IP Library › Granted Patent US 12,257,278
Granted Patent B2
US 12,257,278 · App. 17/259,849 · Granted Mar 25, 2025

Methods of treating cancer with TNF expressing myxoma virus

Inventors: Douglas Grant McFadden (Tempe, AZ); John Christie (Portage, MI); Joseph Blattman (Scottsdale, AZ); Mohammed Masmudur Rahman (Chandler, AZ); Nancy Yaneth Villa (Scottsdale, AZ)
Assignee: Arizona Board of Regents on behalf of Arizona State University
A61K35/768A61K35/14A61K35/28A61K45/06A61P35/00C07K14/525
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,257,278
App. No.
17/259,849
Granted
Mar 25, 2025
Kind
B2
Abstract

Disclosed herein, in certain embodiments, is a method of inhibiting or treating a cancer with use of a TNF expressing myxoma virus. Also disclosed herein are methods of inhibiting or treating a cancer with use of a mononuclear peripheral blood cells and/or a bone marrow cells treated with a TNF-expressing myxoma virus. Some aspects relate to engineered myxoma virus and pharmaceutical compositions for use with one or more of the methods described herein.

Claims (15)

1. A pharmaceutical composition comprising a myxoma virus (MYXV) and a pharmaceutically-acceptable excipient, wherein the MYXV is engineered to express a tumor necrosis factor (TNF) protein, wherein a gene encoding the TNF protein is inserted between M134 gene and M136 gene within the MYXV genome.

2. The pharmaceutical composition of claim 1 , wherein the TNF protein is a TNF alpha protein.

3. The pharmaceutical composition of claim 1 , wherein the TNF protein is a cell surface expressed TNF protein.

4. The pharmaceutical composition of claim 1 , wherein the TNF protein is secreted by cells infected by the MYXV.

5. The pharmaceutical composition of claim 1 , wherein the TNF protein is a human TNF protein.

6. The pharmaceutical composition of claim 1 , wherein the MYXV is a genetically modified Laussane strain MYXV.

7. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for systemic administration.

8. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for local administration.

9. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for parenteral administration.

10. The pharmaceutical composition of claim 1 , wherein the MYXV is capable of directly killing cancer cells infected by the MYXV and eliciting off-target killing of uninfected cancer cells.

11. The pharmaceutical composition of claim 10 , wherein the MYXV exhibits enhanced off-target killing of uninfected cancer cells as compared to a MYXV that is not engineered to express the TNF protein.

12. A composition comprising peripheral blood mononuclear cells (PBMCs), bone marrow (BM) cells, or a combination thereof treated ex vivo by a myxoma virus (MYXV) engineered to express a tumor necrosis factor (TNF) protein, wherein a gene encoding the TNF protein is inserted between M134 gene and M136 gene within the MYXV genome.

13. The composition of claim 12 , wherein the MYXV comprises a modification within or adjacent to one or more genes associated with rabbit cell tropism.

14. The composition of claim 12 , wherein the MYXV comprises a modification of M135R that impairs function of the M135R.

15. A method of inhibiting or treating a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a myxoma virus (MYXV) and a pharmaceutically-acceptable excipient, wherein the MYXV is engineered to express a tumor necrosis factor (TNF) protein, wherein a gene encoding the TNF protein is inserted between M134 gene and M136 gene within the MYXV genome.

