Preclinical safety assessment of MV-s-NAP, a novel oncolytic measles virus strain armed with an H . pylori immunostimulatory bacterial transgene

Kimberly B Viker, Michael B Steele, Ianko D Iankov, Susanna C Concilio, Arun Ammayappan, Brad Bolon, Nathan J Jenks, Matthew P Goetz, Eleni Panagioti, Mark J Federspiel, Minetta C Liu, Kah Whye Peng, Evanthia Galanis, Kimberly B Viker, Michael B Steele, Ianko D Iankov, Susanna C Concilio, Arun Ammayappan, Brad Bolon, Nathan J Jenks, Matthew P Goetz, Eleni Panagioti, Mark J Federspiel, Minetta C Liu, Kah Whye Peng, Evanthia Galanis

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.

Keywords: IFNAR KO-CD46Ge mouse model; MV-s-NAP; NAP; measles; metastatic breast cancer; neutrophil activating protein; oncolytic virus.

Conflict of interest statement

E.G. receives personal compensation as an advisory board member from Kiyatec, Inc., and compensation paid to employer from Karyopharm Therapeutics, Inc. She also receives grant/research/clinical trial funding paid to employer from Servier Pharmaceuticals LLC (formerly Agios Pharmaceuticals, Inc.), Celgene, MedImmune, Inc., and Tracon Pharmaceuticals. K.W.P. and the Mayo Clinic have a financial interest in the technology used in this research. The remaining authors cite no conflicts of interest.

© 2022 Mayo Clinic.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Treatment with MV-s-NAP did not affect body weight Single refers to mice that received one dose of MV-s-NAP and were terminated on day 11 (s.c. group) or day 12 (i.v. group). Multiple refers to mice that received three doses of MV-s-NAP and were terminated on day 56 (s.c. group) or day 54 (i.v. group). Each line represents a single animal in that group. (A) Animal weights in the s.c. single or multiple injection groups that received buffer. (B) Animal weights in the s.c. single or multiple injection groups that received 1x106 MV-s-NAP. (C) Animal weights in the s.c. single or multiple injection groups that received 1x107 MV-s-NAP. (D) Mean and standard deviation of animal weights in the s.c. injected groups. (E) Animal weights in the i.v. single or multiple injection groups that received buffer. (F) Animal weights in the i.v. single or multiple injection groups that received 1x106 MV-s-NAP. (G) Animal weights in the i.v. single or multiple injection groups that received 1x107 MV-s-NAP. (H) Mean and standard deviation of animal weights the i.v. injected groups.
Figure 2
Figure 2
Treatment with MV-s-NAP does not impact hematologic parameters or liver function (A–F) Evaluation of laboratory parameters at the time of scheduled euthanasia included (A) white blood cells, (B) lymphocytes, (C) platelets, (D) alanine aminotransferase (ALT), (E) aspartate aminotransferase (AST), and (F) alkaline phosphatase (ALP). Single (treatment) refers to mice that received one dose of MV-s-NAP and were necropsied on 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 necropsied at day 56 (s.c. group) or 54 (i.v. group). s.c., subcutaneous; i.v., intravenous. Bars indicate group means. Due to the number of potential comparisons, statistical significance is only indicated if p

Figure 3

Treatment with MV-s-NAP does not…

Figure 3

Treatment with MV-s-NAP does not increase circulating levels of pro-inflammatory cytokines in plasma…

Figure 3
Treatment with MV-s-NAP does not increase circulating levels of pro-inflammatory cytokines in plasma Single (treatment) refers to mice that received one dose of MV-s-NAP and were euthanized on day 11 (s.c. group) or day 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 day 54 (i.v. group). Panels A-K depict circulating levels of proinflammatory cytokines in s.c. and i.v. treated mouse groups for both the single and multiple administration schedule. Each panel represents the results for a single cytokine as follows: (A) IL-1β. (B) IL-2. (C) IL-4. (D) IL-5. (E) IL-6. (F) IL-13. (G) IFN-γ. (H) IL-12 p70. (I) GM-CSF. (J) TNF-α. (K) IL-18; s.c., subcutaneous; i.v., intravenous; IFN-γ, interferon gamma; GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF-α, tumor necrosis factor alpha; LOD, limit of detection. Bars indicate group mean. Due to the number of potential comparisons, statistical significance is only indicated if p

Figure 4

Quantification of MV-s-NAP genomes recovered…

Figure 4

Quantification of MV-s-NAP genomes recovered from tissues as detected by quantitative real-time reverse…

