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• W4289080147 abstract "Despite recent therapeutic advances, metastatic breast cancer (MBC) remains incurable. Engineered measles virus (MV) constructs based on the attenuated MV Edmonston vaccine platform have demonstrated significant oncolytic activity against solid tumors. The Helicobacter pylori neutrophil-activating protein (NAP) is responsible for the robust inflammatory reaction in gastroduodenal mucosa during bacterial infection. NAP attracts and activates immune cells at the site of infection, inducing expression of pro-inflammatory mediators. We engineered an MV strain to express the secretory form of NAP (MV-s-NAP) and showed that it exhibits anti-tumor and immunostimulatory activity in human breast cancer xenograft models. In this study, we utilized a measles-infection-permissive mouse model (transgenic IFNAR KO-CD46Ge) to evaluate the biodistribution and safety of MV-s-NAP. The primary objective was to identify potential toxic side effects and confirm the safety of the proposed clinical doses of MV-s-NAP prior to a phase I clinical trial of intratumoral administration of MV-s-NAP in patients with MBC. Both subcutaneous delivery (corresponding to the clinical trial intratumoral administration route) and intravenous (worst case scenario) delivery of MV-s-NAP were well tolerated: no significant clinical, laboratory or histologic toxicity was observed. This outcome supports the safety of MV-s-NAP for oncolytic virotherapy of MBC. The first-in-human clinical trial of MV-s-NAP in patients with MBC (ClinicalTrials.gov: NCT04521764) was subsequently activated. Despite recent therapeutic advances, metastatic breast cancer (MBC) remains incurable. Engineered measles virus (MV) constructs based on the attenuated MV Edmonston vaccine platform have demonstrated significant oncolytic activity against solid tumors. The Helicobacter pylori neutrophil-activating protein (NAP) is responsible for the robust inflammatory reaction in gastroduodenal mucosa during bacterial infection. NAP attracts and activates immune cells at the site of infection, inducing expression of pro-inflammatory mediators. We engineered an MV strain to express the secretory form of NAP (MV-s-NAP) and showed that it exhibits anti-tumor and immunostimulatory activity in human breast cancer xenograft models. In this study, we utilized a measles-infection-permissive mouse model (transgenic IFNAR KO-CD46Ge) to evaluate the biodistribution and safety of MV-s-NAP. The primary objective was to identify potential toxic side effects and confirm the safety of the proposed clinical doses of MV-s-NAP prior to a phase I clinical trial of intratumoral administration of MV-s-NAP in patients with MBC. Both subcutaneous delivery (corresponding to the clinical trial intratumoral administration route) and intravenous (worst case scenario) delivery of MV-s-NAP were well tolerated: no significant clinical, laboratory or histologic toxicity was observed. This outcome supports the safety of MV-s-NAP for oncolytic virotherapy of MBC. The first-in-human clinical trial of MV-s-NAP in patients with MBC (ClinicalTrials.gov: NCT04521764) was subsequently activated. Breast cancer is the most common malignancy in women and also the second leading cause of female cancer mortality in the United States.1Bray 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 Cancer J. Clin. 2018; 68: 394-424https://doi.org/10.3322/caac.21492Crossref PubMed Scopus (45651) Google Scholar Despite the availability of a growing therapeutic arsenal of biologic and chemical agents including endocrine therapy, chemotherapy, targeted agents, and immunotherapy, metastatic breast cancer (MBC) remains incurable.2Sledge G.W. Mamounas E.P. Hortobagyi G.N. Burstein H.J. Goodwin P.J. Wolff A.C. Past, present, and future challenges in breast cancer treatment.J. Clin. Oncol. 