Assignments (2)
CONFIRMATORY LICENSE Recorded Nov 14, 2023
From: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065566/0382 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 2, 2021
From: MCFADDEN, DOUGLAS GRANT; CHRISTIE, JOHN; BLATTMAN, JOSEPH; RAHMAN, MOHAMMED MASMUDUR; VILLA, NANCY
To: ARIZONA BOARD OF REGENTS ON BEHALF OF ARIZONA STATE UNIVERSITY
Reel/Frame 058269/0117 →
Continuity (2)
Provisional Application 62697581 · Jul 13, 2018
Related Publication 20210268050A1 · Sep 2, 2021
References Cited (72)
US 11117934B2 · McFadden · 2021 [cited by examiner]
US 20130209406A1 · Tenoever · 2013 [cited by applicant]
US 20140328804A1 · Mcfadden et al. · 2014 [cited by applicant]
US 20180303886A1 · Hwang et al. · 2018 [cited by applicant]
US 20190160115A1 · Falb et al. · 2019 [cited by applicant]
US 20210061864A1 · McFadden et al. · 2021 [cited by applicant]
CN 104039333 · 2014 [cited by applicant]
EP 0972840B1 · 2004 [cited by applicant]
WO WO2007143545A2 · 2007 [cited by applicant]
WO WO2015078856A1 · 2015 [cited by applicant]
WO 2018049248A1 · 2018 [cited by applicant]
WO WO2020014670A1 · 2020 [cited by applicant]
WO WO2020037206A1 · 2020 [cited by applicant]
WO WO2020051248A1 · 2020 [cited by applicant]
WO WO2020198690A1 · 2020 [cited by applicant]
WO WO2021046048A1 · 2021 [cited by applicant]
WO WO2021046125A1 · 2021 [cited by applicant]
Balkwill. Tumour necrosis factor and cancer. Nat Rev Cancer 9(5):361-371 (2009). [cited by applicant]
Barrett et al. M135R is a Novel Cell Surface Virulence Factor of Myxoma Virus. Journal of Virology 81(1):106-114 (2007). [cited by applicant]
Bartee et al., Selective purging of human multiple myeloma cells from autologous stem cell transplant grafts using oncolytic myxoma virus. Biol Blood Marrow Transplant 18(10):1540-1551 (2012). [cited by applicant]
Bartee et al. The addition of tumor necrosis factor plus beta interferon induces a novel synergistic antiviral state against poxviruses in primary human fibroblasts. Journal of virology 83:498-511 (2009). [cited by applicant]
Burton et al. Targeting TNF-alpha for cancer therapy. J Biol 8:85 (2009). [cited by applicant]
Cameron et al., The complete DNA sequence of myxoma virus. Virology 264(2):298-318 (1999). [cited by applicant]
Chan et al., Oncolytic Myxoma Virus: The path to clinic. Vaccine 31(39):4252-4258 (2013). [cited by applicant]
Chan et al., Oncolytic Poxviruses. Annu Rev Virol 1(1):119-141 (2014). [cited by applicant]
Choi et al., Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF. Gene Ther 19(7):711-723 (2012). [cited by applicant]
Coley. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am. J. Med. Sci. 105:487-511 (1893). [cited by applicant]
Collin et al., The poxviral scrapin MV-LAP requires a myxoma viral infection context to efficiently downregulate MHC-I molecules. Virology 343(2):171-178 (2005). [cited by applicant]
Colombo et al.: Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 13(2):155-168 (2002). [cited by applicant]
Del Vecchio et al., Interleukin-12: biological properties and clinical application. Clin Cancer Res 13(16):4677-4685 (2007). [cited by applicant]
GenBank Accession No. AF170726.2 (2019). [cited by applicant]
GenBank Accession No. EU552530 (2019). [cited by applicant]
GenBank Accession No. EU552531 (2019). [cited by applicant]
Guerin et al., Myxoma Virus Leukemia-Associated Protein is Responsible for Major Histocompatibility Complex Class I and Fas-CD95 Down-Regulation and Defines Scrapins, a New Group of Surface Cellular Receptor Abductor Pr… [cited by applicant]
Harrington et al., Optimizing Oncolytic Virotherapy in Cancer Treatment. Nat. Reviews Drug Discovery 19:689-706 (2019). [cited by applicant]
Hess et al., Antitumor efficacy of a human interleukin-12 expression plasmid demonstrated in a human peripheral blood leukocyte/human lung tumor xenograft SCID mouse model. Cancer Gene Ther 8(5):371-377 (2001). [cited by applicant]
Kashii et al., Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells. J Immunol 163(10):5358-5366 (1999). [cited by applicant]
Kelly et al. History of oncolytic viruses: genesis to genetic engineering. Molecular Therapy 15:651-659 (2007). [cited by applicant]
Kim et al., Myxoma virus targets primary human leukemic stem and progenitor cells while sparing normal hematopoietic stem and progenitor cells. Leukemia 23(12):2313-2317 (2009). [cited by applicant]
Laverty et al., TGF-beta3 and cancer: a review. Cytokine Growth Factor Rev 20(4):305-317 (2009). [cited by applicant]
Lichty et al. Going viral with cancer immunotherapy. Nature Reviews Cancer 14:559-567 (2014). [cited by applicant]
Liu et al., The immunoregulatory properties of oncolytic myxoma virus and their implications in therapeutics. Microbes Infect 12(14-15):1144-1152 (2010). [cited by applicant]
