Abstract
Swine biomedical models have been gaining in popularity over the last decade, particularly for applications in oncology research. Swine models for cancer research include pigs that have severe combined immunodeficiency for xenotransplantation studies, genetically modified swine models which are capable of developing tumors in vivo, as well as normal immunocompetent pigs. In recent years, there has been a low success rate for the approval of new oncological therapeutics in clinical trials. The two leading reasons for these failures are either due to toxicity and safety issues or lack of efficacy. As all therapeutics must be tested within animal models prior to clinical testing, there are opportunities to expand the ability to assess efficacy and toxicity profiles within the preclinical testing phases of new therapeutics. Most preclinical in vivo testing is performed in mice, canines, and non-human primates. However, swine models are an alternative large animal model for cancer research with similarity to human size, genetics, and physiology. Additionally, tumorigenesis pathways are similar between human and pigs in that similar driver mutations are required for transformation. Due to their larger size, the development of orthotopic tumors is easier than in smaller rodent models; additionally, porcine models can be harnessed for testing of new interventional devices and radiological/surgical approaches as well. Taken together, swine are a feasible option for preclinical therapeutic and device testing. The goals of this resource are to provide a broad overview on regulatory processes required for new therapeutics and devices for use in the clinic, cross-species differences in oncological therapeutic responses, as well as to provide an overview of swine oncology models that have been developed that could be used for preclinical testing to fulfill regulatory requirements.
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References
Adam SJ, Rund LA, Kuzmuk KN et al (2007) Genetic induction of tumorigenesis in Swine. Oncogene 26:1038–1045. https://doi.org/10.1038/sj.onc.1209892
Andrews AR, Wang Z, Wilkinson RA et al (2019) Development of transplantable B-cell lymphomas in the MHC-defined miniature swine model. Cancer Cell Int 19:236. https://doi.org/10.1186/s12935-019-0954-3
Basel MT, Balivada S, Beck AP et al (2012) Human xenografts are not rejected in a naturally occurring immunodeficient porcine line: a human tumor model in pigs. Biores Open Access 1:63–68. https://doi.org/10.1089/biores.2012.9902
Boas FE, Nurili F, Bendet A et al (2020) Induction and characterization of pancreatic cancer in a transgenic pig model. PLoS One 15:e0239391. https://doi.org/10.1371/journal.pone.0239391
Boettcher AN, Cino-Ozuna AG, Solanki Y et al (2020a) CD3ε(+) cells in pigs with severe combined immunodeficiency due to defects in ARTEMIS. Front Immunol 11:510. https://doi.org/10.3389/fimmu.2020.00510
Boettcher AN, Kiupel M, Adur MK et al (2019) Human ovarian cancer tumor formation in Severe Combined Immunodeficient (SCID) Pigs. Front Oncol 9:9
Boettcher AN, Li Y, Ahrens AP et al (2020b) Novel Engraftment and T cell differentiation of human hematopoietic cells in ART (-/-) IL2RG (-/Y) SCID Pigs. Front Immunol 11:100. https://doi.org/10.3389/fimmu.2020.00100
Boettcher AN, Loving CL, Cunnick JE, Tuggle CK (2018) Development of Severe Combined Immunodeficient (SCID) pig models for translational cancer modeling: future insights on how humanized SCID pigs can improve preclinical cancer research. Front Oncol 8:559
