Oncolytic Tanapoxvirus Variants Expressing mIL-2 and mCCL-2 Regress Human Pancreatic Cancer Xenografts in Nude Mice †
Abstract
:1. Introduction
2. Methods and Materials
2.1. Cells, Viruses, and Reagents
2.2. Viral Replication Assessment via Phase Contrast and Florescent Microscopy
2.3. Viral Plaque Assay
2.4. Animal Model
2.5. In Vivo Study Design Summary
BxPc-3 Human PDAC Xenografts and Virotherapy
2.6. CD3+ T-Cell Isolation and Adoptive Transfer
2.7. [18F]-FDG and [18F]-FLT PET Imaging Agents
2.8. [125I]-Anti GFP Antibody and [125I]-Anti-mCherry Antibody SPECT Imaging Agents
2.9. PET/CT Imaging
2.10. SPECT/CT Imaging
2.11. Quantitative Whole-Body Autoradiography (QWBA)
2.12. CD-3+ T-Cell Biomarker Assay
2.13. Tissue Processing and Histopathological Assessment
2.14. Statistical Analysis
3. Results
3.1. Replication Kinetics of TPV in Human Pancreatic Cancer Cells
3.2. Treatment of BxPc-3 Xenografts with Tanapoxvirus Recombinants In Vivo
3.3. Tumor Metabolic Activity Assessment via [18F]-FDG PET/CT Imaging
3.4. Tumor Cell Proliferation Assessment via [18F]-FLT PET/CT Imaging
3.5. In Vivo Tumor TPV Transgene Expression Assessment via SPECT/CT Imaging
3.6. Ex Vivo Tumor TPV Transgene Expression Assessment via Quantitative Whole-Body Autoradiography (QWBA)
3.7. Biomarker Analysis and Pathology
3.8. Pathology
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed]
- Previdi, M.C.; Carotenuto, P.; Zito, D.; Pandolfo, R.; Braconi, C. Noncoding RNAs as Novel Biomarkers in Pancreatic Cancer: What Do We Know? Future Oncol. 2017, 13, 443–453. [Google Scholar] [CrossRef] [PubMed]
- Haeberle, L.; Esposito, I. Pathology of Pancreatic Cancer. Transl. Gastroenterol. Hepatol. 2019, 4, 50. [Google Scholar] [CrossRef]
- Ryan, D.P.; Hong, T.S.; Bardeesy, N. Pancreatic Adenocarcinoma. N. Engl. J. Med. 2014, 371, 1039–1049. [Google Scholar] [CrossRef] [PubMed]
- Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Res. 2014, 74, 2913–2921. [Google Scholar] [CrossRef] [PubMed]
- Rouanet, M.; Lebrin, M.; Gross, F.; Bournet, B.; Cordelier, P.; Buscail, L. Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes. Int. J. Mol. Sci. 2017, 18, 1231. [Google Scholar] [CrossRef] [PubMed]
- Vincent, A.; Herman, J.; Schulick, R.; Hruban, R.H.; Goggins, M. Pancreatic Cancer. Proc. Lancet 2011, 378, 607–620. [Google Scholar] [CrossRef] [PubMed]
- Hruban, R.H.; Canto, M.I.; Goggins, M.; Schulick, R.; Klein, A.P. Update on Familial Pancreatic Cancer. Adv. Surg. 2010, 44, 293–311. [Google Scholar] [CrossRef]
- McGuigan, A.; Kelly, P.; Turkington, R.C.; Jones, C.; Coleman, H.G.; McCain, R.S. Pancreatic Cancer: A Review of Clinical Diagnosis, Epidemiology, Treatment and Outcomes. World J. Gastroenterol. 2018, 24, 4846–4861. [Google Scholar] [CrossRef] [PubMed]
- Zhou, B.; Xu, J.W.; Cheng, Y.G.; Gao, J.Y.; Hu, S.Y.; Wang, L.; Zhan, H.X. Early Detection of Pancreatic Cancer: Where Are We Now and Where Are We Going? Int. J. Cancer 2017, 141, 231–241. [Google Scholar] [CrossRef]
- Islami, F.; Goding Sauer, A.; Miller, K.D.; Siegel, R.L.; Fedewa, S.A.; Jacobs, E.J.; McCullough, M.L.; Patel, A.V.; Ma, J.; Soerjomataram, I.; et al. Proportion and Number of Cancer Cases and Deaths Attributable to Potentially Modifiable Risk Factors in the United States. CA A Cancer J. Clin. 2018, 68, 31–54. [Google Scholar] [CrossRef] [PubMed]
- Chang, H.-H.; Eibl, G. Obesity-Induced Adipose Tissue Inflammation as a Strong Promotional Factor for Pancreatic Ductal Adenocarcinoma. Cells 2019, 8, 673. [Google Scholar] [CrossRef] [PubMed]
- Jones, S.; Zhang, X.; Parsons, D.W.; Lin, J.C.H.; Leary, R.J.; Angenendt, P.; Mankoo, P.; Carter, H.; Kamiyama, H.; Jimeno, A.; et al. Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses. Science 2008, 321, 1801–1806. [Google Scholar] [CrossRef] [PubMed]
- Rozenblum, E.; Schutte, M.; Goggins, M.; Hahn, S.A.; Panzer, S.; Zahurak, M.; Goodman, S.N.; Sohn, T.A.; Hruban, R.H.; Yeo, C.J.; et al. Tumor-Suppressive Pathways in Pancreatic Carcinoma. Cancer Res. 1997, 57, 1731–1734. [Google Scholar] [PubMed]