Mansouri et al., The PHD/LAP-Domain Protein M153R of Myxomavirus is a Ubiquitin Ligase That Induces the Rapid Internalization and Lysosomal Destruction of CD4. J Virol 77(2):1427-1440 (2003). [cited by applicant]
Moriwaki et al., Differential roles of RIPK1 and RIPK3 in TNF-induced necroptosis and chemotherapeutic agent-induced cell death. Cell Death Dis 6(2):e1636 (2015). [cited by applicant]
Mossman et al. Myxoma virus M-T7, a secreted homolog of the interferon-gamma receptor, is a critical virulence factor for the development of myxomatosis in European rabbits. Virology 215:17-30 (1996). [cited by applicant]
Nayerossadat et al. Viral and nonviral delivery systems for gene delivery. Adv Biomed Res 1:27 (2012). [cited by applicant]
Neill et al., Decorin as a multivalent therapeutic agent against cancer. Adv Drug Deliv Rev 97:174-185 (2016). [cited by applicant]
Ogbomo et al., Myxoma Virus Infection Promotes NK Lysis of Malignant Gliomas In Vitro and In Vivo. PLoS One 8(6): e66825 (2013). [cited by applicant]
PCT/US2019/041700 International Search Report and Written Opinion dated Nov. 12, 2019. [cited by applicant]
PCT/US2020/049061 International Search Report and Written Opinion dated Dec. 7, 2020. [cited by applicant]
PCT/US2020/055083 International Search Report and Written Opinion dated Jan. 26, 2021. [cited by applicant]
Prevost-Blondel et al., Crucial Role of TNF-α in CD8 T Cell-Mediated Elimination of 3LL-A9 Lewis Lung Carcinoma Cells In Vivo. J Immunol 164(7): 3645-3651 (2000). [cited by applicant]
Rahman et al., Methods for Identifying Virus-Derived Serpins: Methods and Protocols. Methods in molecular biology 1826:73-86 (2018). [cited by applicant]
Russell et al. Oncolytic virotherapy. Nature Biotechn 30:658-670 (2012). [cited by applicant]
Stanford et al., Myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer. Expert Opin Biol Ther 7(9):1415-1425 (2007). [cited by applicant]
Stanford et al., Myxoma Virus Expressing Human Interleukin-12 Does Not Induce Myxomatosis in European Rabbits. Journal of Virology 81(22):12704-12708 (2007). [cited by applicant]
Sypula et al., Myxoma virus tropism in human tumor cells. Gene therapy & molecular biology 8:103-114 (2004). [cited by applicant]
U.S. Appl. No. 17/010,711 Non-Final Office Action dated Dec. 24, 2020. [cited by applicant]
Villa et al., Myxoma virus suppresses proliferation of activated T lymphocytes yet permits oncolytic virus transfer to cancer cells. Blood 125(24):3778-3788 (2015). [cited by applicant]
Wang et al., Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor. PNAS 103 (12): 4640-4645 (2006). [cited by applicant]
Wang et al. RIG-I Mediates the Co-Induction of Tumor Necrosis Factor and Type I Interferon Elicited by Myxoma Virus in Primary Human Macrophages. PLoS Pathog 4(7):e1000099 (2008). [cited by applicant]
Xu et al., The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. Gene Ther 22(3):247-256 (2015). [cited by applicant]
Yao et al., Decorin-mediated inhibition of the migration of U87MG glioma cells involves activation of autophagy and suppression of TGF-β signaling. FEBS Open Bio 6(7):707-719 (2016). [cited by applicant]
Yu et al. Targeting Transmembrane TNF-α Suppresses Breast Cancer Growth. Cancer Res 73(13):4061-4075 (2013). [cited by applicant]
Zhang et al., Optimizing DC vaccination by combination with oncolytic adenovirus coexpressing IL-12 and GM-CSF. Mol Ther 19(8):1558-1568 (2011). [cited by applicant]
EP Application No. 19834625.6 Supplementary Partial European Search Report dated Mar. 15, 2022. [cited by applicant]
Sedger et al.: Poxvirus tumor necrosis factor receptor (TNFR)-like T2 proteins contain a conserved preligand assembly domain that inhibits cellular TNFR1-induced cell death. J Virol. 80(18):9300-9309 doi:10.1128/JVI.024… [cited by applicant]
English translation of Chinese Office Action issued in App. No. CN201980059900, dated May 27, 2024 , 7 pages. [cited by applicant]
Lilly et al., Ex vivo oncolytic virotherapy with myxoma virus arms multiple allogeneic bone marrow transplant leukocytes to enhance graft versus tumor. Molecular Therapy Oncolytics 4:31-40 (2016). URL: https://doi.org/1… [cited by applicant]
Liu J, Wennier S, McFadden G. The immunoregulatory properties of oncolytic myxoma virus and their implications in therapeutics. Microbes Infect. Dec. 2010;12(14-15):1144-52. doi: 10.1016/j.micinf.2010.08.012. Epub Sep. … [cited by applicant]
Office Action issued in App. No. IL280060, dated Jun. 25, 2024, 4 pages. [cited by applicant]
Spiesschaert B, McFadden G, Hermans K, Nauwynck H, Van de Walle GR. The current status and future directions of myxoma virus, a master in immune evasion. Vet Res. Jun. 9, 2011;42(1):76. doi: 10.1186/1297-9716-42-76. PMI… [cited by applicant]