Methods and materials for treating cancer

Abstract

This document provides methods and materials for treating cancer. For example, this document provides methods and materials for using one or more oncolytic viruses (e.g., a vesicular stomatitis virus, such as VSV-IFNβ-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) to treat cancer (e.g., multiple myeloma such as relapsed refractory multiple myeloma) within a mammal (e.g., a human).

Description

Attorney Docket No. 07039-2370W01 / 2025-110 METHODS AND MATERIALS FOR TREATING CANCER CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority' to U.S. Application Serial No. 63 / 763,599, filed on February 26, 2025. The disclosure of the prior application is considered part of the disclosure of this application, and is incorporated in its entirety into this application.TECHNICAL FIELDThis document relates to methods and materials for treating cancer. For example, this document provides methods and materials for using one or more oncolytic viruses (e.g., a vesicular stomatitis virus such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor and / or a proteosome inhibitor such as bortezomib) to treat cancer (e.g., multiple myeloma such as relapsed refractory' multiple myeloma (RRMM)) within a mammal (e.g., a human).BACKGROUND VSV-IFNP-NIS is a Vesicular Stomatitis Virus (VSV) that includes nucleotide sequences encoding interferon beta (IFNP) and a sodium iodide symporter (N1S). 1FNP confers tumor selectivity' and enhances host antitumor immunity, while the NIS acts as an imaging biomarker, allowing noninvasive imaging of viral infection sites using Positron Emission Tomography (PET) and / or Single Photon Emission Computed Tomography (SPECT). Multiple myeloma (MM) is a cancer of plasma cells that can pose a challenge for treatment due to its biological heterogeneity. As MM often relapses and is refractory, current therapies face the issue of drug resistance.SUMMARYThis document provides methods and materials for treating cancer. For example, this document provides methods and materials for using one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) to treat cancer (e.g., multiple myeloma such as RRMM) within a mammal (e.g., a human). In some cases, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor suchAttorney Docket No. 07039-2370W01 / 2025-110as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e.g., a human) having cancer (e.g., multiple myeloma such as RRMM) to treat the mammal.In general, one aspect of this document features a method for treating cancer in a mammal. The method can include, or consist essentially of, administering, to the mammal, an oncolytic virus, an immune checkpoint inhibitor, and a proteosome inhibitor. After the administering, the number of cancer cells within the mammal can be reduced. The mammal can be a human. The cancer can be multiple myeloma. The cancer can be relapsed refractory multiple myeloma. The method can include identifying the mammal as having the cancer. The oncolytic virus can be a VSV. The VSV can encode an IFNP polypeptide or a sodium NIS polypeptide. The VSV can be a VSV-IFNP-NIS oncolytic virus. The immune checkpoint inhibitor can be a PD-1 inhibitor. The PD-1 inhibitor can be pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, tislelizumab, ipilimumab, tremelimumab, durvalumab, avelumab, atezolizumab, relathmab, BMS-8, BMS-37, BMS-202, BMS-230, BMS-242, BMS-1001, BMS-1166, SB415286. vorinostat, decitabine, entitostat. JQ1, BET151, GSK503. panobinostat, ACY-241, azacytidine, DB36, DB71, DB15, CVN, MGCD0103, SNDX-275, IMP32, BMS986016, TSR-022, Sym023, ATIK2a, or DZNep. The proteosome inhibitor can be bortezomib, carfilzomib, ixazomib, marizomib, or oprozomib. The method can include administering two or more different oncolytic viruses to the mammal. The method can include administering two or more different immune checkpoint inhibitors to the mammal. The method can include administering two or more different proteosome inhibitors to the mammal. The method can include administering an additional anti-cancer agent to the mammal. The additional anti-cancer agent can be a chemotherapeutic agent, a targeted anti-cancer therapy, a cytotoxic agent, or an anti-angiogenic agent. The method can include performing an anti-cancer approach on the mammal. The anti-cancer approach can be radiation therapy, adoptive cell transfer therapy, stem cell transplant, plasma exchange, or surgery.In another aspect, this document features a method for prolonging survival of a mammal identified as having cancer. The method can include, or consist essentially of, administering, to the mammal, an oncolytic virus, an immune checkpoint inhibitor, and a proteosome inhibitor. The mammal can be a human. The cancer can be multipleAttorney Docket No. 07039-2370W01 / 2025-110myeloma. The cancer can be relapsed refractory' multiple myeloma. The method can include identifying the mammal as having the cancer. The oncolytic virus can be a VSV. The VSV can encode IFNP polypeptide or aNIS polypeptide. The VSV can be a VSV-IFN -NIS oncolytic virus. The immune checkpoint inhibitor can be a PD-1 inhibitor. The PD-1 inhibitor can be pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, tislelizumab, ipilimumab, tremelimumab, durvalumab, avelumab, atezolizumab, relatlimab, BMS-8, BMS-37, BMS-202, BMS-230, BMS-242. BMS-1001, BMS-1166, SB415286, vorinostat, decitabine, entitostat, JQ1, BET151, GSK.503, panobinostat, ACY-241, azacytidine, DB36, DB71, DB15, CVN, MGCD0103, SNDX-275, IMP32, BMS986016, TSR-022, Sym023, ATIK2a, or DZNep. The proteosome inhibitor can be bortezomib, carfilzomib, ixazomib, marizomib. or oprozomib. The method can include administering two or more different oncolytic viruses to the mammal. The method can include administering two or more different immune checkpoint inhibitors to the mammal. The method can include administering two or more different proteosome inhibitors to the mammal. The method can include administering an additional anti-cancer agent to the mammal. The additional anti-cancer agent can be a chemotherapeutic agent, a targeted anti-cancer therapy, a cytotoxic agent, or a anti-angiogenic agent. The method can include performing an anti-cancer approach on the mammal. The anti-cancer approach can be radiation therapy, adoptive cell transfer therapy, stem cell transplant, plasma exchange, or surgery.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.Attorney Docket No. 07039-2370W01 / 2025-110BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A-1B include graphs and representative images of protein gels showing that MM can be detected noninvasively via a M protein (M-spike band) in the gamma region of a serum protein gel. While no M-spike band was detected in a protein gel for a serum sample from a normal, healthy subject (FIG. 1A), a large M-spike band was detected in a protein gel for a serum sample from a patient with MM (FIG. IB).FIG. 2 shows a representative experimental workflow for in vivo experiments in two mouse models of multiple myeloma (Vkl2598 and Vkl2653).FIG. 3 is a graph plotting survival of Vkl2598 mice treated with (a) saline, (b) bortezomib, (c) an anti-PDl antibody ( "aPD I ; " InVivoMab anti-mouse PD-1 (CD279), Clone 29F.1 Al 2; BioXCell, Lebanon. NH). or (d) aPDl + bortexomib.FIG. 4 is a graph plotting survival of Vkl2598 mice treated with (a) saline, (b) IxlO6TCIDso / mL VSV-IFN0-NIS (VV1), (c) IxlO7TCIDso / mL VV1, or (d) IxlO8TCIDso / mL VV1.FIG. 5 is a graph plotting weight changes in Vkl2598 mice treated with (a) saline, (b) IxlO6TCIDso / mL VVL (c) IxlO7TCIDso / mL VV1, or (d) IxlO8TCIDso / mL VV1.FIG. 6 is a graph plotting survival of Vkl2598 mice treated with (a) saline, (b) IxlO8TCIDso / mL VV1, (c) aPDl, (d) IxlO8TCIDso / mL VV1 + 1 dose of aPDl, or (e) IxlO8TCIDso / mL VV1 + 4 doses of aPDl.FIG. 7 is a graph plotting survival of Vkl2598 mice treated with (a) saline, (b) IxlO8TCIDso / mL VV1, (c) bortezomib, or (d) IxlO8TCIDso / mL VV1 + bortezomib.FIG. 8 is a graph plotting survival of Vkl2598 mice treated with (a) saline, (b) IxlO8TCIDso / mL VV1, (c) IxlO8TCIDso / mL VV1 + bortezomib, (d) IxlO8TCIDso / mL VV1 + aPDl, or (e) IxlO8TCIDso / mL VV1 + aPDl + bortezomib.FIG. 9 is a graph plotting survival of Vkl2598 mice treated with (a) saline, (b) IxlO8TCIDso / mL VV1, (c) IxlO8TCIDso / mL VV1 + one dose of aPDl + bortezomib, (d) or IxlO8TCIDso / mL VV1 + four doses of aPDl + bortezomib.FIG. 10 is a graph plotting survival of Vkl2598 mice treated with (a) saline, (b) IxlO8TCIDso / mL VV1, (c) IxlO8TCIDso / mL VV1 + aPDl + aCTLA4, (d) aPDl + aCTLA4, (e) IxlO8TCIDso / mL VV1 + bortezomib, (f) bortezomib, (g) IxlO8TCIDso / mLAttorney Docket No. 07039-2370W01 / 2025-110VV1 + aPDl, (h) aPDl, (i) IxlO8TCIDso / mL VV1 + aPDl + bortezomib, or (j) aPDl + bortezomib.FIG. 11 includes images for a series of Western blots showing serum proteins at various time points in mice treated with (a) saline, (b) IxlO8TCIDso / mL VV1, (c) IxlO8TCIDso / mL VV1 + bortezomib, (d) bortezomib, (e) IxlO8TCIDso / mL VV1 + aPDl, (f) aPDl, (g) IxlO8TCIDso / mL VV1 + aPDl + bortezomib, or (h) aPDl + bortezomib. Bands indicating the M-spike tumor burden at days 7 and 14 are boxed. The thicker the band, the higher the tumor burden.FIG. 12 is a series of graphs plotting T cell population levels in spleens of Vkl2598 mice treated with (a) saline, (b) VV1, (c) VV1 + aPDl, or (d) VV1 + aPDl + bortezomib.FIGS. 13A-13C are a series of graphs plotting the percentage of interferon gamma (IFNy) (FIG. 13A), granzyme B (GrzB) (FIG. 13B), and K167 (FIG. 13C) positive CD8+T cells following treatment of Vkl2598 mice with (a) saline, (b) VV1, (c) VV1 + aPDl, or (d) VV1 + aPDl + bortezomib.FIGS. 14A-14C are a series of graphs plotting the percentage of IFNy (FIG. 14A), GrzB (FIG. 14B), and Ki67 (FIG. 14C) positive CD4+T cells following treatment of Vkl2598 mice with (a) saline, (b) VV1, (c) VV1 + aPDl, or (d) VV1 + aPDl + bortezomib.FIG. 15 is a graph plotting the percentage of MM (CD138+B220‘) cells in spleen and bone marrow of Vkl2653 and Vkl2598 mice upon re-transplantation of splenocytes from these mice, as determined by flow cytometry.DETAILED DESCRIPTIONThis document provides methods and materials for treating cancer. For example, this document provides methods and materials for using one or more (e.g., one, two, three, four, or more) oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more (e.g., one, two, three, four, or more) anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) to treat cancer (e.g., MM such as RRMM) within a mammal (e.g., a human). In some cases, a mammal (e.g., a