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EP-3577132-B1 - ONCOLYTIC VIRUS THERAPY

EP3577132B1EP 3577132 B1EP3577132 B1EP 3577132B1EP-3577132-B1

Inventors

  • GUO, Zong, Sheng
  • BARTLETT, DAVID
  • LIU, Zuqiang
  • FEIST, Mathilde

Dates

Publication Date
20260506
Application Date
20180205

Claims (15)

  1. An oncolytic virus and tumor-infiltrated T-cells for use in a method of treating cancer in a subject suffering from cancer, the method comprising: (a) administering, to the subject, an effective amount of the oncolytic virus to induce the infiltration of one or more T cells into the cancer; (b) isolating the tumor-infiltrated T cells from the cancer of the subject; (c) expanding the tumor-infiltrated T cells ex vivo ; and (d) transferring the expanded tumor-infiltrated T cells to the subject suffering from cancer, wherein the oncolytic virus is an armed oncolytic virus that comprises a nucleic acid operably linked to a promoter and encoding a membrane-associated protein comprising an immunomodulator molecule linked to an anchoring peptide via a linker, wherein the immunomodulator molecule is selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, IL-21, IL-23, IL-24, IL-27, CXCL11, CCL5, an IFN, IFN-alpha, IFN-alpha2, IFN-beta, IFN-gamma, a TNF, TNF-alpha, TNF-beta, GM-CSF, or a combination thereof; and wherein the armed oncolytic virus is a vaccinia virus.
  2. The oncolytic virus and tumor-infiltrated T-cells for use of claim 1, wherein the armed oncolytic virus is a recombinant vaccinia virus with an inactivating mutation of its thymidine kinase gene, vaccinia growth factor gene, or both.
  3. The composition for use of any of one claims 1-2, wherein the anchoring peptide comprises a GPI-anchor acceptor peptide, or wherein the anchoring peptide comprises a PD-L1 transmembrane domain.
  4. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-3, wherein the linker is a flexible linker or a rigid linker.
  5. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-4, wherein the cancer is locally invasive, or wherein the cancer is metastatic.
  6. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-5, wherein expanding the tumor-infiltrated T cells ex vivo comprises co-culturing the tumor-infiltrated T cells with dendritic cells and cancer cells.
  7. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-6, wherein expanding the tumor-infiltrated T cells comprises culturing the tumor-infiltrated T cells with cytokines and/or agents.
  8. The oncolytic virus and tumor-infiltrated T-cells for use of claim 7, wherein the cytokines and/or the agents comprise one or more of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, IL-21, IL-23, IL-24, IL-27, IFN-alpha, IFN-alpha2, IFN-beta, or IFN-gamma, TNF-alpha, TNF-beta, and GM-CSF.
  9. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-8, wherein expanding the tumor-infiltrated T cells comprises culturing the tumor-infiltrated T cells with IL-2, IL-7, and/or GSK3b.
  10. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-9, wherein before transferring the tumor-infiltrated T cells to the subject suffering from cancer, the subject suffering from cancer is treated with a cancer therapy.
  11. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-10, further comprising treating the subject suffering from cancer with a cancer therapy.
  12. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-11, further comprising providing to the subject suffering from cancer with one or more exogenous cytokines and/or agents.
  13. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-11, further comprising providing to the subject suffering from cancer with exogenous IL-2, after transferring the tumor-infiltrated T cells.
  14. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-13, where the tumor-infiltrated cells are transferred intraperitoneally.
  15. The oncolytic virus and tumor-infiltrated T-cells for use of any one of claims 1-13, where the tumor-infiltrated cells are transferred intratumorally.