- van Heek, N.T.; Meeker, A.K.; Kern, S.E.; Yeo, C.J.; Lillemoe, K.D.; Cameron, J.L.; Offerhaus, G.J.A.; Hicks, J.L.; Wilentz, R.E.; Goggins, M.G.; et al. Telomere Shortening Is Nearly Universal in Pancreatic Intraepithelial Neoplasia. Am. J. Pathol. 2002, 161, 1541–1547. [Google Scholar] [CrossRef] [PubMed]
- Hong, S.M.; Heaphy, C.M.; Shi, C.; Eo, S.H.; Cho, H.; Meeker, A.K.; Eshleman, J.R.; Hruban, R.H.; Goggins, M. Telomeres Are Shortened in Acinar-to-Ductal Metaplasia Lesions Associated with Pancreatic Intraepithelial Neoplasia but Not in Isolated Acinar-to-Ductal Metaplasias. Mod. Pathol. 2011, 24, 256–266. [Google Scholar] [CrossRef] [PubMed]
- Hruban, R.H.; Goggins, M.; Parsons, J.; Kern, S.E. Progression Model for Pancreatic Cancer. Clin. Cancer Res. 2000, 6, 2969–2972. [Google Scholar] [PubMed]
- Carter, H.; Samayoa, J.; Hruban, R.H.; Karchin, R. Prioritization of Driver Mutations in Pancreatic Cancer Using Cancer-Specific High-Throughput Annotation of Somatic Mutations (CHASM). Cancer Biol. Ther. 2010, 10, 582–587. [Google Scholar] [CrossRef] [PubMed]
- Omura, N.; Goggins, M. Epigenetics and Epigenetic Alterations in Pancreatic Cancer. Int. J. Clin. Exp. Pathol. 2009, 15, 89–110. [Google Scholar]
- Schutte, M.; Hruban, R.H.; Geradts, J.; Maynard, R.; Hilgers, W.; Rabindran, S.K.; Moskaluk, C.A.; Hahn, S.A.; Schwarte-Waldhoff, I.; Schmiegel, W.; et al. Abrogation of the Rb/P16 Tumor-Suppressive Pathway in Virtually All Pancreatic Carcinomas. Cancer Res. 1997, 15, 3126–3130. [Google Scholar]
- Matsubayashi, H.; Canto, M.; Sato, N.; Klein, A.; Abe, T.; Yamashita, K.; Yeo, C.J.; Kalloo, A.; Hruban, R.; Goggins, M. DNA Methylation Alterations in the Pancreatic Juice of Patients with Suspected Pancreatic Disease. Cancer Res. 2006, 66, 1208–1217. [Google Scholar] [CrossRef]
- Sato, N.; Matsubayashi, H.; Abe, T.; Fukushima, N.; Goggins, M. Epigenetic Down-Regulation of CDKN1C/P57KIP2 in Pancreatic Ductal Neoplasms Identified by Gene Expression Profiling. Clin. Cancer Res. 2005, 11, 4681–4688. [Google Scholar] [CrossRef] [PubMed]
- Sato, N.; Fukushima, N.; Hruban, R.H.; Goggins, M. CpG Island Methylation Profile of Pancreatic Intraepithelial Neoplasia. Mod. Pathol. 2008, 21, 238–244. [Google Scholar] [CrossRef] [PubMed]
- Sato, N.; Fukushima, N.; Maitra, A.; Matsubayashi, H.; Yeo, C.J.; Cameron, J.L.; Hruban, R.H.; Goggins, M. Discovery of Novel Targets for Aberrant Methylation in Pancreatic Carcinoma Using High-Throughput Microarrays. Cancer Res. 2003, 63, 3735–3742. [Google Scholar] [PubMed]
- Sato, N.; Fukushima, N.; Chang, R.; Matsubayashi, H.; Goggins, M. Differential and Epigenetic Gene Expression Profiling Identifies Frequent Disruption of the RELN Pathway in Pancreatic Cancers. Gastroenterology 2006, 130, 548–565. [Google Scholar] [CrossRef] [PubMed]
- Sato, N.; Fukushima, N.; Maehara, N.; Matsubayashi, H.; Koopmann, J.; Su, G.H.; Hruban, R.H.; Goggins, M. SPARC/Osteonectin Is a Frequent Target for Aberrant Methylation in Pancreatic Adenocarcinoma and a Mediator of Tumor-Stromal Interactions. Oncogene 2003, 22, 5021–5030. [Google Scholar] [CrossRef] [PubMed]
- Sato, N.; Maitra, A.; Fukushima, N.; van Heek, N.T.; Matsubayashi, H.; Iacobuzio-Donahue, C.A.; Rosty, C.; Goggins, M. Frequent Hypomethylation of Multiple Genes Overexpressed in Pancreatic Ductal Adenocarcinoma. Cancer Res. 2003, 63, 4158–4166. [Google Scholar] [PubMed]
- Parsi, M.A.; Li, A.; Li, C.P.; Goggins, M. DNA Methylation Alterations In Endoscopic Retrograde Cholangiopancreatography Brush Samples of Patients With Suspected Pancreaticobiliary Disease. Clin. Gastroenterol. Hepatol. 2008, 6, 1270–1278. [Google Scholar] [CrossRef] [PubMed]
- Vincent, A.; Ducourouble, M.; van Seuningen, I. Epigenetic Regulation of the Human Mucin Gene MUC4 in Epithelial Cancer Cell Lines Involves Both DNA Methylation and Histone Modifications Mediated by DNA Methyltransferases and Histone Deacetylases. FASEB J. 2008, 22, 3035–3045. [Google Scholar] [CrossRef] [PubMed]