human) having cancer (e.g., MM such as RRMM) can be administered, or can be instructed to self- administer, one or more (e.g., one, two, three, four, or more)Attorney Docket No. 07039-2370W01 / 2025-110oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more (e.g., one, two, three, four, or more) anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib).In some cases, one or more oncolytic viruses (e g., a VSV) and one or more anticancer agents (e.g., an immune checkpoint inhibitor and / or a proteosome inhibitor) can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having cancer such as MM) to reduce the number of cancer cells in the mammal. For example, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e.g., a human) in need thereof (e.g.. a human having cancer such as MM) as described herein to reduce the number of cancer cells in the mammal. In some cases, the methods and materials provided herein can be used as described herein to reduce the number of cancer cells in the mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent.In some cases, one or more oncolytic viruses (e.g., a VSV ) and one or more anticancer agents (e.g., an immune checkpoint inhibitor and / or a proteosome inhibitor) can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having cancer such as MM) to improve survival of the mammal. For example, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g.. an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e g., a human) in need thereof (e.g., a human having cancer such as MM) as described herein to improve survival of the mammal. In some cases, the methods and materials provided herein can be used as described herein to improve the survival of the mammal by. for example. 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the methods and materials provided herein can be used as described herein to improve the survival of the mammal by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).Any appropriate mammal having cancer (e.g., MM such as RRMM) can be treated as described herein (e.g., by administering one or more oncolytic viruses and one or moreAttorney Docket No. 07039-2370W01 / 2025-110anti-cancer agents). Examples of mammals that can be treated as described herein include, without limitation, humans, non-human primates (e.g., monkeys), horses, bovine species, porcine species, dogs, cats, mice, and rats. In some cases, a human having cancer (e.g., MM such as RRMM) can be treated by administering one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib).A mammal (e.g., a human) having any type of cancer can be treated as described herein (e.g., by administering one or more oncolytic viruses and one or more anti-cancer agents). In some cases, a mammal having cancer that can be treated as described herein can be a mammal (e.g., a human) having a blood cancer. In some cases, a mammal having cancer that can be treated as described herein can be a mammal (e.g.. a human) having one or more solid tumors. In some cases, a mammal having cancer that can be treated as described herein can be a mammal (e.g., a human) having a cancer that is resistant to one or more proteosome inhibitors (e.g., bortezomib). In some cases, a mammal having cancer that can be treated as described herein can be a mammal (e.g., a human) having a cancer that is resistant to one or more treatments that were previously successful in treating the cancer in the mammal. Examples of cancers that can be treated as described herein include, without limitation, multiple myeloma (e.g., RRMM), lymphoma, AL amyloidosis, Waldenstrom macroglobulinemia, breast cancer, prostate cancer, renal cancer, and gastric cancer.In some cases, the methods described herein can include identifying a mammal as having cancer. Examples of methods for identifying a mammal as having cancer include, without limitation, physical examination, laboratory tests (e.g., assays of blood and / or urine such as serum protein gel analysis), tissue biopsy (e.g., a bone marrow biopsy), imaging tests (e.g., X-ray, PET / CT, MRI, and / or ultrasound), liquid biopsy, genetic testing, and / or cytogenetic analysis. Once identified as having cancer, a mammal can be treated as described herein (e.g., by administering one or more oncolytic viruses and one or more anti-cancer agents).A mammal (e.g., a human) having cancer (e.g., MM such as RRMM) can be administered, or can be instructed to self-administer, any appropriate one or more (e.g., one, two, three, four, or more) oncolytic viruses. In some cases, an oncolytic virus canAttorney Docket No. 07039-2370W01 / 2025-110have anti-cancer activity7. Examples of oncolytic viruses that can have anti-cancer activity7and can be used as described herein include, without limitation, a vesiculovirus (e.g., a VSV such as VSV-IFN[3-NIS), a reovirus. a herpes virus, an adenovirus, a vaccinia virus, an influenza virus, a measles virus, and a Newcastle disease virus. In some cases, the oncolytic virus having anti-cancer activity7that can be used as described herein can be a recombinant oncolytic virus such as a VSV-IFNP-NIS virus. An example of a VSV-IFNp-NIS virus that can be used as described herein is described elsewhere (e.g.. in U.S. Publication No. US2018 / 0237492, which is incorporated herein by reference in its entirety ). See, e.g., paragraphs

