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Novel Oncolytic Chimeric Orthopoxvirus Causes Regression of Pancreatic Cancer Xenografts and Exhibits Abscopal Efect at a Single Low Dose Michael P

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Novel Oncolytic Chimeric Orthopoxvirus Causes Regression of Pancreatic Cancer Xenografts and Exhibits Abscopal Efect at a Single Low Dose Michael P O’Leary et al. J Transl Med (2018) 16:110 https://doi.org/10.1186/s12967-018-1483-x Journal of Translational Medicine RESEARCH Open Access Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal efect at a single low dose Michael P. O’Leary1, Audrey H. Choi1, Sang‑In Kim1, Shyambabu Chaurasiya1, Jianming Lu1, Anthony K. Park1, Yanghee Woo1, Susanne G. Warner1, Yuman Fong1,2 and Nanhai G. Chen1,2,3* Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and charac‑ terization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer. Methods: After chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopox‑ virus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efcacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models. Results: CF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC-1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of ­103 plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs. Conclusion: The low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufac‑ turing and dosing challenges currently facing oncolytic viral therapy. Keywords: Cancer therapy, Immunotherapy, Translational, Vaccinia, Viral vectors Background with unresectable regionally advanced or metastatic dis- New cases of pancreatic ductal adenocarcinoma (PDAC) ease at the time of diagnosis [1]. In the setting of meta- have been increasing by 0.5% per year in the United States static disease, recent trials using FOLFIRINOX resulted and a dismal mortality rate persists. Currently, PDAC is in an incremental improvement of overall survival to the fourth leading cause of cancer-related death and is 11.1 months compared to 6.8 months seen with gemcit- anticipated to be the second leading cause in the United abine [2]. Tus, PDAC will continue to portend a dismal States by 2030. Cancer-related 5-year survival from 1975 prognosis unless novel therapies are introduced. to 2008 has had an overall survival increase from 49 to Immuno-oncolytic therapy is an exciting area of cur- 68%, however, PDAC survival has only increased from rent cancer research. An enriched understanding of 2 to 6% [1]. Surgical resection is the mainstay of cura- tumor biology and patient immunology has led to the tive treatment but as many as 80% of patients present development of the current generation of oncolytic viruses (OVs). Orthopoxviruses, such as vaccinia virus (VACV), have been investigated for their tumoricidal *Correspondence: [email protected] potential in numerous cancers, including pancreatic 1 Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA 91010, USA cancer [3–5]. Characteristics of these viruses that made Full list of author information is available at the end of the article them favorable candidates as clinical agents include © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. O’Leary et al. J Transl Med (2018) 16:110 Page 2 of 11 cytoplasmic replication, the excellent safety profle in of orthopoxvirus. Following the co-infection, one hun- the global eradication of smallpox, and a short life cycle dred individual plaques were picked and subjected to a [6–8]. Clinical trials data from a number of these agents total of three rounds of plaque purifcation in CV-1 cells have confrmed a favorable toxicity profle. However, the to obtain 100 clonally purifed chimeric orthopoxviruses. feld would beneft from viruses that are more potent in High-throughput screening was used to compare the cancer killing, and that cost less to produce. cytotoxic efcacy of these chimeric clones and the paren- Te novel oncolytic virus presented in the current tal strains against the NCI-60 panel. CF33 was selected as study is CF33. It is a chimeric orthopoxvirus selected in a the chimeric isolate that demonstrated superior cell kill- high throughput screen for its efcient viral proliferation ing in the NCI-60 panel when compared to all parental and tumoricidal capabilities. In the following studies, we viruses and other plaque-purifed isolates. demonstrate the potent ability of this virus and its imag- ing capable derivative