Burkina V, Rasmussen MK, Pilipenko N, Zamaratskaia G (2017) Comparison of xenobiotic-metabolising human, porcine, rodent, and piscine cytochrome P450. Toxicology 375:10–27. https://doi.org/10.1016/j.tox.2016.11.014
Chatzistamou I, Farmaki E, Kaza V, Kiaris H (2018) The value of outbred rodent models in cancer research. Trends in Cancer 4:468–471. https://doi.org/10.1016/j.trecan.2018.05.004
Chiodin D, Cox EM, Edmund AV et al (2019) Regulatory affairs 101: introduction to investigational new drug applications and clinical trial applications. Clin Transl Sci 12:334–342. https://doi.org/10.1111/cts.12635
Choi WJ, Moon J-H, Min JS et al (2018) Real-time detection system for tumor localization during minimally invasive surgery for gastric and colon cancer removal: In vivo feasibility study in a swine model. J Surg Oncol 117:699–706. https://doi.org/10.1002/jso.24922
Choi Y-J, Kim E, Reza AMMT, et al (2017) Recombination activating gene-2(null) severe combined immunodeficient pigs and mice engraft human induced pluripotent stem cells differently. Oncotarget 8:69398–69407. https://doi.org/10.18632/oncotarget.20626
Cizkova J, Sinkorova Z, Strnadova K, et al (2019) The role of αβ T-cells in spontaneous regression of melanoma tumors in swine. Dev Comp Immunol 92:60–68. https://doi.org/10.1016/j.dci.2018.10.001
Conlon J, Burdette DL, Sharma S et al (2013) Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J Immunol 190:5216–5225. https://doi.org/10.4049/jimmunol.1300097
Dawson HD, Loveland JE, Pascal G et al (2013) Structural and functional annotation of the porcine immunome. BMC Genomics 14:332. https://doi.org/10.1186/1471-2164-14-332
Dežman R, Čemažar M, Serša G et al (2020) Safety and feasibility of electrochemotherapy of the pancreas in a porcine model. Pancreas 49:1168–1173. https://doi.org/10.1097/MPA.0000000000001642
Donninger H, Hobbing K, Schmidt ML et al (2015) A porcine model system of BRCA1 driven breast cancer. Front Genet 6:269. https://doi.org/10.3389/fgene.2015.00269
Duran-Struuck R, Cho PS, Teague AGS et al (2010) Myelogenous leukemia in adult inbred MHC-defined miniature swine: a model for human myeloid leukemias. Vet Immunol Immunopathol 135:243–256. https://doi.org/10.1016/j.vetimm.2009.12.005
FDA (2018) Immunomagnetic Circulating Cancer Cell Selection and Enumeration System - Class II Special Controls Guidance Document for Industry and FDA Staff
FDA (2017) Medical Devices; Gastroenterology-Urology Devices; Classification of the High Intensity Ultrasound System for Prostate Tissue Ablation
Flisikowska T, Merkl C, Landmann M et al (2012) A porcine model of familial adenomatous polyposis. Gastroenterology 143:1173-1175.e7. https://doi.org/10.1053/j.gastro.2012.07.110
Flisikowska T, Stachowiak M, Xu H et al (2017) Porcine familial adenomatous polyposis model enables systematic analysis of early events in adenoma progression. Sci Rep 7:6613. https://doi.org/10.1038/s41598-017-06741-8
Fogel DB (2018) Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: a review. Contemp Clin Trials Commun 11:156–164. https://doi.org/10.1016/j.conctc.2018.08.001
Gaba RC, Elkhadragy L, Boas FE, et al (2020) Development and comprehensive characterization of porcine hepatocellular carcinoma for translational liver cancer investigation. Oncotarget 11:2686–2701. https://doi.org/10.18632/oncotarget.27647
Gardner HL, Fenger JM, London CA (2016) Dogs as a model for cancer. Annu Rev Anim Biosci 4:199–222. https://doi.org/10.1146/annurev-animal-022114-110911