[0025] to

[0034] and

[0046] to

[0048] ofUS2018 / 0237492.A mammal (e.g., a human) having cancer (e.g., MM such as RRMM) can be administered, or can be instructed to self-administer, any appropriate one or more (e.g., one, two, three, four, or more) anti-cancer agents. Suitable examples of anti-cancer agents that can be used as described herein include, without limitation, immune checkpoint inhibitors, proteosome inhibitors, chemotherapeutic agents, targeted anti-cancer therapies, cytotoxic agents, anti-angiogenics. and any combination thereof.In some cases, a mammal having cancer can be administered, or can be instructed to self-administer, any appropriate immune checkpoint inhibitor. An immune checkpoint inhibitor can inhibit one or more polypeptides involved in an immune checkpoint pathway. Examples of immune checkpoint pathways include, without limitation, PD-1 / PD-L1 pathways, PD-1 / PD-L2 pathways, CTLA-4 pathways, TRAIL pathways, T1M3 pathways, and TIGIT pathways. An immune checkpoint inhibitor can inhibit any polypeptide involved in an immune checkpoint pathway. Examples of polypeptides involved in an immune checkpoint pathway that can be inhibited by an immune checkpoint inhibitor as described herein include, without limitation, PD-1 polypeptides, PD-L1 polypeptides, CTLA4 polypeptides, LAG-3 polypeptides, TIM3 polypeptides, and TIGIT polypeptides.An immune checkpoint inhibitor can inhibit polypeptide activity7of a polypeptide involved in an immune checkpoint pathway or can inhibit polypeptide expression of a polypeptide involved in an immune checkpoint pathway. Examples of compounds that can inhibit polypeptide activity of a polypeptide involved in an immune checkpoint pathw ay include, without limitation, antibodies (e.g., neutralizing antibodies) that targetAttorney Docket No. 07039-2370W01 / 2025-110(e.g., target and bind) to a polypeptide involved in an immune checkpoint pathway and small molecules that target (e.g., target and bind) to a polypeptide involved in an immune checkpoint pathway. Examples of compounds that can inhibit polypeptide expression of a polypeptide involved in an immune checkpoint pathway include, without limitation, nucleic acid molecules designed to induce RNA interference of polypeptide expression of a polypeptide involved in an immune checkpoint pathway (e.g., a siRNA molecule or a shRNA molecule), antisense molecules that can target (e.g.. are complementary to) nucleic acid encoding a polypeptide involved in an immune checkpoint pathway, and miRNAs that can target (e.g., are complementary to) nucleic acid encoding a polypeptide involved in an immune checkpoint pathway. Examples of immune checkpoint inhibitors that can be administered to mammal (e.g., a human) having cancer (e g., a cancer that exhibits little or no response to treatment with immune checkpoint inhibitors) include, without limitation, anti-PD-1 antibodies, anti-PD-Ll antibodies, anti-CTL4A antibodies, anti-LAG-3 antibodies, anti-TIM3 antibodies, and anti-TIGIT antibodies. In some cases, an immune checkpoint inhibitor that can be administered to mammal (e.g., a human) having cancer (e.g., a cancer that exhibits little or no response to treatment with immune checkpoint inhibitors) as described herein can be as shown in TABLE 1.TABLE 1. Exemplary immune checkpoint inhibitors.Attorney Docket No. 07039-2370W01 / 2025-110In some cases, an immune checkpoint inhibitor can be as described elsewhere (see, e.g., Smith et a\.,Am. J. Transl. Res., 11(2):529-541 (2019) at, for example. Table 1; and Terranova-Barberio et al., Immunotherapy, 8(6):705-719 (2016) at, for example, Table 1).In some cases, a mammal having cancer can be administered, or can be instructed to self-administer, any appropriate proteosome inhibitor. Examples of proteosome inhibitors that can be administered to mammals having cancer as described herein include, without limitation, bortezomib, carfilzomib, ixazomib, marizomib, and oprozomib.In some cases, a mammal having cancer can be administered, or can be instructed to self-administer, any appropriate chemotherapeutic agent. Examples of chemotherapeutic agents that can be administered to mammals having cancer as describedAttorney Docket No. 07039-2370W01 / 2025-110herein include, without limitation, cyclophosphamide, 5-fluorouracil (5-FU), Adriamycin, paclitaxel, and carboplatin.In some cases, a mammal having cancer can be administered, or can be instructed to self-administer, any appropriate targeted anti-cancer therapy. Examples of targeted anti-cancer therapies that can be administered to mammals having cancer as described herein include, without limitation, tyrosine kinase inhibitor (TKIs), monoclonal antibodies, and BCL-2 inhibitors.In some cases, a mammal having cancer can be administered, or can be instructed to self-administer, any appropriate cytotoxic agent. Examples of cytotoxic agents that can be administered to mammals having cancer as described herein include, without limitation, paclitaxel and cisplatin.In some cases, a mammal having cancer can be administered, or can be instructed to self-administer, any appropriate anti -angiogenic agent. Examples of anti-angiogenic agents that can be administered to mammals having cancer as described herein include, without limitation, bevacizumab, sorafenib, sunitinib, and axitinib.In some cases, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be formulated into a composition (e.g., a pharmaceutically acceptable composition) for administration to a mammal (e.g., a human) having cancer (e.g., MM such as RRMM). For example, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be formulated into a single composition. In some cases, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS), one or more immune checkpoint inhibitors (e.g., a PD1 inhibitor), and one or more proteosome inhibitors (e g., bortezomib) can be formulated into a single composition. In some cases, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be formulated together with one or more pharmaceutically acceptable earners (additives), excipients, and / or diluents. In some cases, a pharmaceutically acceptable carrier, excipient, or diluent can be a naturally occurring pharmaceutically acceptable carrier, excipient, or diluent. In some cases, aAttorney Docket No. 07039-2370W01 / 2025-110pharmaceutically acceptable carrier, excipient, or diluent can be a non-naturally occurring (e.g., an artificial or synthetic) pharmaceutically acceptable carrier, excipient, or diluent. Examples of pharmaceutically acceptable carriers, excipients, and diluents that can be used in a composition described herein (e.g., a pharmaceutically acceptable composition including one or more oncolytic viruses and one or more anti-cancer agents) include, without limitation, serum proteins (e.g., human serum albumin), water, and salts or electrolytes (e.g.. phosphate salts, saline, protamine sulfate, and DMSO).In some cases, the one or more oncolytic viruses (e.g., a VSV such as VSV-IFN0-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD 1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e.g., a