CF33-Fluc, to replicate in and kill Generation of recombinant chimeric orthopoxvirus a panel of pancreatic cancer cells in vitro. In vivo models expressing frefy luciferase of pancreatic cancer xenografts in nude mice were then To construct thymidine kinase (TK) shuttle vector, the used to demonstrate the selectivity of this virus for can- left and right fanking sequences of the TK gene were cer while sparing normal tissues, and to demonstrate the PCR-amplifed from CF33 genomic DNA using Q5 safety of this virus in preclinical models. We also show High-Fidelity 2X Master Mix (New England Biolabs Inc., that treatment of tumors by direct tumor injection can Ipswich, MA) and the primers: 5′-GCG CAT ATG ATC not only produce tumor regression of the injected tumor TAT GGA TTA CCA TG GAT GAC AACTC-3′ and 5′-CGT but also lead to viral spread to distant non-injected TTA ACT CGT CTA ATT AAT TCT GTAC-3′ (left fank), tumors and distant tumor regression. 5′-CAG GTA AAA GTA CA GAA TTA ATT AGA CGA GTT AAA CGA GC CGT CGA CGG ATC CGC TAG CGG CCG Methods CGG AGG TAA TGA TAT GTA TCA ATC GGT GTG TAG- Cell lines and maintenance 3′ and 5′-GCG GAA TTC GTA ATT ACT TAGTA AAT African green monkey kidney fbroblasts (CV-1) were CCG CCG TAC TAGG-3′ (right fank). Te two fragments purchased from the American Type Culture Collection were joined together using the method of gene splicing (ATCC). CV-1 cells were cultured in Dulbecco’s modi- by overlapping extension [9]. Te resulting fragment was fed Eagle’s medium (DMEM) supplemented with 10% digested with NdeI and EcoRI and cloned into plasmid fetal bovine serum (FBS) and 1% antibiotic–antimycotic pGPT to yield p33NC-TK. Te fanking sequences of solution. Human pancreatic cancer cell lines PANC-1, TK in the shuttle vector were confrmed by sequencing. MIA PaCa-2, BxPC-3, SU.86.86 and AsPC-1 were pur- p33NC-TK contains the left and right fanking sequences chased from ATCC. Capan-1 was a kind gift from Dr. T. of TK separated by SacI, SalI, BamHI, NheI and NotI, and Ku’s lab (City of Hope, Duarte, CA, USA). All pancreatic Escherichia coli guanine phosphoribosyltransferase (gpt) cancer cell lines were cultured in Roswell Park Memorial gene driven by the VACV early promoter p7.5E as a tran- Institute medium (RPMI) 1640 supplemented with 10% sient dominant selectable marker. FBS and 1% antibiotic–antimycotic solution. Media and Te Emerald expression cassette with the VACV H5 supplements were purchased from Corning (Corning, early/late promoter was PCR-amplifed from the plasmid NY). All cells were maintained in a humidifed incuba- Emerald-pBAD (Addgene, Cambridge, MA) using Q5 tor at 37 °C and 5% CO 2. Cell lines were authenticated by High-Fidelity 2X Master Mix (New England Biolabs Inc., Genetica® DNA Laboratories. Ipswich, MA) and the primers: 5′-GCG AAG CTT GAG CTC AAA AAT TGA AAA TAA ATA CAA AGG TTC TTG Viruses AGG GTT GTG TTA AAT TGA AAG CGA GAA ATA ATC Cowpox virus strain Brighton, raccoonpox virus strain ATA AAT AGT CGA CCA CCA TGG TGA GCA AGG GCG Herman, rabbitpox virus strain Utrecht, VACV strains AGG AGC TGT TCACC-3′ and 5′-GCG GGA TCC ATA Western Reserve, International Health Department, AAA ATT AAT TAA TCA GTA CAG CTC GTC CAT GCC Elstree, CL, Lederle-Chorioallantoic (LC) and AS were GAG AGT GAT C-3′. Te PCR fragment was digested with purchased from ATCC. CV-1 cells were used for both SacI and BamHI and cloned into plasmid p33NC-TK to amplifcation and titration of these orthopoxviruses. yield p33NCTK-H5-Emerald. Te sequence of the Emer- ald expression cassette was confrmed by sequencing. To Chimerization of orthopoxviruses and high‑throughput generate a shuttle vector containing the frefy luciferase screening expression cassette with the VACV H5 promoter, the Chimerization of orthopoxviruses was achieved by co- frefy luciferase cDNA was PCR-amplifed from the plas- infecting CV-1 cells with all the aforementioned strains mid pCDNA3.1(+)/Luc2 = tdT (Addgene, Cambridge, O’Leary et al. J Transl Med (2018) 16:110 Page 3 of 11 MA) using Q5 High-Fidelity 2X Master Mix (New Eng- Sixteen hours post-infection, supernatants were collected land Biolabs Inc., Ipswich, MA) and the primers: 5′-GCG and ATP concentration was measured by the ATP Deter- GTC GAC CAC C ATG GAA GAT GCC AAA AAC ATT mination kit (Cat# A22066; Invitrogen, Carlsbad, CA) AAG AA GGG CCC AGC-3′ and 5′-GCG GGA TCC ATA following manufacturer’s instructions.
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