2014; 32: 1979-1986https://doi.org/10.1200/jco.2014.55.4139Crossref PubMed Scopus (0) Google Scholar,3Nielsen D.L. Andersson M. Kamby C. HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors.Cancer Treat Rev. 2009; 35: 121-136https://doi.org/10.1016/j.ctrv.2008.09.003Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar The field of immunotherapy is expanding quickly throughout oncology, but to date, breast cancer studies focused on vaccines and immune checkpoint antagonists have achieved only modest success, with the only notable exception being the recent approval of an anti-PD1 antibody for a subgroup of triple negative breast cancer patients.4Chia S. Bedard P.L. Hilton J. Amir E. Gelmon K. Goodwin R. Villa D. Cabanero M. Tu D. Tsao M. Seymour L. A phase ib trial of durvalumab in combination with trastuzumab in HER2-positive metastatic breast cancer (CCTG IND.229).Oncologist. 2019; 24: 1439-1445https://doi.org/10.1634/theoncologist.2019-0321Crossref PubMed Scopus (26) Google Scholar, 5Mittendorf E.A. Lu B. Melisko M. Price Hiller J. Bondarenko I. Brunt A.M. Sergii G. Petrakova K. Peoples G.E. Efficacy and safety analysis of nelipepimut-S vaccine to prevent breast cancer recurrence: a randomized, multicenter, phase III clinical trial.Clin. Cancer Res. 2019; 25: 4248-4254https://doi.org/10.1158/1078-0432.Ccr-18-2867Crossref PubMed Scopus (0) Google Scholar, 6Loi S. Giobbie-Hurder A. Gombos A. Bachelot T. Hui R. Curigliano G. Campone M. Biganzoli L. Bonnefoi H. Jerusalem G. et al.Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.Lancet Oncol. 2019; 20: 371-382https://doi.org/10.1016/s1470-2045(18)30812-xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar To date, only one oncolytic virus platform, a herpes simplex virus 1 (HSV-1) construct engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF) (talimogene laherparepvec [T-VEC]), is commercially available for treatment of solid tumors in the United States and Europe.7Doniņa S. Strēle I. Proboka G. Auziņš J. Alberts P. Jonsson B. Venskus D. Muceniece A. Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study.Melanoma Res. 2015; 25: 421-426https://doi.org/10.1097/cmr.0000000000000180Crossref PubMed Scopus (0) Google Scholar, 8Xia Z.J. Chang J.H. Zhang L. Jiang W.Q. Guan Z.Z. Liu J.W. Zhang Y. Hu X.H. Wu G.H. Wang H.Q. et al.[Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus].Ai Zheng. 2004; 23: 1666-1670PubMed Google Scholar, 9Andtbacka R.H. 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: 2780-2788https://doi.org/10.1200/jco.2014.58.3377Crossref PubMed Scopus (0) Google Scholar Intratumoral injection of T-VEC (Imlygic) has resulted in single-agent efficacy in patients with recurrent melanoma with a favorable adverse-effect profile.9Andtbacka R.H. 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: 2780-2788https://doi.org/10.1200/jco.2014.58.3377Crossref PubMed Scopus (0) Google Scholar, 10Ribas A. Dummer R. Puzanov I. VanderWalde A. Andtbacka R.H.I. Michielin O. Olszanski A.J. Malvehy J. Cebon J. Fernandez E. et al.Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy.Cell. 2017; 170: 1109-1119.e10https://doi.org/10.1016/j.cell.2017.08.027Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar, 11Chesney J. Puzanov I. Collichio F. Singh P. Milhem M.M. Glaspy J. Hamid O. Ross M. Friedlander P. Garbe C. et al.Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma.J. Clin. Oncol. 2018; 36: 1658-1667https://doi.org/10.1200/jco.2017.73.7379Crossref PubMed Scopus (0) Google Scholar Case reports of patients with breast cancer included in phase I trials of oncolytic virotherapy suggest the potential of clinical benefit from this approach.12Hu J.C. Coffin R.S. Davis C.J. Graham N.J. Groves N. Guest P.J. Harrington K.J. James N.D. Love C.A. McNeish I. et al.A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor.Clin. Cancer Res. 2006; 12: 6737-6747https://doi.org/10.1158/1078-0432.Ccr-06-0759Crossref PubMed Scopus (0) Google Scholar, 13Kimata H. Imai T. Kikumori T. Teshigahara O. Nagasaka T. Goshima F. Nishiyama Y. Nakao A. Pilot study of oncolytic viral therapy using mutant herpes simplex virus (HF10) against recurrent metastatic breast cancer.Ann. Surg Oncol. 