human) at the same time. For example, one or more oncolytic viruses (e.g., a VSV such as VSV-IFN0-NIS) and one or more anti-cancer agents (e.g.. an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitors such as bortezomib) can be administered to a mammal (e.g., a human) having cancer (e.g., MM such as RRMM) in a single composition containing the one or more oncolytic viruses and the one or more anti-cancer agents. In some cases, one or more oncolytic viruses (e.g., a VSV such as VSV-IFN0-NIS), one or more immune checkpoint inhibitors (e.g., a PD1 inhibitor), and one or more proteosome inhibitors (e.g., bortezomib) can be administered to a mammal (e.g., a human) having cancer (e.g., MM such as RRMM) in a single composition containing the one or more oncolytic viruses, the one or more immune checkpoint inhibitors, and the one or more proteosome inhibitors.In some cases, one or more oncolytic viruses (e.g., a VSV such as VSV-IFN0-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be separately administered to a mammal (e.g., a human) having cancer (e.g., MM such as RRMM). For example, one or more oncolytic viruses (e g., a VSV such as VSV-IFN0-NIS) can be administered to a mammal (e.g., a human) having cancer (e.g., MM such as RRMM), and subsequently one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to the mammal. In some cases, one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e.g., a human) having cancer (e.g., MMAttorney Docket No. 07039-2370W01 / 2025-110such as RRMM), and subsequently one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) can be administered to the mammal.One or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e.g., a human) by any appropriate route (e.g., oral, intranasal, inhalation, transdermal, and parenteral). In some cases, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal locally or systemically. For example, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and / or one or more anti-cancer agents (e g., an immune checkpoint inhibitor such as a PD1 inhibitor and / or a proteosome inhibitor such as bortezomib) can be administered locally by intratumoral (IT) administration to a mammal (e.g., a human). In another example, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and / or one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered systemically by intravenous administration to a mammal (e.g., a human). When a mammal (e.g., a human) is administered one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib), and the one or more oncolytic viruses and one or more anti-cancer agents are administered separately, the one or more oncolytic viruses and the one or more anticancer agents can be administered by the same route of administration or by different routes of administration.One or more oncolytic viruses can be administered to a mammal (e.g., a human) having cancer (e.g., multiple myeloma such as RRMM) in any appropriate amount (e.g., any appropriate dose). An effective amount of one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) can be any amount that can treat a mammal having cancer (e.g., MM such as RRMM) without producing significant toxicity to the mammal. In some cases, an effective amount of one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) can be any amount that reduces the number of cancer cells in a mammal having cancer (e.g., MM such as RRMM) without producing significant toxicity to theAttorney Docket No. 07039-2370W01 / 2025-110mammal. In some cases, an effective amount of one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) can be any amount that prolongs the survival of a mammal having cancer (e.g., MM such as RRMM) without producing significant toxicity to the mammal. In cases where the one or more oncolytic viruses include VSV-IFNP-NIS, an effective amount of the VSV-IFNP-NIS can be from about IxlO650% Tissue Culture Infectious Dose (TCIDso) units to about IxlO11TCIDso units (e.g., from about IxlO6to about IxlO7TCIDso units, from about IxlO7to about IxlO8TCIDso units, from about IxlO8to about IxlO9TCIDso units, from about IxlO9to about IxlO10TCIDso units, or from about IxlO10to about IxlO11TCIDso units).One or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e.g., a human) having cancer (e.g., MM such as RRMM) in any appropriate amount (e.g., any appropriate dose). An effective amount of one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be any amount that can treat a mammal having cancer (e.g., MM such as RRMM) without producing significant toxicity to the mammal. In cases where the one or more anti-cancer agents include an immune checkpoint inhibitor (e.g., an anti-PDl inhibitor), an effective amount of the immune checkpoint inhibitor can be from about 0.1 mg / kg to about 1000 mg / kg (e.g., from about 0.1 mg / kg to about 1 mg / kg, from about 1 mg / kg to about 10 mg / kg, from about 5 mg / kg to about 20 mg / kg, from about 10 mg / kg to about 50 mg / kg, from about 50 mg / kg to about 100 mg / kg, from about 50 mg / kg to about 150 mg / kg, from about 100 mg / kg to about 500 mg / kg, or from about 500 mg / kg to about 1000 mg / kg). In cases where the one or more anti-cancer agents include a proteosome inhibitor (e.g., bortezomib), an effective amount of the proteosome inhibitor can be from about 0.01 mg / kg to about 100 mg / kg (e.g., from about 0.01 mg / kg to about 0.1 mg / kg, from about 0.1 mg / kg to about 0.5 mg / kg, from about 0.5 mg / kg to about 1 mg / kg, from about 0.5 mg / kg to about 1.5 mg / kg, from about 1 mg / kg to about 2 mg / kg, from about 2 mg / kg to about 5 mg / kg, from about 5 mg / kg to about 10 mg / kg, from about 10 mg / kg to about 50 mg / kg. or from about 50 mg / kg to about 100 mg / kg).The effective amount of one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor suchAttorney Docket No. 07039-2370W01 / 2025-110as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can remain constant or can be adjusted as a sliding scale or variable dose depending on a mammal’s response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and / or severity of the cancer (e.g., MM such as RRMM) in the mammal being treated may require an increase or decrease in the actual effective amount administered.One or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e.g., a human) having cancer (e.g., MM such as RRMM) at any appropriate frequency. The frequency of administration can be any frequency that can treat a mammal having cancer (e g., MM such as RRMM) without producing significant toxicity to the mammal. In some cases, an effective frequency of administration for one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be any frequency that reduces the number of cancer cells in a mammal having cancer (e.g., MM such as RRMM) without producing significant toxicity to the mammal. In some cases, an effective frequency of administration for one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti -cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be any frequency that prolongs the survival of a mammal having cancer (e.g., MM