Figure 4
Quantification of MV-s-NAP genomes recovered from tissues as detected by quantitative real-time reverse transcription PCR (A) MV-s-NAP genome detection in mice treated via the s.c. route. (B) MV-s-NAP genome detection in mice treated via the i.v. route. Single refers to mice that received one dose of MV-s-NAP and were euthanized on day 11 (s.c. group) or day 12 (i.v. group). Multiple refers to mice that received three doses of MV-s-NAP and were euthanized on day 56 (s.c. group) or day 54 (i.v. group). Each point represents a single mouse with detectable genome copies. LOD, limit of detection: 1,000 copies per μg RNA. Tissue name abbreviations: Ing., inguinal; Inj., injection.

Figure 5

Minor histopathological findings in MV-s-NAP…

Figure 5

Minor histopathological findings in MV-s-NAP treated mice (A) H&E stain of lung tissue.…

Figure 5
Minor histopathological findings in MV-s-NAP treated mice (A) H&E stain of lung tissue. Minimal hemorrhage observed in lungs of a mouse treated with multiple (3) 1 × 106 TCID50 doses of MV-s-NAP via the i.v. route. Asterisks indicate small foci of acute intraalveolar hemorrhage (indicated by intact red blood cells) surrounding small blood vessels. Original objective magnification 20×. (B) H&E stain of injection site skin. Limited possible MV-s-NAP-related effects following s.c. administration in mouse treated with a single 1 × 106 dose MV-s-NAP via the s.c. route. Arrow indicates small foci of mononuclear cell infiltration (i.e., leukocyte accumulation with no damage to the involved tissue) and rarely inflammation (accumulation with damage to the local tissue). Original objective magnification 4×.

Figure 6

Antibody responses to measles virus…

Figure 6

Antibody responses to measles virus and NAP protein Antibody production against MV or…

Figure 6
Antibody responses to measles virus and NAP protein Antibody production against MV or NAP protein was assessed via ELISA. Each pie represents all eight animals in each group. (A) Antibody titers in mice treated via the s.c. route. (B) Antibody titers in mice treated via the i.v. route. Anti-MV antibodies were not assessed in two mice in the single 1 × 106 s.c. dose group due to insufficient serum volume.

Figure 7

Schema of the phase I…

Figure 7

Schema of the phase I clinical trial of intratumoral MV-s-NAP administration to treat…

Figure 7
Schema of the phase I clinical trial of intratumoral MV-s-NAP administration to treat metastatic breast cancer (ClinicalTrials.gov: NCT04521764)
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References
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    1. Nielsen D.L., Andersson M., Kamby C. HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Cancer Treat Rev. 2009;35:121–136. doi: 10.1016/j.ctrv.2008.09.003. - DOI - PubMed
    1. Chia 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;24:1439–1445. doi: 10.1634/theoncologist.2019-0321. - DOI - PMC - PubMed
    1. Mittendorf 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;25:4248–4254. doi: 10.1158/1078-0432.Ccr-18-2867. - DOI - PubMed
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Figure 3
Figure 3
Treatment with MV-s-NAP does not increase circulating levels of pro-inflammatory cytokines in plasma Single (treatment) refers to mice that received one dose of MV-s-NAP and were euthanized on day 11 (s.c. group) or day 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 day 54 (i.v. group). Panels A-K depict circulating levels of proinflammatory cytokines in s.c. and i.v. treated mouse groups for both the single and multiple administration schedule. Each panel represents the results for a single cytokine as follows: (A) IL-1β. (B) IL-2. (C) IL-4. (D) IL-5. (E) IL-6. (F) IL-13. (G) IFN-γ. (H) IL-12 p70. (I) GM-CSF. (J) TNF-α. (K) IL-18; s.c., subcutaneous; i.v., intravenous; IFN-γ, interferon gamma; GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF-α, tumor necrosis factor alpha; LOD, limit of detection. Bars indicate group mean. Due to the number of potential comparisons, statistical significance is only indicated if p

Figure 4

Quantification of MV-s-NAP genomes recovered…

Figure 4

Quantification of MV-s-NAP genomes recovered from tissues as detected by quantitative real-time reverse…

Figure 4
Quantification of MV-s-NAP genomes recovered from tissues as detected by quantitative real-time reverse transcription PCR (A) MV-s-NAP genome detection in mice treated via the s.c. route. (B) MV-s-NAP genome detection in mice treated via the i.v. route. Single refers to mice that received one dose of MV-s-NAP and were euthanized on day 11 (s.c. group) or day 12 (i.v. group). Multiple refers to mice that received three doses of MV-s-NAP and were euthanized on day 56 (s.c. group) or day 54 (i.v. group). Each point represents a single mouse with detectable genome copies. LOD, limit of detection: 1,000 copies per μg RNA. Tissue name abbreviations: Ing., inguinal; Inj., injection.