Description

PRIORITY CLAIM This patent application claims priority to United States Provisional Application No. 62/454,526, filed February 3, 2017. GRANT INFORMATION None applicable. 1. INTRODUCTION The presently disclosed subject matter relates to oncolytic viruses, armed oncolytic viruses encoding, in an expressible form, an immunomodulator molecule, and to compositions of, and methods of making and using said oncolytic viruses. The presently disclosed subject matter also relates to tumor infiltrated T cells - induced by oncolytic virus ("OV-induced T cells"), and to methods of making and using said OV-induced T cells for adoptive T-cell therapy. 2. BACKGROUND OF THE INVENTION Oncolytic viruses, which selectively replicate in and kill cancer cells, exert their anti-cancer effects through a number of modalities (Bartlett DL et al., 2013, Molecular Cancer 12:103-120). The first, as their name implies, is cell lysis, which can be achieved through apoptosis, necrosis, pyroptosis, autophagy, or a combination of these (Guo ZS et al., 2014, Front Oncol 4:74). Further, oncolytic viruses can attack a cancer's blood supply, leading to apoptosis and necrosis of infected as well as non-infected cells. Finally, oncolytic viruses induce immunogenic cell death (ICD) of cancer cells, release and present danger signal molecules (signal 0), along with inflammatory cytokines, and cross-present tumor-associated antigens (TAAs) to naive T cells, leading to elicitation of anti-tumor immunity (Guo ZS et al., 2014, Front Oncol 4:74). The potent oncolytic viruses not only elicit potent and systemic adaptive antitumor immunity, but also promote the trafficking of tumor-specific CD8+ T cells into the tumor tissues (Bartlett DL et al., 2013, Mol Cancer 12:103; Guo ZS et al., 2017, 8:555). This immune response against the cancer is not restricted to infected cancer cells, but extends to metastatic lesions. The approval of the first-in-class drug, T-VEC, by the FDA to treat advanced melanoma in 2015, showcased the potential of this type of novel treatment for cancer (Andtbacka RH et al., 2015, J Clin Oncol 33:2780-8). Despite their advantages, oncolytic viruses have, to date, faced challenges, including gaining access to cancer cells within tumor nodules in adequate numbers, anti-virus immune responses, and a highly immunosuppressive tumor environment (Zou W., 2005, Nat Rev Cancer 5:263-74). In addition, infiltration of tumor-specific T cells, if they indeed are generated and activated, encounter hurdles, the major one being to infiltrate to tumor tissue where they exert their cytotoxicity to cancer cells and associated stromal cells. These challenges would be desirably improved by agents that modulate the immune system - for example agents that increase anti-cancer immunity and/or decrease anti-virus immunity. However, agents capable of such immunomodulation - cytokines and the like - can have profound, potentially dangerous effects on a treated subject when systemically dispersed. WO 2017/044780 A1 describes methods for treating cancer including vaccinating a patient with a vaccine made up of the patient's own malignancy and an immunologic adjuvant, isolating and expanding T lymphocytes, and administrating stimulated T lymphocytes and an oncolytic virus back to the patient. Rosenberg et al., 348(6230):62-68 (2015) describe the use of adoptive cell therapies for the treatment of cancer. 3. SUMMARY OF THE INVENTION The presently disclosed subject matter relates to compositions and methods which promote anti-cancer immunity in the context on oncolytic virus therapy. Adoptive T cell therapy is used as part of an anti-cancer regimen employing oncolytic virus to promote an immune response against cancer cells, and the oncolytic virus is optionally administered with an immunomodulator. In certain embodiments, the immunomodulator is linked to the oncolytic virus. In certain embodiments, the presently disclosed subject matter provides an oncolytic virus and tumor-infiltrated T-cells for use in a method of treating a subject suffering from cancer, comprising: (a) administering, to the subject, an effective amount of an oncolytic virus to induce the infiltration of one or more T cells into the cancer;(b) isolating the tumor-infiltrated T cells from the cancer of the subject;(c) expanding the tumor-infiltrated T cells ex vivo; and(d) transferring the expanded tumor-infiltrated T cells to the subject suffering from cancer. The oncolytic virus is an armed oncolytic virus that includes a nucleic acid operably linked to a promoter and encoding a membrane-associated protein including an immunomodulator molecule linked to an anchoring peptide via a linker, where the immunomodulator molecule is IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-18, IL-21, IL-23, IL-24, IL-27, CXCL11, CCL5, an IFN, IFN-alpha, IFN-alpha2, IFN-beta, IFN-gamma, a TNF, TNF-alpha, TNF-beta, GM-CSF, or a combination thereof wherein the arm