such as RRMM) without producing significant toxicity to the mammal. For example, the frequency of administration can be from about twice a day to about once every other day. from about once a day to about once a week, from about once a day to about once a month, from about once a week to about once a month, or from about twice a month to about once a month. When a mammal (e.g., a human) is administered one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) separately, the one or more oncolytic viruses and the one or more anti-cancer agents can be administered at the same frequency or at different frequencies. The frequency of administration can remain constant or can beAttorney Docket No. 07039-2370W01 / 2025-110variable during the duration of treatment. As with the elfective amount, various factors can influence the actual frequency of administration used for a particular application. For example, the effective amount, duration of treatment, use of multiple treatment agents, and / or route of administration may require an increase or decrease in administration frequency.One or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered to a mammal (e.g., a human) having cancer (e.g., MM such as RRMM) for any appropriate duration. An effective duration for administering one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be any duration that can treat a mammal (e.g., a human) having cancer (e g., MM such as RRMM) without producing significant toxicity to the mammal. In some cases, an effective duration of administration for one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g.. an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be any duration that reduces the number of cancer cells in a mammal having cancer (e.g., MM such as RRMM) without producing significant toxicity to the mammal. In some cases, an effective duration of administration for one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be any duration that prolongs the survival of a mammal having cancer (e.g., MM such as RRMM) without producing significant toxicity to the mammal. For example, the effective duration can vary from several weeks to several months, from several months to several years, or from several years to a lifetime. Multiple factors can influence the actual effective duration used for a particular treatment. For example, an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, and / or route of administration.In some cases, methods for treating a mammal (e.g., a human) as described herein (e.g., by administering one or more oncolytic viruses and one or more anti-cancer agents) can include administering to the mammal the one or more oncolytic viruses (e.g., a VSVAttorney Docket No. 07039-2370W01 / 2025-110such as VSV-IFNP-NIS) and the one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) as the sole active ingredients. For example, a composition containing one or more oncolytic viruses (e g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can include the one or more oncolytic viruses and the one or more anti-cancer agents as the sole active ingredients in the composition for treating a mammal (e.g., a human) having cancer (e.g., MM such as RRMM).In some cases, methods for treating a mammal (e.g., a human) as described herein (e.g., by administering one or more oncolytic viruses and one or more anti-cancer agents) also can include administering to the mammal one or more (e g., one, two, three, or more) additional therapeutic agents and / or performing one or more (e.g., one, two, three, or more) anti-cancer approaches. For example, a combination therapy used to treat a mammal (e.g., a human) having cancer (e.g., MM such as RRMM) can include administering to the mammal one or more oncolytic viruses (e.g., a VSV such as VSV-IFNp-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib), and administering to the mammal one or more (e.g., one, two, three, or more) additional therapeutic agents that do not have anti-cancer activity. Examples of additional therapeutic agents that do not have anti-cancer activity and that can be administered to a mammal in combination with one or more oncolytic viruses and one or more anti-cancer agents to treat cancer (e.g., MM such as RRMM) as described herein include, without limitation, ruxolitinib (a JAK1 / 2 inhibitor), tofacitinib (a JAK1 / 3 inhibitor), fedratinib (a JAK2 inhibitor), pacritinib (a JAK2 / IRAK1 inhibitor), losartan (an angiotensin receptor blocker that may improve drug delivery), and thalidomide.In cases where one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD 1 inhibitor, and / or a proteosome inhibitor such as bortezomib) are used in combination with one or more additional therapeutic agents that do not have anti-cancer activity to treat a mammal (e.g., a human) having cancer (e.g., MM such as RRMM), the one or more additional therapeutic agents that do not have anti-cancer activity can be administered at the same time (e.g., in a single composition containing the one or moreAttorney Docket No. 07039-2370W01 / 2025-110oncolytic viruses, the one or more anti-cancer agents, and the one or more additional therapeutic agents that do not have anti-cancer activity ) or separately. For example, a composition including one or more oncolytic viruses (e.g., a VSV such as VSV-IFN0-NIS) and one or more anti-cancer agents (e g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered first, and the one or more additional therapeutic agents that do not have anti-cancer activity administered second, or vice versa.In some cases, a combination therapy used to treat a mammal (e.g., a human) having cancer (e.g., MM such as RRMM) can include administering one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib). and can include performing one or more (e.g.. one, two, three, or more) anti-cancer approaches to treat cancer. Examples of anti-cancer approaches that can be used in combination with one or more oncolytic viruses and one or more anti-cancer agents to treat a mammal (e.g.. a human) having cancer (e.g., MM such as RRMM) as described herein include, without limitation, radiation therapies, adoptive cell transfer therapies, stem cell transplants, plasma exchange, and surgery. In cases where one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) are used in combination with one or more anti-cancer approaches to treat a mammal (e.g., a human) having cancer (e.g., MM such as RRMM), the one or more anti -cancer approaches can be performed at the same time as or independently of the administration of the one or more oncolytic viruses and the one or more anti-cancer agents. For example, one or more oncolytic viruses (e.g., a VSV such as VSV-IFNP-NIS) and one or more anti-cancer agents (e.g., an immune checkpoint inhibitor such as a PD1 inhibitor, and / or a proteosome inhibitor such as bortezomib) can be administered before, during, or after the one or more anti-cancer approaches are performed.In some cases, the cancer (e.g.. the number of cancer cells ) present within a mammal can be monitored. Any appropriate method can be used to