Groenen MAM, Archibald AL, Uenishi H et al (2012) Analyses of pig genomes provide insight into porcine demography and evolution. Nature 491:393–398. https://doi.org/10.1038/nature11622
Hara H, Shibata H, Nakano K et al (2018) Production and rearing of germ-free X-SCID pigs. Exp Anim 67:139–146. https://doi.org/10.1538/expanim.17-0095
Helke KL, Swindle MM (2013) Animal models of toxicology testing: the role of pigs. Expert Opin Drug Metab Toxicol 9:127–139. https://doi.org/10.1517/17425255.2013.739607
Hendricks-Wenger A, Aycock KN, Nagai-Singer MA et al (2021) Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation. Sci Rep 11:7584. https://doi.org/10.1038/s41598-021-87228-5
Horák V, Fortýn K, Hruban V, Klaudy J (1999) Hereditary melanoblastoma in miniature pigs and its successful therapy by devitalization technique. Cell Mol Biol (Noisy-le-grand) 45:1119–1129
Huang G, Ye X, Yang X et al (2019) Experimental study in vivo ablation of swine pancreas using high-intensity focused ultrasound. J Cancer Res Ther 15:286–290. https://doi.org/10.4103/jcrt.JCRT_986_17
Huang J, Guo X, Fan N et al (2014) RAG1/2 knockout pigs with severe combined immunodeficiency. J Immunol 193:1496–1503. https://doi.org/10.4049/jimmunol.1400915
Ito T, Sendai Y, Yamazaki S et al (2014) Generation of recombination activating gene-1-deficient neonatal piglets: a model of T and B cell deficient severe combined immune deficiency. PLoS One 9:e113833. https://doi.org/10.1371/journal.pone.0113833
Jin J (2014) FDA authorization of medical devices. JAMA 311:435. https://doi.org/10.1001/jama.2013.286274
Kang J-T, Cho B, Ryu J et al (2016) Biallelic modification of IL2RG leads to severe combined immunodeficiency in pigs. Reprod Biol Endocrinol 14:74. https://doi.org/10.1186/s12958-016-0206-5
Kapetanovic R, Fairbairn L, Beraldi D et al (2012) Pig bone marrow-derived macrophages resemble human macrophages in their response to bacterial lipopolysaccharide. J Immunol 188:3382–3394. https://doi.org/10.4049/jimmunol.1102649
Käser T (2021) Swine as biomedical animal model for T-cell research—Success and potential for transmittable and non-transmittable human diseases. Mol Immunol 135:95–115. https://doi.org/10.1016/j.molimm.2021.04.004
Khoshnevis M, Carozzo C, Bonnefont-Rebeix C, et al (2017) Development of induced glioblastoma by implantation of a human xenograft in Yucatan minipig as a large animal model. J Neurosci Methods 282:61–68. https://doi.org/10.1016/j.jneumeth.2017.03.007
Kratkiewicz K, Manwar R, Rajabi-Estarabadi A et al (2019) Photoacoustic/ultrasound/optical coherence tomography evaluation of melanoma lesion and healthy skin in a swine model. Sensors (basel) 19:2815. https://doi.org/10.3390/s19122815
Kurihara T, Matsuda S, Nakamura Y et al (2019) Establishment of a model of sentinel lymph node metastasis using immunodeficient swine. Sci Rep 9:7923. https://doi.org/10.1038/s41598-019-44171-w
Lara PNJ, Douillard J-Y, Nakagawa K et al (2011) Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol off J Am Soc Clin Oncol 29:2965–2971. https://doi.org/10.1200/JCO.2011.35.0660
Lawrence J, Cameron D, Argyle D (2015) Species differences in tumour responses to cancer chemotherapy. Philos Trans R Soc Lond B Biol Sci 370:20140233. https://doi.org/10.1098/rstb.2014.0233
League-Pascual JC, Lester-McCully CM, Shandilya S et al (2017) Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model. J Neurooncol 132:401–407. https://doi.org/10.1007/s11060-017-2388-x