Figure 5

Minor histopathological findings in MV-s-NAP…

Figure 5

Minor histopathological findings in MV-s-NAP treated mice (A) H&E stain of lung tissue.…

Figure 5
Minor histopathological findings in MV-s-NAP treated mice (A) H&E stain of lung tissue. Minimal hemorrhage observed in lungs of a mouse treated with multiple (3) 1 × 106 TCID50 doses of MV-s-NAP via the i.v. route. Asterisks indicate small foci of acute intraalveolar hemorrhage (indicated by intact red blood cells) surrounding small blood vessels. Original objective magnification 20×. (B) H&E stain of injection site skin. Limited possible MV-s-NAP-related effects following s.c. administration in mouse treated with a single 1 × 106 dose MV-s-NAP via the s.c. route. Arrow indicates small foci of mononuclear cell infiltration (i.e., leukocyte accumulation with no damage to the involved tissue) and rarely inflammation (accumulation with damage to the local tissue). Original objective magnification 4×.

Figure 6

Antibody responses to measles virus…

Figure 6

Antibody responses to measles virus and NAP protein Antibody production against MV or…

Figure 6
Antibody responses to measles virus and NAP protein Antibody production against MV or NAP protein was assessed via ELISA. Each pie represents all eight animals in each group. (A) Antibody titers in mice treated via the s.c. route. (B) Antibody titers in mice treated via the i.v. route. Anti-MV antibodies were not assessed in two mice in the single 1 × 106 s.c. dose group due to insufficient serum volume.

Figure 7

Schema of the phase I…

Figure 7

Schema of the phase I clinical trial of intratumoral MV-s-NAP administration to treat…

Figure 7
Schema of the phase I clinical trial of intratumoral MV-s-NAP administration to treat metastatic breast cancer (ClinicalTrials.gov: NCT04521764)
All figures (8)
Figure 4
Figure 4
Quantification of MV-s-NAP genomes recovered from tissues as detected by quantitative real-time reverse transcription PCR (A) MV-s-NAP genome detection in mice treated via the s.c. route. (B) MV-s-NAP genome detection in mice treated via the i.v. route. Single refers to mice that received one dose of MV-s-NAP and were euthanized on day 11 (s.c. group) or day 12 (i.v. group). Multiple refers to mice that received three doses of MV-s-NAP and were euthanized on day 56 (s.c. group) or day 54 (i.v. group). Each point represents a single mouse with detectable genome copies. LOD, limit of detection: 1,000 copies per μg RNA. Tissue name abbreviations: Ing., inguinal; Inj., injection.
Figure 5
Figure 5
Minor histopathological findings in MV-s-NAP treated mice (A) H&E stain of lung tissue. Minimal hemorrhage observed in lungs of a mouse treated with multiple (3) 1 × 106 TCID50 doses of MV-s-NAP via the i.v. route. Asterisks indicate small foci of acute intraalveolar hemorrhage (indicated by intact red blood cells) surrounding small blood vessels. Original objective magnification 20×. (B) H&E stain of injection site skin. Limited possible MV-s-NAP-related effects following s.c. administration in mouse treated with a single 1 × 106 dose MV-s-NAP via the s.c. route. Arrow indicates small foci of mononuclear cell infiltration (i.e., leukocyte accumulation with no damage to the involved tissue) and rarely inflammation (accumulation with damage to the local tissue). Original objective magnification 4×.
Figure 6
Figure 6
Antibody responses to measles virus and NAP protein Antibody production against MV or NAP protein was assessed via ELISA. Each pie represents all eight animals in each group. (A) Antibody titers in mice treated via the s.c. route. (B) Antibody titers in mice treated via the i.v. route. Anti-MV antibodies were not assessed in two mice in the single 1 × 106 s.c. dose group due to insufficient serum volume.
Figure 7
Figure 7
Schema of the phase I clinical trial of intratumoral MV-s-NAP administration to treat metastatic breast cancer (ClinicalTrials.gov: NCT04521764)

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