2006; 13: 1078-1084https://doi.org/10.1245/aso.2006.08.035Crossref PubMed Scopus (0) Google Scholar, 14Bernstein V. Ellard S.L. Dent S.F. Tu D. Mates M. Dhesy-Thind S.K. Panasci L. Gelmon K.A. Salim M. Song X. et al.A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group.Breast Cancer Res. Treat. 2018; 167: 485-493https://doi.org/10.1007/s10549-017-4538-4Crossref PubMed Scopus (34) Google Scholar, 15Zeh H.J. Downs-Canner S. McCart J.A. Guo Z.S. Rao U.N. Ramalingam L. Thorne S.H. Jones H.L. Kalinski P. Wieckowski E. et al.First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity.Mol. Ther. 2015; 23: 202-214https://doi.org/10.1038/mt.2014.194Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 16Laurie S.A. Bell J.C. Atkins H.L. Roach J. Bamat M.K. O'Neil J.D. Roberts M.S. Groene W.S. Lorence R.M. A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization.Clin. Cancer Res. 2006; 12: 2555-2562https://doi.org/10.1158/1078-0432.Ccr-05-2038Crossref PubMed Scopus (0) Google Scholar We hypothesized that rational development of oncolytic platforms with activity against breast cancer, such as measles virus (MV), can create novel, potent therapies against this disease. MV is an enveloped paramyxovirus with a negative-sense single-stranded RNA genome. Wild-type MV enters cells by binding of its hemagglutinin (HA) attachment protein to one of two cellular receptors: Nectin-4 or signaling lymphocyte activation molecule (SLAM). The live, attenuated, non-pathogenic MV Edmonston vaccine strain (MV-Edm) enters cells using any of three known receptors, CD46, SLAM, or Nectin-4. Both CD46 and Nectin-4 expression is upregulated on breast cancer cells.17Noyce R.S. Richardson C.D. Nectin 4 is the epithelial cell receptor for measles virus.Trends Microbiol. 2012; 20: 429-439https://doi.org/10.1016/j.tim.2012.05.006Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar MV-Edm infection of cancer cells leads to extensive intercellular fusion (syncytia) followed by cell death.18Li H. Peng K.W. Dingli D. Kratzke R.A. Russell S.J. Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy.Cancer Gene Ther. 2010; 17: 550-558https://doi.org/10.1038/cgt.2010.10Crossref PubMed Scopus (95) Google Scholar MV-Edm causes minimal or no cytopathic effect in non-transformed cells.19Anderson B.D. Nakamura T. Russell S.J. Peng K.W. High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus.Cancer Res. 2004; 64: 4919-4926https://doi.org/10.1158/0008-5472.Can-04-0884Crossref PubMed Scopus (0) Google Scholar Engineered MV constructs based on the attenuated MV-Edm strain have demonstrated oncolytic properties and significant anti-tumor activity against multiple solid tumors in vitro and in vivo.20Msaouel P. Opyrchal M. Dispenzieri A. Peng K.W. Federspiel M.J. Russell S.J. Galanis E. Clinical trials with oncolytic measles virus: current status and future prospects.Curr. Cancer Drug Targets. 2018; 18: 177-187https://doi.org/10.2174/1568009617666170222125035Crossref PubMed Scopus (75) Google Scholar In addition, MV-Edm has an outstanding safety record with millions of doses administered annually for human immunization against measles.21Phuong L.K. Allen C. Peng K.W. Giannini C. Greiner S. TenEyck C.J. Mishra P.K. Macura S.I. Russell S.J. Galanis E.C. Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme.Cancer Res. 2003; 63: 2462-2469PubMed Google Scholar Few severe adverse events and no cases of subacute sclerosing panencephalitis (SSPE), a rare fatal complication of wild-type MV infection, have been reported as a result of vaccination with MV-Edm.22Baldo A. Galanis E. Tangy F. Herman P. Biosafety considerations for attenuated measles virus vectors used in virotherapy and vaccination.Hum. Vaccin. Immunother. 2016; 12: 1102-1116https://doi.org/10.1080/21645515.2015.1122146Crossref PubMed Scopus (27) Google Scholar, 23Griffin D.E. Pan C.H. Measles: old vaccines, new vaccines.Curr. Top. Microbiol. Immunol. 2009; 330: 191-212https://doi.org/10.1007/978-3-540-70617-5_10Crossref PubMed Scopus (54) Google Scholar, 24Miller C. Andrews N. Rush M. Munro H. Jin L. Miller E. The epidemiology of subacute sclerosing panencephalitis in England and Wales 1990-2002.Arch. Dis. Child. 