Lee K, Kwon D-N, Ezashi T et al (2014) Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency. Proc Natl Acad Sci U S A 111:7260–7265. https://doi.org/10.1073/pnas.1406376111
Lei S, Ryu J, Wen K et al (2016) Increased and prolonged human norovirus infection in RAG2/IL2RG deficient gnotobiotic pigs with severe combined immunodeficiency. Sci Rep 6:25222. https://doi.org/10.1038/srep25222
Leuchs S, Saalfrank A, Merkl C et al (2012) Inactivation and inducible oncogenic mutation of p53 in gene targeted pigs. PLoS One 7:e43323
Li S, Edlinger M, Saalfrank A et al (2015) Viable pigs with a conditionally-activated oncogenic KRAS mutation. Transgenic Res 24:509–517. https://doi.org/10.1007/s11248-015-9866-8
Maxwell AWP, Park WKC, Baird GL et al (2019) Effects of a thermal accelerant gel on microwave ablation zone volumes in lung: a porcine study. Radiology 291:504–510. https://doi.org/10.1148/radiol.2019181652
Meurens F, Summerfield A, Nauwynck H et al (2012) The pig: a model for human infectious diseases. Trends Microbiol 20:50–57. https://doi.org/10.1016/j.tim.2011.11.002
Millecam J, De Clerck L, Govaert E et al (2018) The ontogeny of cytochrome p450 enzyme activity and protein abundance in conventional pigs in support of preclinical pediatric drug research. Front Pharmacol 9:470
Mishima K, Itano O, Matsuda S et al (2021) Development of human hepatocellular carcinoma in X-linked severe combined immunodeficient pigs: an orthotopic xenograft model. PLoS One 16:e0248352. https://doi.org/10.1371/journal.pone.0248352
Misra SK, Ghoshal G, Gartia MR et al (2015) Trimodal therapy: combining hyperthermia with repurposed bexarotene and ultrasound for treating liver cancer. ACS Nano 9:10695–10718. https://doi.org/10.1021/acsnano.5b05974
Musther H, Olivares-Morales A, Hatley OJD et al (2014) Animal versus human oral drug bioavailability: do they correlate? Eur J Pharm Sci off J Eur Fed Pharm Sci 57:280–291. https://doi.org/10.1016/j.ejps.2013.08.018
Nedelcovych MT, Tenora L, Kim B-H et al (2017) N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-l-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders. J Med Chem 60:7186–7198. https://doi.org/10.1021/acs.jmedchem.7b00966
Nguyen F, Peña L, Ibisch C et al (2018) Canine invasive mammary carcinomas as models of human breast cancer. Part 1: natural history and prognostic factors. Breast Cancer Res Treat 167:635–648. https://doi.org/10.1007/s10549-017-4548-2
Nurili F, Monette S, Michel AO et al (2021) Transarterial embolization of liver cancer in a transgenic pig model. J Vasc Interv Radiol 32:510-517.e3. https://doi.org/10.1016/j.jvir.2020.09.011
Okada S, Vaeteewoottacharn K, Kariya R (2019) Application of highly immunocompromised mice for the establishment of Patient-Derived Xenograft (PDX) models. Cells 8:889. https://doi.org/10.3390/cells8080889
Ortega-Palacios R, Trujillo-Romero CJ, Cepeda Rubio MFJ, et al (2018) Feasibility of using a novel 2.45 GHz double short distance slot coaxial antenna for minimally invasive cancer breast microwave ablation therapy: computational model, phantom, and in vivo swine experimentation. J Healthc Eng 2018:5806753. https://doi.org/10.1155/2018/5806753
Oxenhandler RW, Adelstein EH, Haigh JP et al (1979) Malignant melanoma in the Sinclair miniature swine: an autopsy study of 60 cases. Am J Pathol 96:707–720
Paoloni M, Mazcko C, Selting K et al (2015) Defining the pharmacodynamic profile and therapeutic index of NHS-IL12 immunocytokine in dogs with malignant melanoma. PLoS One 10:e0129954–e0129954. https://doi.org/10.1371/journal.pone.0129954
