to occur in a xenograft model. Direct IT injection of TPV/Δ66R/mIL-2 led to significantly greater rates of tumor regression compared to reconstituted control (RC) mice in the primary and distant tumor sites, whereas TPV/Δ2L/Δ66R/FliC treatment led to significantly greater rates of tumor regression in distant tumor sites only. A second experiment used TPV/Δ66R/mIL-2 to test whether TPV could be administered intravenously (IV), intramuscularly (IM), or both routes simultaneously to exert similar anti-tumor effects in an indirectly treated tumor. A single SK-MEL3 tumor was transplanted into one flank of BALB/c nude mice and was treated either into the tail vein, the nearest rear leg to the tumor, or both. All mice then received adoptive transfers of splenocytes in the same way as previously described on day 4 and received an additional TPV treatment on day 14. The results demonstrated that TPV/Δ66R/mIL-2 treatment IV or IM had significantly greater rates of tumor regression than RC-treated mice but failed to exert this effect when both routes were used simultaneously. Data obtained through these experiments support the continued development of Tanapoxvirus for the treatment of human melanoma and using immune reconstitution to create intact adaptive immunity in a xenograft context, which can allow other tropism-limited OVs to be studied against human cancers.

The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC is very rarely detected in early stages when surgical resection can be performed. Only 20% of cases are suitable for surgical resection; this remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention such as chemotherapeutic treatments are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC and immuno-oncolytic viruses (OVs) have been of particular interest since 2006 when the first oncolytic virus was approved as a therapy for nasopharyngeal cancers in China. Interest resurged in 2015 when T-Vec, an oncolytic herpes simplex virus, was approved in the United States for treatment of advanced melanoma. While many vectors have been explored, few show promise as treatment for pancreatic cancer, and fewer still have progressed to clinical trial evaluation. This review outlines recent strategies in the development of OVs targeting treatment of PDAC, current state of preclinical and clinical investigation and application.

Role of the "dogbone" effect of balloon-expandable stents: quantitative coronary analysis of DUET and NIR stent implantation introducing a novel indexing system.

UNLABELLED: Stent design and deployment characteristics of balloon-expandable stents may play an important role in determining both early and late outcomes of stenting. The purpose of this study was to compare the percent residual stenosis (RS) of two new-generation stent delivery systems, DUET and NIR, in patients with CAD. From September 1998 1999, a total of 100 consecutive patients with CAD receiving either a DUET (18 or 23 mm length; n = 50) or NIR stent (16 or 25 mm length; n = 50) using a 3.0 or 3.5 mm stent delivery system were compared by quantitative coronary analysis. The ability of each balloon delivery system to fully expand the stent was assessed using a new scoring index entitled the stent delivery balloon expansion ratio (SDBR; %). A high SDBR correlates with the angiographic appearance of a "dogbone" that is sometimes seen during stent deployment. A stent "scalloping" score was developed to quantitatively assess the cobblestone appearance observed angiographically with plaque protrusion after stent implantation. Mean deployment pressures were 14 +/- 2 atm (DUET) and 13 +/- 2 atm (NIR) (p=NS). Extent of elastic recoil was similar (6 +/- 5% for DUET vs. 6 +/- 4% for NIR; (p=NS). "Scalloping" was more pronounced in the DUET stent (score, 0.66 +/- 0.6 for DUET vs. 0.24 +/- 0.4 for NIR; p < 0.001). SDBR and RS were higher with DUET than with NIR stent implantation (SDBR, 15 +/- 5% vs. 12 +/- 5%; RS, 14 +/- 5% vs. 11 +/- 6%; p < 0.01). Multivariate analysis showed that SDBR and stent recoil, but not "scalloping", were associated with increased RS after stent implantation (r = 0.45 and p < 0.001 for "dogbone" effect; r = 0.39 and p < 0.001 for stent recoil). CONCLUSION: The second-generation DUET and NIR stents and their respective delivery systems show angiographically different acute performance characteristics. Insufficient deployment of stents visualized by the "dogbone" effect plays a role in the extent of RS after stenting. The introduced angiographic indexes require further validation.