determine whether or not the number of cancer cells present within a mammal is reduced. For example, flow cytometry, imaging techniques (e.g., MRI, CT, and / or PET scans), liquid biopsy, boneAttorney Docket No. 07039-2370W01 / 2025-110marrow biopsy, complete blood count (CBC), minimal residual disease (MRD) assays, and biomarker analysis (e.g.. circulating tumor DNA, tumor-specific antigens, or lactate dehydrogenase levels) can be used to assess the amount of cancer present within a mammal (e.g., a human).The invention will be further described in the following example, which does not limit the scope of the invention described in the claims.EXAMPLEExample 1 - Assessment of combination therapies for treating RRMM MethodsIn vivo studiesStudies utilized two VK*MYC models that spontaneously develop monoclonal gammopathy in C57BL6 mice. Transplantation or reimplantation of cancer cells (VK12598 and VK12653 splenocyte cell lines) allowed models to mimic end-stage, drugresistant aggressive multiple myeloma in humans. Mice that were intravenously transplanted with 2xl06Vkl2598 cells developed bortezomib-resistant multiple myeloma that responded completely to melphalan treatment and partially responded to doxorubicin. Mice survived about 2 weeks after high multiple myeloma burden. Mice that were intravenously transplanted with 2xl06Vkl2653 cells developed bortezomib-resistant multiple myeloma and survived about four weeks after high multiple myeloma burden.Mice were intravenously injected via the tail vein with Vkl2598 cells (about 2xl06cells, 100 pL per mouse) and treated as described in TABLE 2. VV1 was administered intravenously via the tail vein, and anti-CTLA4 antibody (100 pg / mouse; Clone 9D9), anti-PDl antibody (200 pg / mouse; CD279, Clone 29F.1A12), and bortezomib (20 pg / mouse) were administered intraperitoneally via the lower right abdomen. One dose of IxlO8TCID50 / ml VV1 was administered once on Day 0.Bortezomib was administered four times (on days 0, 4, 8, and 11). In mice receiving anti-PDl antibody treatment, the treatment was administered once on Day 0. In mice receiving repeated anti-PDl antibody treatments, treatments were administered on days 0, 5, 8, and 11. Studies proceeded over 80 days starting from tumor implantation (TABLE 3), and endpoints were assessed (TABLE 4).Attorney Docket No. 07039-2370W01 / 2025-110TABLE 2. In vivo study treatment groupsTABLE 3. In vivo study scheduleAttorney Docket No. 07039-2370W01 / 2025-110TABLE 4. In vivo study endpointsSamples were collected from the mice periodically throughout the study. Blood was collected via cheek bleeding into serum capped tubes. Serum was isolated from the blood and serum gel electrophoresis was run. An M-spike on serum gel electrophoresis was indicative of systemic MM disease. Bone marrow, spleen, lymph nodes, liver, kidney, and spine were harvested from the mice when possible.Flow cytometryFlow cytometry was performed to assess T cell activation. Briefly, a T-cell medium with cell stimulation cocktail (ratio: 100 mL medium + 0.2 mL cocktail) or PMA + lonomycin + Brelfeldin A (BFA) was made. After harvesting or thawing splenocytes and bone marrow cells, about 3-5xl06cells from each sample were incubated in cocktail medium in a 10 mL T25 flask at 37 °C, 5% CO2 for 4 hours. A cell count was performed at the end of the incubation. Cells needed for experiments were centrifuged (600xg for 5 minutes, 4°C) and resuspended in PBS to wash. Single-color compensation bead controls were prepared by mixing by vigorously inverting the beads at least 10 times or by pulse- vortexing. One drop of beads was added to each compensation tube as the compensation samples. Incubation with antibodies was performed in the dark at 4°C for 15-30 minutes).Extracellular staining was performed by resuspending a pellet of cells in 100 pL of PBS and 1 pL of live / dead antibody, mixing well, and incubating in the dark at room temperature for 15-30 minutes. The negative control was fixed with 4% paraformaldehyde. Cells were washed by adding 1 mL of PBS / BSA, centrifuged (600xg for 5 minutes, 4°C), and the supernatant was discarded. The wash step was repeated. Each pellet was resuspended in 100 pL of PBS / BSA and the required amount of cell surface antibodies (TABLE 5). Cells were mixed well and incubated in the dark at roomAttorney Docket No. 07039-2370W01 / 2025-110temperature for 15-30 minutes or 4°C for 30-60 minutes. Cells were washed by adding 1 mL of PBS / BSA, centrifuged (600xg for 5 minutes, 4°C), and the supernatant was discarded. The wash step was repeated.Intracellular staining was performed by resuspending cells in 100 pL (per well) or 250 pL (per tube) of fixation / permeabilization solution and incubating at 4°C for 20 minutes. Cells were washed twice in IX BD Perm / Wash buffer (250 pL per well; 1 mL per tube) and centrifuged to pellet (600xg for 5 minutes, 4°C). Cells were resuspended in 100 pL of BD Perm / Wash buffer containing anti-cytokine antibodies and incubated in the dark at 4°C for 30 minutes. Cells were washed twice with IX BD Perm / Wash buffer (250 pL per well; 1 mL per tube), centrifuged (600xg for 5 minutes, 4°C), and the supernatant was discarded. Cells were resuspended in 500 pL of 4% paraformaldehyde and incubated for 30 minutes. Cells were washed by adding 1 mL of PBS / BSA and centrifuging (600xg for 5 minutes, 4°C), and the supernatant was discarded. The wash step was repeated. Cells were resuspended in 500 pL of PBS / BSA and transferred to a round bottom tube. Data were acquired by flow cytometry.TABLE 5. Flow cytometry antibodiesAttorney Docket No. 07039-2370W01 / 2025-110ResultsTwo resistant Vk*MYC transplantable models (Vkl2598 and Vkl2653), each with distinct genomic features, were used in the experiments described herein. Upon retransplantation of splenocytes from these mice, flow cytometry revealed that both the Vkl2598 mice and the Vkl2653 mice had high MM populations in the spleen and bone marrow (FIG. 15). MM in the mouse models was detected noninvasively via M protein (M-spike band) in the serum. M proteins are dysfunctional antibodies, and MM and plasma cell disorder patients have high levels of these abnormal antibodies and their light chains accumulated in their blood (see, FIG. IB as compared to FIG. 1A). In serum protein assays, M proteins in the mouse models appeared in the gamma band (FIG. 2).VV 1 dose escalation studies performed to assess VV 1 efficacy in tumor-bearing mice demonstrated efficacy of VV1 in delaying MM development and prolonging survival in both mouse models, with Vkl2598 being the more responsive model. VV1 induced tumor remission in Vkl2598 models at low tumor burden (gamma / albumin ratio ~0.2). IFNP levels increased significantly post 24-72 hours of VV1 treatment in VV1 treated mice, indicating targeted infection and replication of the virus in MM cells.However, high doses of VV1 led to toxicity, as observed from early mortality' and weight loss. Timepoint harvests that w ere carried out to determine the sites of MM metastasis and VV1 infection showed the onset of MM