Park MK, Lee CH, Lee H (2018) Mouse models of breast cancer in preclinical research. Lab Anim Res 34:160–165. https://doi.org/10.5625/lar.2018.34.4.160
Powell EJ, Charley S, Boettcher AN et al (2018) Creating effective biocontainment facilities and maintenance protocols for raising specific pathogen-free, severe combined immunodeficient (SCID) pigs. Lab Anim 52:402–412. https://doi.org/10.1177/0023677217750691
Principe DR, Overgaard NH, Park AJ et al (2018) KRAS(G12D) and TP53(R167H) cooperate to induce pancreatic ductal adenocarcinoma in Sus scrofa pigs. Sci Rep 8:12548. https://doi.org/10.1038/s41598-018-30916-6
Prouteau A, André C (2019) Canine melanomas as models for human melanomas: clinical, histological, and genetic comparison. Genes (basel). https://doi.org/10.3390/genes10070501
Rais R, Jančařík A, Tenora L et al (2016) Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma. J Med Chem 59:8621–8633. https://doi.org/10.1021/acs.jmedchem.6b01069
Rao AD, Shin EJ, Beck SE et al (2018) Demonstration of safety and feasibility of hydrogel marking of the pancreas-duodenum interface for Image Guided Radiation Therapy (IGRT) in a porcine model: implications in IGRT for pancreatic cancer patients. Int J Radiat Oncol Biol Phys 101:640–645. https://doi.org/10.1016/j.ijrobp.2018.02.024
Ren J, Yu D, Fu R et al (2020) IL2RG-deficient minipigs generated via CRISPR/Cas9 technology support the growth of human melanoma-derived tumours. Cell Prolif 53:e12863. https://doi.org/10.1111/cpr.12863
Roberts ZJ, Ching L-M, Vogel SN (2008) IFN-beta-dependent inhibition of tumor growth by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). J Interf Cytokine Res off J Int Soc Interf Cytokine Res 28:133–139. https://doi.org/10.1089/jir.2007.0992
Rowson-Hodel AR, Manjarin R, Trott JF et al (2015) Neoplastic transformation of porcine mammary epithelial cells in vitro and tumor formation in vivo. BMC Cancer 15:562. https://doi.org/10.1186/s12885-015-1572-7
Saalfrank A, Janssen K-P, Ravon M et al (2016) A porcine model of osteosarcoma. Oncogenesis 5:e210–e210. https://doi.org/10.1038/oncsis.2016.19
Sato K, Oiwa R, Kumita W et al (2016) Generation of a nonhuman primate model of severe combined immunodeficiency using highly efficient genome editing. Cell Stem Cell 19:127–138. https://doi.org/10.1016/j.stem.2016.06.003
Schachtschneider KM, Liu Y, Mäkeläinen S et al (2017a) Oncopig soft-tissue sarcomas recapitulate key transcriptional features of human sarcomas. Sci Rep 7:2624. https://doi.org/10.1038/s41598-017-02912-9
Schachtschneider KM, Schwind RM, Darfour-Oduro KA, et al (2017b) A validated, transitional and translational porcine model of hepatocellular carcinoma. Oncotarget 8:63620–63634. https://doi.org/10.18632/oncotarget.18872
Schenk M, Matar AJ, Hanekamp I et al (2019) Development of a transplantable GFP+ B-Cell lymphoma tumor cell line from MHC-Defined miniature swine: potential for a large animal tumor model. Front Oncol 9:209
Schook LB, Collares TV, Darfour-Oduro KA et al (2015a) Unraveling the swine genome: implications for human health. Annu Rev Anim Biosci 3:219–244. https://doi.org/10.1146/annurev-animal-022114-110815
Schook LB, Collares TV, Hu W et al (2015b) A genetic porcine model of cancer. PLoS One 10:e0128864. https://doi.org/10.1371/journal.pone.0128864
Selek L, Seigneuret E, Nugue G et al (2014) Imaging and histological characterization of a human brain xenograft in pig: the first induced glioma model in a large animal. J Neurosci Methods 221:159–165. https://doi.org/10.1016/j.jneumeth.2013.10.002