- Scheufele, F.; Hartmann, D.; Friess, H. Treatment of Pancreatic Cancer—Neoadjuvant Treatment in Borderline Resectable/Locally Advanced Pancreatic Cancer. Transl. Gastroenterol. Hepatol. 2019, 4, 32. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.Y.; Yang, F.; Jin, C.; Fu, D.L. Utility of PET/CT in Diagnosis, Staging, Assessment of Resectability and Metabolic Response of Pancreatic Cancer. World J. Gastroenterol. 2014, 20, 15580–15589. [Google Scholar] [CrossRef] [PubMed]
- Konstantinidis, I.T.; Warshaw, A.L.; Allen, J.N.; Blaszkowsky, L.S.; del Castillo, C.F.; Deshpande, V.; Hong, T.S.; Kwak, E.L.; Lauwers, G.Y.; Ryan, D.P.; et al. Borderline Resectable Pancreatic Cancer: Need for Standardization and Methods for Optimal Clinical Trial Design. Ann Surg Oncol 2015, 22, 3409–3413. [Google Scholar] [CrossRef]
- Springfeld, C.; Jäger, D.; Büchler, M.W.; Strobel, O.; Hackert, T.; Palmer, D.H.; Neoptolemos, J.P. Chemotherapy for Pancreatic Cancer. Presse Medicale 2019, 48, e159–e174. [Google Scholar] [CrossRef] [PubMed]
- Klaiber, U.; Hackert, T.; Neoptolemos, J.P. Adjuvant Treatment for Pancreatic Cancer. Transl. Gastroenterol. Hepatol. 2019, 4, 27. [Google Scholar] [CrossRef] [PubMed]
- Gupta, R.; Amanam, I.; Chung, V. Current and Future Therapies for Advanced Pancreatic Cancer. J. Surg. Oncol. 2017, 116, 25–34. [Google Scholar] [CrossRef] [PubMed]
- Gillen, S.; Schuster, T.; zum Büschenfelde, C.M.; Friess, H.; Kleeff, J. Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-Analysis of Response and Resection Percentages. PLoS Med. 2010, 7, e1000267. [Google Scholar] [CrossRef] [PubMed]
- Werner, J.; Combs, S.E.; Springfeld, C.; Hartwig, W.; Hackert, T.; Büchler, M.W. Advanced-Stage Pancreatic Cancer: Therapy Options. Nat. Rev. Clin. Oncol. 2013, 10, 323–333. [Google Scholar] [CrossRef] [PubMed]
- Conroy, T.; Desseigne, F.; Ychou, M.; Bouché, O.; Guimbaud, R.; Bécouarn, Y.; Adenis, A.; Raoul, J.L.; Gourgou-Bourgade, S.; de La Fouchardière, C.; et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N. Engl. J. Med. 2011, 364, 1817–1825. [Google Scholar] [CrossRef] [PubMed]
- von Hoff, D.D.; Ervin, T.; Arena, F.P.; Chiorean, E.G.; Infante, J.; Moore, M.; Seay, T.; Tjulandin, S.A.; Ma, W.W.; Saleh, M.N.; et al. Increased Survival in Pancreatic Cancer with Nab-Paclitaxel plus Gemcitabine. N. Engl. J. Med. 2013, 369, 1691–1703. [Google Scholar] [CrossRef] [PubMed]
- Falasca, M.; Kim, M.; Casari, I. Pancreatic Cancer: Current Research and Future Directions. Biochim. Et Biophys. Acta-Rev. Cancer 2016, 1865, 123–132. [Google Scholar] [CrossRef] [PubMed]
- Rahal, A.; Musher, B. Oncolytic Viral Therapy for Pancreatic Cancer. J. Surg. Oncol. 2017, 116, 94–103. [Google Scholar] [CrossRef] [PubMed]
- LaRocca, C.J.; Warner, S.G. A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer. Biomedicines 2018, 6, 104. [Google Scholar] [CrossRef] [PubMed]
- Russell, S.J.; Peng, K.W.; Bell, J.C. Oncolytic Virotherapy. Nat. Biotechnol. 2012, 30, 658–670. [Google Scholar] [CrossRef] [PubMed]
- Vähä-Koskela, M.J.V.; Heikkilä, J.E.; Hinkkanen, A.E. Oncolytic Viruses in Cancer Therapy. Cancer Lett. 2007, 254, 178–216. [Google Scholar] [CrossRef] [PubMed]
- Bell, J.; McFadden, G. Viruses for Tumor Therapy. Cell Host Microbe 2014, 15, 260–265. [Google Scholar] [CrossRef] [PubMed]
- Lichty, B.D.; Breitbach, C.J.; Stojdl, D.F.; Bell, J.C. Going Viral with Cancer Immunotherapy. Nat. Rev. Cancer 2014, 14, 559–567. [Google Scholar] [CrossRef] [PubMed]
- Kaufman, H.L.; Kohlhapp, F.J.; Zloza, A. Oncolytic Viruses: A New Class of Immunotherapy Drugs. Nat. Rev. Drug Discov. 2015, 14, 642–662. [Google Scholar] [CrossRef] [PubMed]
- Eissa, I.R.; Naoe, Y.; Bustos-Villalobos, I.; Ichinose, T.; Tanaka, M.; Zhiwen, W.; Mukoyama, N.; Morimoto, T.; Miyajima, N.; Hitoki, H.; et al. Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials. Front. Oncol. 2017, 7, 149. [Google Scholar] [CrossRef] [PubMed]