2004; 89: 1145-1148https://doi.org/10.1136/adc.2003.038489Crossref PubMed Scopus (40) Google Scholar Bacterial cell-wall components and released intracellular factors are potent immunostimulators that have been evaluated as adjuvant components in formulated vaccines.25Maisonneuve C. Bertholet S. Philpott D.J. De Gregorio E. Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants.Prod. Natl. Acad. Sci. USA. 2014; 111: 12294-12299https://doi.org/10.1073/pnas.1400478111Crossref PubMed Scopus (199) Google Scholar Helicobacter pylori neutrophil-activating protein (NAP) is a key trigger of the robust inflammatory reaction observed in the gastroduodenal mucosa following H. pylori infection. NAP attracts innate immune cells such as neutrophils and macrophages to the site of infection and promotes production of reactive oxygen species (ROS) and expression of many pro-inflammatory mediators.26Polenghi A. Bossi F. Fischetti F. Durigutto P. Cabrelle A. Tamassia N. Cassatella M.A. Montecucco C. Tedesco F. de Bernard M. The neutrophil-activating protein of Helicobacter pylori crosses endothelia to promote neutrophil adhesion in vivo.J. Immunol. 2007; 178: 1312-1320https://doi.org/10.4049/jimmunol.178.3.1312Crossref PubMed Scopus (75) Google Scholar,27Satin B. Del Giudice G. Della Bianca V. Dusi S. Laudanna C. Tonello F. Kelleher D. Rappuoli R. Montecucco C. Rossi F. The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor.J. Exp. Med. 2000; 191: 1467-1476https://doi.org/10.1084/jem.191.9.1467Crossref PubMed Scopus (263) Google Scholar As a potent Toll-like receptor 2 (TLR2) agonist, NAP stimulates the release of T helper type 1 (Th1) cytokines, including interleukin-12 (IL-12) and IL-23, and chemokines, thereby inducing Th1-type polarization of the immune response.28Amedei A. Cappon A. Codolo G. Cabrelle A. Polenghi A. Benagiano M. Tasca E. Azzurri A. D'Elios M.M. Del Prete G. de Bernard M. The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses.J. Clin. Invest. 2006; 116: 1092-1101https://doi.org/10.1172/jci27177Crossref PubMed Scopus (0) Google Scholar,29Iankov I.D. Federspiel M.J. Galanis E. Measles virus expressed Helicobacter pylori neutrophil-activating protein significantly enhances the immunogenicity of poor immunogens.Vaccine. 2013; 31: 4795-4801https://doi.org/10.1016/j.vaccine.2013.07.085Crossref PubMed Scopus (11) Google Scholar Our laboratory has cloned the secretory form of NAP (s-NAP) into MV-Edm, and in proof-of-principle studies, we have demonstrated the anti-tumor activity of MV constructs and MV-s-NAP against both subcutaneous models and a mouse pleural effusion model of MBC.30Iankov I.D. Penheiter A.R. Carlson S.K. Galanis E. Development of monoclonal antibody-based immunoassays for detection of Helicobacter pylori neutrophil-activating protein.J. Immunol. Methods. 2012; 384: 1-9https://doi.org/10.1016/j.jim.2012.06.010Crossref PubMed Scopus (13) Google Scholar, 31Iankov I.D. Kurokawa C.B. D'Assoro A.B. Ingle J.N. Domingo-Musibay E. Allen C. Crosby C.M. Nair A.A. Liu M.C. Aderca I. et al.Inhibition of the Aurora A kinase augments the anti-tumor efficacy of oncolytic measles virotherapy.Cancer Gene Ther. 2015; 22: 438-444https://doi.org/10.1038/cgt.2015.36Crossref PubMed Scopus (17) Google Scholar, 32Iankov I.D. Msaouel P. Allen C. Federspiel M.J. Bulur P.A. Dietz A.B. Gastineau D. Ikeda Y. Ingle J.N. Russell S.J. Galanis E. Demonstration of anti-tumor activity of oncolytic measles virus strains in a malignant pleural effusion breast cancer model.Breast Cancer Res. Treat. 2010; 122: 745-754https://doi.org/10.1007/s10549-009-0602-zCrossref PubMed Scopus (56) Google Scholar, 33McDonald C.J. Erlichman C. Ingle J.N. Rosales G.A. Allen C. Greiner S.M. Harvey M.E. Zollman P.J. Russell S.J. Galanis E. A measles virus vaccine strain derivative as a novel oncolytic agent against breast cancer.Breast Cancer Res. Treat. 