Sieren JC, Meyerholz DK, Wang X-J et al (2014) Development and translational imaging of a TP53 porcine tumorigenesis model. J Clin Invest 124:4052–4066. https://doi.org/10.1172/JCI75447
Strauss J, Heery CR, Kim JW et al (2019) First-in-human phase I trial of a tumor-targeted cytokine (NHS-IL12) in subjects with metastatic solid tumors. Clin Cancer Res an off J Am Assoc Cancer Res 25:99–109. https://doi.org/10.1158/1078-0432.CCR-18-1512
Suzuki S, Iwamoto M, Hashimoto M et al (2016) Generation and characterization of RAG2 knockout pigs as animal model for severe combined immunodeficiency. Vet Immunol Immunopathol 178:37–49. https://doi.org/10.1016/j.vetimm.2016.06.011
Suzuki S, Iwamoto M, Saito Y, et al (2012) Il2rg gene-targeted severe combined immunodeficiency pigs. Cell Stem Cell 10:753–758. https://doi.org/10.1016/j.stem.2012.04.021
Tan HL, Kim G, Charles CJ et al (2020) Safety, pharmacokinetics and tissue penetration of PIPAC paclitaxel in a swine model. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol. https://doi.org/10.1016/j.ejso.2020.06.031
Tasher D, Dalal I (2012) The genetic basis of severe combined immunodeficiency and its variants. Appl Clin Genet 5:67–80. https://doi.org/10.2147/TACG.S18693
Tora MS, Texakalidis P, Neill S et al (2020) Lentiviral vector induced modeling of high-grade spinal cord glioma in minipigs. Sci Rep 10:5291. https://doi.org/10.1038/s41598-020-62167-9
Van Norman GA (2019) Limitations of animal studies for predicting toxicity in clinical trials: is it time to rethink our current approach? JACC Basic to Transl Sci 4:845–854. https://doi.org/10.1016/j.jacbts.2019.10.008
Velikyan I, Lindhe Ö (2018) Preparation and evaluation of a (68)Ga-labeled RGD-containing octapeptide for noninvasive imaging of angiogenesis: biodistribution in non-human primate. Am J Nucl Med Mol Imaging 8:15–31
Vozenin M-C, De Fornel P, Petersson K, et al (2019) The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients. Clin Cancer Res 25:35–42. https://doi.org/10.1158/1078-0432.CCR-17-3375
Waide EH, Dekkers JCM, Ross JW et al (2015) Not all SCID pigs are created equally: two independent mutations in the artemis gene cause SCID in pigs. J Immunol 195:3171–3179. https://doi.org/10.4049/jimmunol.1501132
Wong CH, Siah KW, Lo AW (2019) Estimation of clinical trial success rates and related parameters. Biostatistics 20:273–286. https://doi.org/10.1093/biostatistics/kxx069
Yin L, Wang X-J, Chen D-X et al (2020) Humanized mouse model: a review on preclinical applications for cancer immunotherapy. Am J Cancer Res 10:4568–4584
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This project was funded by the Office of the Director, the Office of Research Infrastructure Programs, and the National Institutes of Health 5R24OD028748-02.
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KS receives research funding from Guerbet United States LLC, NeoTherma Oncology, and Janssen Research Development LLC. KS is a scientific consultant for Sus Clinicals, Inc. LBS receives research funding from Guerbet United States LLC, and NeoTherma Oncology. LBS is CSO for Sus Clinicals, Inc.
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Boettcher, A.N., Schachtschneider, K.M., Schook, L.B. et al. Swine models for translational oncological research: an evolving landscape and regulatory considerations. Mamm Genome 33, 230–240 (2022). https://doi.org/10.1007/s00335-021-09907-y
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DOI: https://doi.org/10.1007/s00335-021-09907-y