- Bretscher, C.; Marchini, A. H-1 Parvovirus as a Cancer-Killing Agent: Past, Present, and Future. Viruses 2019, 11, 562. [Google Scholar] [CrossRef] [PubMed]
- Clemens, M.J. Targets and Mechanisms for the Regulation of Translation in Malignant Transformation. Oncogene 2004, 23, 3180–3188. [Google Scholar] [CrossRef] [PubMed]
- Liang, M. Oncorine, the World First Oncolytic Virus Medicine and Its Update in China. Curr. Cancer Drug Targets 2018, 18, 171–176. [Google Scholar] [CrossRef] [PubMed]
- Yokoda, R.T.; Nagalo, B.M.; Borad, M.J. Oncolytic Adenoviruses in Gastrointestinal Cancers. Biomedicines 2018, 6, 33. [Google Scholar] [CrossRef] [PubMed]
- Freytag, S.O.; Barton, K.N.; Brown, S.L.; Narra, V.; Zhang, Y.; Tyson, D.; Nall, C.; Lu, M.; Ajlouni, M.; Movsas, B.; et al. Replication-Competent Adenovirus-Mediated Suicide Gene Therapy with Radiation in a Preclinical Model of Pancreatic Cancer. Mol. Ther. 2007, 15, 1600–1606. [Google Scholar] [CrossRef] [PubMed]
- Eissa, I.R.; Bustos-Villalobos, I.; Ichinose, T.; Matsumura, S.; Naoe, Y.; Miyajima, N.; Morimoto, D.; Mukoyama, N.; Zhiwen, W.; Tanaka, M.; et al. The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. Cancers 2018, 10, 356. [Google Scholar] [CrossRef] [PubMed]
- Yokoda, R.; Nagalo, B.M.; Arora, M.; Egan, J.B.; Bogenberger, J.M.; DeLeon, T.T.; Zhou, Y.; Ahn, D.H.; Borad, M.J. Oncolytic Virotherapy in Upper Gastrointestinal Tract Cancers. Oncolytic Virotherapy 2018, 7, 13–24. [Google Scholar] [CrossRef]
- Andtbacka, R.H.I.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S.; et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients with Advanced Melanoma. J. Clin. Oncol. 2015, 33, 2780–2788. [Google Scholar] [CrossRef] [PubMed]
- Chang, K.J.; Senzer, N.N.; Binmoeller, K.; Goldsweig, H.; Coffin, R. Phase I Dose-Escalation Study of Talimogene Laherparepvec (T-VEC) for Advanced Pancreatic Cancer (Ca). J. Clin. Oncol. 2012, 30, e14546. [Google Scholar] [CrossRef]
- Gayral, M.; Lulka, H.; Hanoun, N.; Biollay, C.; Sèlves, J.; Vignolle-Vidoni, A.; Berthommé, H.; Trempat, P.; Epstein, A.L.; Buscail, L.; et al. Targeted Oncolytic Herpes Simplex Virus Type 1 Eradicates Experimental Pancreatic Tumors. Hum. Gene Ther. 2015, 26, 104–113. [Google Scholar] [CrossRef] [PubMed]
- Toolan, H.W. A Virus Associated with Transplantable Human Tumors. Bull. N. Y. Acad. Med. 1961, 37, 305–310. [Google Scholar] [PubMed]
- Toolan, H.W.; Ledinko, N. Inhibition by H-1 Virus of the Incidence of Tumors Produced by Adenovirus 12 in Hamsters. Virology 1968, 35, 475–478. [Google Scholar] [CrossRef] [PubMed]
- Bryant, K.L.; Mancias, J.D.; Kimmelman, A.C.; Der, C.J. KRAS: Feeding Pancreatic Cancer Proliferation. Trends Biochem. Sci. 2014, 39, 91–100. [Google Scholar] [CrossRef]
- Noonan, A.M.; Farren, M.R.; Geyer, S.M.; Huang, Y.; Tahiri, S.; Ahn, D.; Mikhail, S.; Ciombor, K.K.; Pant, S.; Aparo, S.; et al. Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma. Mol. Ther. 2016, 24, 1150–1158. [Google Scholar] [CrossRef] [PubMed]
- Ahn, D.H.; Bekaii-Saab, T. The Continued Promise and Many Disappointments of Oncolytic Virotherapy in Gastrointestinal Malignancies. Biomedicines 2017, 5, 10. [Google Scholar] [CrossRef] [PubMed]
- Smith, G.L.; Moss, B. Infectious Poxvirus Vectors Have Capacity for at Least 25 000 Base Pairs of Foreign DNA. Gene 1983, 25, 21–28. [Google Scholar] [CrossRef]
- Yu, Y.A.; Galanis, C.; Woo, Y.; Chen, N.; Zhang, Q.; Fong, Y.; Szalay, A.A. Regression of Human Pancreatic Tumor Xenografts in Mice after a Single Systemic Injection of Recombinant Vaccinia Virus GLV-1h68. Mol. Cancer Ther. 2009, 8, 141–151. [Google Scholar] [CrossRef] [PubMed]
- Dai, M.H.; Liu, S.L.; Chen, N.G.; Zhang, T.P.; You, L.; Zhang, F.; Chou, T.C.; Szalay, A.A.; Fong, Y.; Zhao, Y.P. Oncolytic Vaccinia Virus in Combination with Radiation Shows Synergistic Antitumor Efficacy in Pancreatic Cancer. Cancer Lett. 2014, 344, 282–290. [Google Scholar] [CrossRef] [PubMed]