2006; 99: 177-184https://doi.org/10.1007/s10549-006-9200-5Crossref PubMed Scopus (74) Google Scholar NAP expression by infected tumor cells in these models resulted in the induction of a strong Th1 immune response with increased levels of pro-inflammatory cytokines such as IL-12/-23, IL-6, and tumor necrosis factor alpha (TNF-α) in pleural fluid and IL-6 in serum. No toxicity was observed in these models.30Iankov I.D. Penheiter A.R. Carlson S.K. Galanis E. Development of monoclonal antibody-based immunoassays for detection of Helicobacter pylori neutrophil-activating protein.J. Immunol. Methods. 2012; 384: 1-9https://doi.org/10.1016/j.jim.2012.06.010Crossref PubMed Scopus (13) Google Scholar Prior to clinical translation of a first-in-human trial of MV-s-NAP in MBC (ClinicalTrials.gov: NCT04521764; principal investigator [PI]: M.C.L.), we performed preclinical toxicity studies to examine the biodistribution and evaluate the safety of the MV-s-NAP platform in measles replication-susceptible IFNAR KO-CD46Ge mice. These animals have a targeted mutation inactivating the interferon-α/β receptor (IFNAR) and express the human CD46 gene in a distribution that mimics the distribution in humans.34Mrkic B. Pavlovic J. Rülicke T. Volpe P. Buchholz C.J. Hourcade D. Atkinson J.P. Aguzzi A. Cattaneo R. Measles virus spread and pathogenesis in genetically modified mice.J. Virol. 1998; 72: 7420-7427https://doi.org/10.1128/jvi.72.9.7420-7427.1998Crossref PubMed Scopus (246) Google Scholar Although murine cells are not infectable by MV, this transgenic model allows MV infection and propagation and has been accepted by the US Food and Drug Administration (FDA) as a small-animal toxicology model in support of human trials for oncolytic MV strains. The primary objective of this study was to define the highest dose of injected MV-s-NAP that will not result in toxicity, when the virus is administered locally within the subcutaneous tissues, which mimics as closely as possible the direct intratumoral route of administration proposed in the clinical trial. Due to intact T and B cell immunity, IFNAR KO-CD46Ge mice do not allow the growth of human tumor xenografts; as such, toxicology testing of oncolytic MV strains in MV-replication-permissive tumor-bearing mice is not possible. Per FDA’s recommendation, intravenous administration was added to this toxicity study in order to address a “worst-case” scenario in which the virus would gain access to the bloodstream and spread systemically. Here, we report that both subcutaneous (s.c.) and intravenous (i.v.) delivery of MV-s-NAP, an oncolytic MV construct expressing the immunostimulatory s-NAP transgene, were well tolerated and resulted in minimal histopathologic abnormalities in vivo. This outcome supports the in vivo safety of this agent and led to activation of the first-in-human trial for clinical investigation of the MV-s-NAP platform in patients with MBC. A detailed description of the study design is included in the materials and methods and in Table 1. In summary, mice received either a single virus treatment or three virus treatments over a 28-day period. For each treatment schedule cohort, 8 mice per group received either buffer (control) or MV-s-NAP at either 1 × 106 median tissue culture infectious dose (TCID50) or 1 × 107 TCID50 by either the s.c. or i.v. route for a total of 96 animals. Virus-treated mice that received a single dose were euthanized on day 11 or 12. Mice that received multiple (3) doses were euthanized on day 54 or 56. The 1 × 107 TCID50 dose in this toxicology study is equivalent to 350× the initial proposed dose in the human trial. The 2-week repeat administration schedule in the toxicology study versus 3 weeks in the human trial was chosen in order to increase dose intensity and simulate a worst-case scenario.Table 1Toxicology study design and treatment groups assessed in this studyGroup nameBuffer s.c.MV-s-NAP (1 × 106 s.c.)MV-s-NAP (1 × 107 s.c.)Buffer IVMV-s-NAP (1 × 106 i.v.)MV-s-NAP (1 × 107 i.v.)TreatmentbufferMV-s-NAPMV-s-NAPbufferMV-s-NAPMV-s-NAPDose (TCID50)NA1 × 1061 × 107NA1 × 1061 × 107Dose routes.c.s.c.s.c.i.v.i.v.i.v.SingleNumber of doses111111Number of mice888888Harvest day111111121212MultipleNumber of doses333333Number of mice888888Harvest day565656545454Single (treatment) refers