- Yaghchi, C.; Zhang, Z.; Alusi, G.; Lemoine, N.R.; Wang, Y. Vaccinia Virus, a Promising New Therapeutic Agent for Pancreatic Cancer. Immunotherapy 2015, 7, 1249–1258. [Google Scholar] [CrossRef] [PubMed]
- Downs-Canner, S.; Guo, Z.S.; Ravindranathan, R.; Breitbach, C.J.; O’Malley, M.E.; Jones, H.L.; Moon, A.; McCart, J.A.; Shuai, Y.; Zeh, H.J.; et al. Phase 1 Study of Intravenous Oncolytic Poxvirus (VvDD) in Patients with Advanced Solid Cancers. Mol. Ther. 2016, 24, 1492–1501. [Google Scholar] [CrossRef] [PubMed]
- Chan, W.M.; McFadden, G. Oncolytic Poxviruses. Annu. Rev. Virol. 2014, 1, 191–214. [Google Scholar] [CrossRef] [PubMed]
- Monroe, B.P.; Nakazawa, Y.J.; Reynolds, M.G.; Carroll, D.S. Estimating the Geographic Distribution of Human Tanapox and Potential Reservoirs Using Ecological Niche Modeling. Int. J. Health Geogr. 2014, 13, 34. [Google Scholar] [CrossRef] [PubMed]
- Downie, A.W.; Taylor-Robinson, C.H.; Caunt, A.E.; Nelson, G.S.; Manson-Bahr, P.E.C.; Matthews, T.C.H. Tanapox: A New Disease Caused by a Pox Virus. Br. Med. J. 1971, 1, 363–368. [Google Scholar] [CrossRef] [PubMed]
- Brunetti, C.R.; Amano, H.; Ueda, Y.; Qin, J.; Miyamura, T.; Suzuki, T.; Li, X.; Barrett, J.W.; McFadden, G. Complete Genomic Sequence and Comparative Analysis Of The Tumorigenic Poxvirus Yaba Monkey TumorVirus. J. Virol. 2003, 77, 13335–13347. [Google Scholar] [CrossRef] [PubMed]
- Lee, H.J.; Essani, K.; Smith, G.L. The Genome Sequence of Yaba-like Disease Virus, a Yatapoxvirus. Virology 2001, 281, 170–192. [Google Scholar] [CrossRef] [PubMed]
- Broët, P.; Romain, S.; Daver, A.; Ricolleau, G.; Quillien, V.; Rallet, A.; Asselain, B.; Martin, P.M.; Spyratos, F. Thymidine Kinase as a Proliferative Marker: Clinical Relevance in 1,692 Primary Breast Cancer Patients. J. Clin. Oncol. 2001, 19, 2778–2787. [Google Scholar] [CrossRef] [PubMed]
- Alegre, M.M.; Robison, R.A.; O’Neill, K.L. Thymidine Kinase 1 Upregulation Is an Early Event in Breast Tumor Formation. J. Oncol. 2012, 2012, 1–5. [Google Scholar] [CrossRef] [PubMed]
- Park, B.H.; Hwang, T.; Liu, T.C.; Sze, D.Y.; Kim, J.S.; Kwon, H.C.; Oh, S.Y.; Han, S.Y.; Yoon, J.H.; Hong, S.H.; et al. Use of a Targeted Oncolytic Poxvirus, JX-594, in Patients with Refractory Primary or Metastatic Liver Cancer: A Phase I Trial. Lancet Oncol. 2008, 9, 533–542. [Google Scholar] [CrossRef] [PubMed]
- Hengstschläger, M.; Knöfler, M.; Müllner, E.W.; Ogris, E.; Wintersberger, E.; Wawra, E. Different Regulation of Thymidine Kinase during the Cell Cycle of Normal versus DNA Tumor Virus-Transformed Cells. J. Biol. Chem. 1994, 269, 13836–13842. [Google Scholar] [CrossRef] [PubMed]
- Martuza, R.L.; Malick, A.; Markert, J.M.; Ruffner, K.L.; Coen, D.M. Experimental Therapy of Human Glioma by Means of a Genetically Engineered Virus Mutant. Science 1991, 252, 854–856. [Google Scholar] [CrossRef] [PubMed]
- Kaur, B.; Cripe, T.; Chiocca, E. “Buy One Get One Free”: Armed Viruses for the Treatment of Cancer Cells and Their Microenvironment. Curr. Gene Ther. 2009, 9, 341–355. [Google Scholar] [CrossRef] [PubMed]
- Cattaneo, R.; Miest, T.; Shashkova, E.; Barry, M.A. Reprogrammed Viruses as Cancer Therapeutics: Targeted, Armed and Shielded. Nat. Rev. Microbiol. 2008, 6, 529–540. [Google Scholar] [CrossRef] [PubMed]
- Conrad, S.J.; El-Aswad, M.; Kurban, E.; Jeng, D.; Tripp, B.C.; Nutting, C.; Eversole, R.; Mackenzie, C.; Essani, K. Oncolytic Tanapoxvirus Expressing FliC Causes Regression of Human Colorectal Cancer Xenografts in Nude Mice. J. Exp. Clin. Cancer Res. 2015, 34, 19. [Google Scholar] [CrossRef] [PubMed]
- Zhang, T.; Suryawanshi, Y.R.; Kordish, D.H.; Woyczesczyk, H.M.; Jeng, D.; Essani, K. Tanapoxvirus Lacking a Neuregulin-like Gene Regresses Human Melanoma Tumors in Nude Mice. Virus Genes 2017, 53, 52–62. [Google Scholar] [CrossRef] [PubMed]
- Suryawanashi, Y.R.; Zhang, T.; Woyczesczyk, H.M.; Christie, J.; Byers, E.; Kohler, S.; Eversole, R.; Mackenzie, C.; Essani, K. T-Independent Response Mediated by Oncolytic Tanapoxvirus Recombinants Expressing Interleukin-2 and Monocyte Chemoattractant Protein-1 Suppresses Human Triple Negative Breast Tumors. Med. Oncol. 2017, 34, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Conti, I.; Rollins, B.J. CCL2 (Monocyte Chemoattractant Protein-1) and Cancer. Semin. Cancer Biol. 2004, 14, 149–154. [Google Scholar] [CrossRef] [PubMed]
- Xu, L.L.; Warren, M.K.; Rose, W.L.; Gong, W.; Wang, J.M. Human Recombinant Monocyte Chemotactic Protein and Other C-c Chemokines Bind and Induce Directional Migration of Dendritic Cells in Vitro. J. Leukoc. Biol. 1996, 60, 365–371. [Google Scholar] [CrossRef] [PubMed]
- Collington, S.J.; Hallgren, J.; Pease, J.E.; Jones, T.G.; Rollins, B.J.; Westwick, J.; Austen, K.F.; Williams, T.J.; Gurish, M.F.; Weller, C.L. The Role of the CCL2/CCR2 Axis in Mouse Mast Cell Migration In Vitro and In Vivo. J. Immunol. 2010, 184, 6114–6123. [Google Scholar] [CrossRef] [PubMed]
- Carr, M.W.; Roth, S.J.; Luther, E.; Rose, S.S.; Springer, T.A. Monocyte Chemoattractant Protein 1 Acts as a T-Lymphocyte Chemoattractant. Proc. Natl. Acad. Sci. USA 1994, 91, 3652–3656. [Google Scholar] [CrossRef] [PubMed]
- Lim, S.Y.; Yuzhalin, A.E.; Gordon-Weeks, A.N.; Muschel, R.J. Targeting the CCL2-CCR2 Signaling Axis in Cancer Metastasis. Oncotarget 2016, 7, 28697–28710. [Google Scholar] [CrossRef] [PubMed]
- Parker, J.N.; Meleth, S.; Hughes, K.B.; Gillespie, G.Y.; Whitley, R.J.; Markert, J.M. Enhanced Inhibition of Syngeneic Murine Tumors by Combinatorial Therapy with Genetically Engineered HSV-1 Expressing CCL2 and IL-12. Cancer Gene Ther. 2005, 12, 359–368. [Google Scholar] [CrossRef] [PubMed]
- Monti, P.; Leone, B.E.; Marchesi, F.; Balzano, G.; Zerbi, A.; Scaltrini, F.; Pasquali, C.; Calori, G.; Pessi, F.; Sperti, C.; et al. The CC Chemokine MCP-1/CCL2 in Pancreatic Cancer Progression: Regulation of Expression and Potential Mechanisms of Antimalignant Activity. Cancer Res. 2003, 63, 7451–7461. [Google Scholar] [PubMed]
- Henney, C.S.; Kuribayashi, K.; Kern, D.E.; Gillis, S. Interleukin-2 Augments Natural Killer Cell Activity. Nature 1981, 291, 335–338. [Google Scholar] [CrossRef] [PubMed]
- Liao, W.; Lin, J.X.; Leonard, W.J. IL-2 Family Cytokines: New Insights into the Complex Roles of IL-2 as a Broad Regulator of T Helper Cell Differentiation. Curr. Opin. Immunol. 2011, 23, 598–604. [Google Scholar] [CrossRef]
- Vacchelli, E.; Aranda, F.; Obrist, F.; Eggermont, A.; Galon, J.; Cremer, I.; Zitvogel, L.; Kroemer, G.; Galluzzi, L. Trial Watch: Immunostimulatory Cytokines in Cancer Therapy. OncoImmunology 2014, 3, e29030. [Google Scholar] [CrossRef] [PubMed]
- Zhang, T.; Suryawanshi, Y.R.; Szymczyna, B.R.; Essani, K. Neutralization of Matrix Metalloproteinase-9 Potentially Enhances Oncolytic Efficacy of Tanapox Virus for Melanoma Therapy. Med. Oncol. 2017, 34, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Cheers, C.; Waller, R. Activated Macrophages in Congenitally Athymic “nude” Mice and in Lethally Irradiated Mice. J. Immunol. 1975, 115, 844–847. [Google Scholar] [CrossRef] [PubMed]
- Richmond, A.; Yingjun, S. Mouse Xenograft Models vs GEM Models for Human Cancer Therapeutics. DMM Dis. Models Mech. 2008, 1, 78–82. [Google Scholar] [CrossRef] [PubMed]
- Essani, K.; Dugre, R.; Dales, S. Biogenesis of Vaccinia: Involvement of Spicules of the Envelope during Virion Assembly Examined by Means of Conditional Lethal Mutants and Serology. Virology 1982, 118, 279–292. [Google Scholar] [CrossRef] [PubMed]
- Martin, S.J.; Eisenbarth, J.A.; Wagner-Utermann, U.; Mier, W.; Henze, M.; Pritzkow, H.; Haberkorn, U.; Eisenhut, M. A New Precursor for the Radiosynthesis of [18F]FLT. Nucl. Med. Biol. 2002, 29, 263–273. [Google Scholar] [CrossRef] [PubMed]
- Orlhac, F.; Soussan, M.; Maisonobe, J.A.; Garcia, C.A.; Vanderlinden, B.; Buvat, I. Tumor Texture Analysis in 18F-FDG PET: Relationships between Texture Parameters, Histogram Indices, Standardized Uptake Values, Metabolic Volumes, and Total Lesion Glycolysis. J. Nucl. Med. 2014, 55, 414–422. [Google Scholar] [CrossRef] [PubMed]