to mice that received one dose of MV-s-NAP and were euthanized at day 11 (s.c. group) or 12 (i.v. group). Multiple (treatments) refers to mice that received three doses of MV-s-NAP and were euthanized on day 56 (s.c. group) or 54 (i.v. group). MV-s-NAP doses are presented as amount (1 × 106 [1 × 106] or 1 × 107 [1 × 107]) relative to the 50% tissue culture infectious dose (TCID50). s.c., subcutaneous; i.v., intravenous; NA, not applicable. Open table in a new tab Single (treatment) refers to mice that received one dose of MV-s-NAP and were euthanized at day 11 (s.c. group) or 12 (i.v. group). Multiple (treatments) refers to mice that received three doses of MV-s-NAP and were euthanized on day 56 (s.c. group) or 54 (i.v. group). MV-s-NAP doses are presented as amount (1 × 106 [1 × 106] or 1 × 107 [1 × 107]) relative to the 50% tissue culture infectious dose (TCID50). s.c., subcutaneous; i.v., intravenous; NA, not applicable. All groups were observed for clinical signs of toxicity, and body weight was measured at least 5 times per week for the duration of the study. Animal weights remained stable throughout the study (Figure 1). All mice were observed to be clinically normal throughout the experiment, and all animals survived to the end of the study. These results indicate that both a single dose and intermittently repeated treatments with MV-s-NAP do not induce clinically adverse health effects. Hematologic analysis of non-clotted whole blood consisted of an automated complete blood count (CBC) with differential cell count were obtained at the time of euthanasia. Blood cell parameters, including the number of white blood cells (WBCs), lymphocytes (LYMs), and platelets (PLTs) that would be expected to be impacted by an active viral infection, were not significantly different compared with control groups (Figure 2). These results indicate that MV-s-NAP treatment does not negatively impact hematologic function. Clinical chemistry analysis of plasma samples was obtained at the time of euthanasia to evaluate potential liver and kidney toxicity, electrolytes, calcium, and glucose. Plasma activities of alkaline phosphatase (ALP) and alanine and aspartate aminotransferases (ALT and AST, respectively) were within normal limits for the animals that received MV-s-NAP, with a few exceptions: one mouse (of 8) in the single-dose s.c. group at day 11 showed elevated ALT, and two mice (of 8) in the multiple-dose i.v. group at day 54 exhibited higher ALT and AST activities. These altered values in individual mice were associated with hemolysis during collection of blood, which can interfere with liver enzyme analysis. All other serum chemical parameters were normal. These results indicate that MV-s-NAP treatment does not significantly impact liver or kidney function or other key metabolic processes (Figure 2). A multiplex assay (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-12, IL-13, IL-18, IFN-γ, GM-CSF, and TNF-α) was performed to determine the possible effect of single or multiple doses of MV-s-NAP on immunostimulatory cytokine expression. This analysis was performed to ensure that the immunostimulatory potential of NAP did not lead to an adverse systemic pro-inflammatory cytokine response (i.e., a “cytokine storm”). A systemic pro-inflammatory response was not observed in any of the groups treated with MV-s-NAP. In addition, the majority of samples for control and treated animals tested below the limit of detection (LOD) for the assay. Detectable cytokine expression was limited to IL-18 (following i.v. and s.c. administration) and TNF-α (after i.v. delivery only). However, plasma cytokine expression levels of both IL-18 and TNF-α were comparable between control and treated mice (Figure 3). Gene expression of MV-nucleocapsid protein RNA (MV-N), by quantitative real-time reverse transcription PCR of total RNA, was performed to assess viral distribution following s.c. or i.v. administration (Figure 4). As expected, expression following s.c. (local) injection was primarily found near the site of administration. In contrast, viral genomes were detected in several organs following i.v. (systemic) injection. S.c. administration of the MV-s-NAP, which was conducted to simulate the proposed intratumoral route of administration in clinical trial patients, resulted in low viral-genome copy numbers (close to the assay detection limits) on day 11 in the inguinal lymph nodes (i.e., the regional lymphoid organ closest to the injection site) of 2–3 (of 8) animals that received a single injection. No animals in the high-dose s.c. group had detectable MV RNA on day 56 after three MV-s-NAP SC injections (the last of which occurred on day 28). Administration of the MV-s-NAP via the i.v. route resulted in the detection of viral genomes in most organs on day 11 (after one injection) in both the low- and high-dose groups. Among animals that received three virus injections, the low-dose mice had detectable MV-s-NAP genomes in brain (2/8 animals), lung (2/8 animals), liver (2/8 animals), spleen (8/8 animals), kidney, heart, spinal cord, ovary, bone marrow, small intestine, and large intestine (1/8 animals) on day 54. There were no detectable viral copy numbers in the inguinal lymph nodes or the stomach. Following three virus injections in the high-dose i.v. group, viral genomes were detected in multiple organs but not in the gastrointestinal (GI) tract, i.e., stomach, small intestine, or large intestine. Two main changes occurred following MV-s-NAP administration: limited acute hemorrhage in the lung and leukocyte infiltration or inflammation in skin at the s.c. injection site. Hemorrhage in the lung occurred as one or a few small regions of erythrocyte accumulation in randomly dispersed alveoli (Figure 5A ). This change was always of minimal (i.e., one or two foci comprised of 2–4 affected alveoli per lobe) or occasionally mild (i.e., three to five foci comprised of 5–10 affected alveoli per lobe) severity. The involved alveoli typically contained, but were not occluded by blood, indicating that neither airway patency nor lung function was compromised; moreover, affected alveoli exhibited no evidence of cell disruption impacting either capillary endothelium or pneumocytes. Following s.c. injection, this finding was observed at minimal severity at day 11 in 1–2 mice in both dose groups. No hemorrhage was observed on day 56. Following i.v. injection, this change was seen on day 11 in 1 (of 8) animal which received the high viral dose and on day 54 in 5 (of 8) low-dose mice and 1 (of 8) high-dose animal. A possible explanation for this finding in only a few treated animals, independent of dose level and route of administration, is the use of carbon dioxide in euthanasia (which commonly produces focal agonal alveolar hemorrhage in rodents as an incidental artifact).35McKevitt T.P. Lewis D.J. Respiratory system.in: Sahota P.S. Popp J.A. Bouchard P.R. Hardisty J.F. Gopinath C. Toxicologic Pathology: Nonclinical Safety Assessment. Second edition. CRC Press (Taylor & Francis), 2019: 515-567Google Scholar Still, these changes were limited, transient, self-resolving, and they were not associated with clinical signs of toxicity at any time point. At the MV-s-NAP s.c. injection site, mononuclear cell infiltration (i.e., groups of leukocytes, usually lymphocytes and occasional macrophages, without any damage to the resident tissue) and inflammation (i.e., groups of leukocytes, typically a mixture of mononuclear cells and a few neutrophils resulting in limited damage to the injected tissue), were localized to the deep dermis and subcutis in 1 or 2 animals per 8 animal group (Figure 5B)." @default.
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• W4289080147 date "2022-09-01" @default.
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• W4289080147 title "Preclinical safety assessment of MV-s-NAP, a novel oncolytic measles virus strain armed with an H. pylori immunostimulatory bacterial transgene" @default.
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• W4289080147 doi "https://doi.org/10.1016/j.omtm.2022.07.014" @default.
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