- Reynolds, J.C.; Maass-Moreno, R.; Thomas, A.; Ling, A.; Padiernos, E.B.; Steinberg, S.M.; Hassan, R. 18F-FDG PET Assessment of Malignant Pleural Mesothelioma: Total Lesion Volume and Total Lesion Glycolysis—The Central Role of Volume. J. Nucl. Med. 2020, 61, 1570–1575. [Google Scholar] [CrossRef] [PubMed]
- Lee, E.J.; Chang, S.H.; Lee, T.Y.; Yoon, S.Y.; Cheon, Y.K.; Shim, C.S.; So, Y.; Chung, H.W. Prognostic Value of FDG-PET/CT Total Lesion Glycolysis for Patients with Resectable Distal Bile Duct Adenocarcinoma. Anticancer Res. 2015, 35, 6985–6991. [Google Scholar] [PubMed]
- Im, H.J.; Bradshaw, T.; Solaiyappan, M.; Cho, S.Y. Current Methods to Define Metabolic Tumor Volume in Positron Emission Tomography: Which One Is Better? Nucl. Med. Mol. Imaging 2018, 52, 5–15. [Google Scholar] [CrossRef] [PubMed]
- Draper, N.R. Analysis of Messy Data Volume 1: Designed Experiments, Second Edition by George A. Milliken, Dallas E. Johnson. Int. Stat. Rev. 2009, 77, 321–322. [Google Scholar] [CrossRef]
- Royston, P. Approximating the Shapiro-Wilk W-Test for Non-Normality. Stat. Comput. 1992, 2, 117–119. [Google Scholar] [CrossRef]
- Ziegel, E.R.; Littell, R.; Milliken, G.; Stroup, W.; Wolfinger, R. SAS® System for Mixed Models. Technometrics 1997, 39, 344. [Google Scholar] [CrossRef]
- Edwards, D.; Berry, J.J. The Efficiency of Simulation-Based Multiple Comparisons. Biometrics 1987, 43, 913–928. [Google Scholar] [CrossRef] [PubMed]
- Shimada, M.; Andoh, A.; Araki, Y.; Fujiyama, Y.; Bamba, T. Ligation of the Fas Antigen Stimulates Chemokine Secretion in Pancreatic Cancer Cell Line PANC-1. J. Gastroenterol. Hepatol. 2001, 16, 1060–1067. [Google Scholar] [CrossRef] [PubMed]
- Incio, J.; Suboj, P.; Chin, S.M.; Vardam-Kaur, T.; Liu, H.; Hato, T.; Babykutty, S.; Chen, I.; Deshpande, V.; Jain, R.K.; et al. Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages. PLoS ONE 2015, 10, e0141392. [Google Scholar] [CrossRef] [PubMed]
- Xie, K. Interleukin-8 and Human Cancer Biology. Cytokine Growth Factor Rev. 2001, 12, 375–391. [Google Scholar] [CrossRef] [PubMed]
- Solez, K.; Battaglia, D.; Fahmy, H.; Trpkov, K. Pathology of Kidney Transplant Rejection. Curr. Opin. Nephrol. Hypertens. 1993, 2, 904–911. [Google Scholar] [CrossRef] [PubMed]
- Stojicevic, A.; Jovanovic, M.; Matkovic, M.; Nestorovic, E.; Stanojevic, N.; Dozic, B.; Glumac, S. Heart Transplant Rejection Pathology. Vojnosanit. Pregl. 2021, 9, 1073–1077. [Google Scholar] [CrossRef]
- Hafez, G.R.; Gilbert-Barness, E.F. Pathology of Transplant Rejection and Immunosuppressive Therapy: Part I--Graft-vs.-Host Disease and Organ Rejection. Adv. Pediatr. 1990, 37, 307–327. [Google Scholar] [CrossRef] [PubMed]
- Xiu, M.; Liu, Z.; Tang, J. Screening and Identification of Key Regulatory Connections and Immune Cell Infiltration Characteristics for Lung Transplant Rejection Using Mucosal Biopsies. Int. Immunopharmacol. 2020, 87, 106827. [Google Scholar] [CrossRef] [PubMed]
- del Pilar López Panqueva, R. Liver Biopsies in Transplant Pathology: Histopathological Diagnosis and Clinicopathological Correlation in the Early Post-Transplant Period. Rev. Colomb. De Gastroenterol. 2016, 31, 169–179. [Google Scholar] [CrossRef]
Immune System Status | Oncolytic Virotherapy | Mean Tumor Volume (mm3) | SUV | TLG |
---|---|---|---|---|
Immunocompromised | NA—control | 428.62 | 0.165 | 0.048 |
Immunocompromised | TPV/eGFP | 348.68 | 0.227 | 0.041 |
Immunocompromised | TPV/∆66R/m-IL-2/mCherry | 300.44 | 0.281 | 0.029 |
Immunocompromised | TPV/∆66R/m-CCL-2/mCherry | 235.50 | 0.241 | 0.045 |
Immune reconstituted | NA—control | 39.99 | 0.328 | 0.195 |
Immune reconstituted | TPV/eGFP | 117.62 | 0.231 | 0.033 |
Immune reconstituted | TPV/∆66R/m-IL-2/mCherry | 145.87 | 0.333 | 0.033 |
Immune reconstituted | TPV/∆66R/m-CCL-2/mCherry | 168.06 | 0.258 | 0.035 |
Immune System Status | Oncolytic Virotherapy | Mean Tumor Volume (mm3) | SUV | TLP |
---|---|---|---|---|
Immunocompromised | NA—control | 428.62 | 0.959 | 0.404 |
Immunocompromised | TPV/eGFP | 348.68 | 1.14 | 0.237 |
Immunocompromised | TPV/∆66R/m-IL-2/mCherry | 300.44 | 1.16 | 0.139 |
Immunocompromised | TPV/∆66R/m-CCL-2/mCherry | 235.50 | 0.843 | 0.151 |
Immune reconstituted | NA—control | 39.99 | 0.404 | 0.017 |
Immune reconstituted | TPV/eGFP | 117.62 | 0.465 | 0.745 |
Immune reconstituted | TPV/∆66R/m-IL-2/mCherry | 145.87 | 0.454 | 0.051 |
Immune reconstituted | TPV/∆66R/m-CCL-2/mCherry | 168.06 | 0.411 | 0.049 |
Immune System Status | Oncolytic Virotherapy | Mean Tumor Volume (mm3) | Percent Injected Dose/Gram Tissue |
---|---|---|---|
Immunocompromised | NA—control | 428.62 | 1.95 |
Immunocompromised | TPV/eGFP | 348.68 | 3.14 |
Immunocompromised | TPV/∆66R/m-IL-2/mCherry | 300.44 | 2.49 |
Immunocompromised | TPV/∆66R/m-CCL-2/mCherry | 235.50 | 2.09 |
Immune reconstituted | NA—control | 39.99 | 1.22 |
Immune reconstituted | TPV/eGFP | 117.62 | 1.58 |
Immune reconstituted | TPV/∆66R/m-IL-2/mCherry | 145.87 | 1.69 |
Immune reconstituted | TPV/∆66R/m-CCL-2/mCherry | 168.06 | 1.41 |
Immune System Status | Oncolytic Virotherapy | Mean Tumor Volume (mm3) | Nanogram Antibody/Gram Myocardium | Nanogram Antibody/Gram Tumor |
---|---|---|---|---|
Immunocompromised | NA—control | 428.62 | 110 | 441 |
Immunocompromised | TPV/eGFP | 348.68 | 158 | 528 |
Immunocompromised | TPV/∆66R/m-IL-2/mCherry | 300.44 | 38 | 156 |
Immunocompromised | TPV/∆66R/m-CCL-2/mCherry | 235.50 | 36 | 138 |
Immune reconstituted | NA—control | 39.99 | 88 | 325 |
Immune reconstituted | TPV/eGFP | 117.62 | 82 | 281 |
Immune reconstituted | TPV/∆66R/m-IL-2/mCherry | 145.87 | 50 | 149 |
Immune reconstituted | TPV/∆66R/m-CCL-2/mCherry | 168.06 | 48 | 81 |
Treatment | Vehicle | TPV/eGFP | TPV/∆66R/mCCL-2 | TPV/∆66R/mIL-2 |
---|---|---|---|---|
No. Animals per Group | 6 | 6 | 6 | 6 |
Tumor transplant (number examined) | (6) | (6) | (6) | (6) |
Adenocarcinoma; malignant, primary | ||||
Present | 6 | 6 | 6 | 6 |
Caspase positive | ||||
Moderate | - | - | 1 | - |
Marked | 6 | 6 | 5 | 6 |
CD3 positive | ||||
Minimal | 2 | 2 | - | 2 |
Mild | 4 | 4 | 1 | 3 |
Moderate | - | - | 4 | 1 |
Marked | - | - | 1 | - |
CD4 positive | ||||
Minimal | 4 | 5 | - | 5 |
Mild | 2 | - | 4 | 1 |
Moderate | - | - | 2 | - |
CD68 positive | ||||
Minimal | - | - | - | 1 |
Mild | 4 | 5 | 1 | 4 |
Moderate | 2 | 1 | 5 | 1 |
CD8 positive | ||||
Minimal | 2 | 3 | 1 | 1 |
Treatment | Vehicle | TPV/eGFP | TPV/∆66R/mCCL-2 | TPV/∆66R/mIL-2 |
---|---|---|---|---|
No. Animals per Group | 6 | 6 | 6 | 6 |
Tumor transplant (number examined) | (5) | (6) | (6) | (6) |
Adenocarcinoma; malignant, primary | ||||
Present | - | 2 | - | 1 |
Caspase positive | ||||
Minimal | 2 | 2 | - | - |
Moderate | - | 1 | - | - |
Marked | - | 1 | - | 1 |
CD3 positive | ||||
Mild | 1 | 1 | - | - |
Moderate | 3 | 3 | 1 | 2 |
Marked | 1 | 2 | 5 | 4 |
CD4 positive | ||||
Minimal | - | 1 | - | - |
Mild | - | 2 | 1 | 4 |
Moderate | 4 | 3 | 4 | 2 |
Marked | 1 | - | 1 | - |
CD68 positive | ||||
Minimal | - | - | 1 | - |
Mild | - | - | 1 | 1 |
Moderate | - | 5 | 4 | 4 |
Marked | 5 | 1 | - | - |
CD8 positive | ||||
Minimal | 1 | - | - | 1 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Haller, S.D.; Essani, K. Oncolytic Tanapoxvirus Variants Expressing mIL-2 and mCCL-2 Regress Human Pancreatic Cancer Xenografts in Nude Mice. Biomedicines 2024, 12, 1834. https://doi.org/10.3390/biomedicines12081834
Haller SD, Essani K. Oncolytic Tanapoxvirus Variants Expressing mIL-2 and mCCL-2 Regress Human Pancreatic Cancer Xenografts in Nude Mice. Biomedicines. 2024; 12(8):1834. https://doi.org/10.3390/biomedicines12081834
Chicago/Turabian StyleHaller, Scott D., and Karim Essani. 2024. "Oncolytic Tanapoxvirus Variants Expressing mIL-2 and mCCL-2 Regress Human Pancreatic Cancer Xenografts in Nude Mice" Biomedicines 12, no. 8: 1834. https://doi.org/10.3390/biomedicines12081834