of Vk*MYC in the bone marrow and spleen first, then later in the liver. Immunofluorescent staining confirmed that the higher the tumor burden observed, the more VV1 was present in the tissues.As described herein, combination therapies ofVVl with anti-PD-1 (aPDl) (an inhibitor of PD-1, which is overexpressed on MM patient T cells) and / or bortezomib (which inhibits NF-KB and in turn prevents IFN pathway protein transcription) were administered to the mouse models to determine whether VV1 efficacy was enhanced.In Vkl2598 mice intravenously implanted with 2x106splenocytes, treatment with aPDl or bortezomib alone or in combination did not result in a significant difference in survival (FIG.3).Treatment of Vkl2598 mice with VV1 was efficacious at extending median survival at a dose of IxlO8TCIDso / ml when compared to saline and doses of 1x106TCIDso / ml and 1 x lO7TCID5o / ml (FIG. 4). Treatment of mice with doses of IxlO6,Attorney Docket No. 07039-2370W01 / 2025-1101x107, or 1x108TCIDso / ml VV1 were well tolerated, wi th no significant weight changes or early mortality observed (FIG. 5).Treatment with aPDl alone did not increase median survival and was not efficacious, whereas VV1 + aPDl treatment was significantly efficacious and enhanced survival when compared to saline in Vkl2598 mice (FIG. 6). The addition of VV1 to aPDl increased median survival but was not significantly different from treatment with aPDl alone. Survival following VV1 + aPDl treatment also was not significantly different from that of VV 1 -only treated mice (FIG.6). Treatment with VV 1 and repeated dosing of aPDl resulted in the longest median survival, but it did not significantly increase survival compared to aPDl-only treatment (FIG. 6).Treatment with bortezomib alone did not increase median survival compared to saline and was not efficacious in Vkl2598 mice (FIG. 7). In contrast, VV1 + bortezomib treatment significantly enhanced survival and was efficacious when compared to saline treatment (FIG. 7). The addition of VV1 to bortezomib increased median survival and significantly increased treatment efficacy as compared to mice treated with bortezomib alone. However, VV1 + bortezomib survival was not significantly different from that of VV 1 treated mice (FIG. 7).VV1 + aPDl + bortezomib treatment was significantly more efficacious than any single or two-agent combination treatment (FIG. 8, FIG. 10, and TABLE 6). Survival of Vkl2598 mice treated with VV1 + aPDl or VV1 + bortezomib was not significantly different from that of VV1 treated mice. However, upon combining VV1, aPDl, and bortezomib, median survival doubled and survival was significantly greater than that of VV1 treated mice. Moreover, survival in mice treated with the three- agent (VV1, aPDl, and bortezomib) combination also was significantly different than that of mice treated with VV 1 + aPDl or VV 1 + bortezomib; in particular, median survival was nearly doubled as compared to survival in mice treated with VV1 + aPDl or VVl+bortezomib (FIG. 8). However, increasing the number of doses of aPDl did not increase survival for mice treated with VV1 + aPDl + bortezomib (FIG.9). The three-agent combination treatment resulted in strong tumor remission and control up to three weeks, as compared to the one- or two-agent treatments (FIG. 11).These results demonstrate that cancer (e.g., multiple myeloma such as RRMM) can be successfully treated using a combination that includes (a) an oncolytic virus (e.g.,Attorney Docket No. 07039-2370W01 / 2025-110a VSV such as VSV-IFNP-NIS), (b) an immune checkpoint inhibitor (e.g., an anti-PD-1, anti-PD-Ll, or anti-CTLA4 antibody), and (c) a proteosome inhibitor (e.g., bortezomib).TABLE 6. Differences in survival among between experimental treatment groupsAttorney Docket No. 07039-2370W01 / 2025-110Changes in T cell populations following treatment with VV1, VV1 + aPDl, or VV1 + aPDl + bortezomib also were assessed. For all treatment groups, the overall percentage of T cells increased from day 3 to day 15 post-treatment, the overall percentage of CD4+T cells decreased from day 3 to day 15, and the percentage of CD8+T cells increased by at least 2-fold (FIG. 12). VV1 + aPDl and VV1 + a-Dl + bortezomib treated groups had less of a decrease in CD4+T cells and stimulated more CD8+T cells by day 15 as compared to the VVl-only treated group.Markers of adaptive immune responses were also evaluated in CD8+and CD4 T cell populations following treatment with VV1, VV1 + aPDl, or VV1 + aPDl + bortezomib. Three days after treatment, mice treated with VV1 + aPDl + bortezomib had higher levels of IFNy secreting CD8+T cells compared to mice treated with only VV1. Fifteen days after treatment, all treatment groups showed an increase in cytotoxic T cells, with the largest increased in VVl-only treatment mice. In addition, a higher M-spike 15 days after treatment was correlated with a higher percentage of IFNy secreting CD8+T cells (FIG. 13A). Mice in all treatment groups showed a decrease in GrzB producing CD8+T cells fifteen days after treatment (FIG. 13B). Mice treated with VV1 + aPDl + bortezomib showed greater proliferation of CD8+cytotoxic T cells three days after treatment, as measured by Ki67 expression, as compared to other treatment groups (FIG. 13C). Mice showed an increase in the number of IFNy secreting CD4+T cells 15 days after treatment with VV1 alone, VV1 + aPDl, or VV1 + aPDl + bortezomib, with the largest increase in the number of IFNy secreting CD4+T seen in VVl-only treated mice (FIG. 14A). All treatment groups showed a decrease in the percentage of GrzB expressing CD4+T cells fifteen days after treatment (FIG. 14B). T cell proliferation took place earlier following all treatments, leading to increased levels of CD4+T cells in the spleen. However, CD4+T cell proliferation for all treatment groups returned back to normal / baseline levels after 15 days of treatment (FIG. 14C)OTHER EMBODIMENTSIt is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and notAttorney Docket No. 07039-2370W01 / 2025-110limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Attomey Docket No. 07039-2370W01 / 2025-110WHAT IS CLAIMED IS:

1. A method for treating cancer in a mammal, wherein said method comprises administering, to said mammal, an oncolytic virus, an immune checkpoint inhibitor, and a proteosome inhibitor, wherein, after said administering, the number of cancer cells within said mammal is reduced.

2. The method of claim 1, wherein said mammal is a human.

3. The method of claim 1 or claim 2, wherein said cancer is multiple myeloma.

4. The method of any one of claims 1-3, wherein said cancer is relapsed refractory multiple myeloma.

5. The method of any one of claims 1-4, further comprising identifying said mammal as having said cancer.

6. The method of any one of claims 1-5, wherein said oncolytic virus is a vesicular stomatitis virus (VSV).

7. The method of claim 6, wherein said VSV encodes an interferon beta (IFN0) polypeptide or a sodium iodide symporter (NIS) polypeptide.

8. The method of claim 7, wherein said VSV is a VSV-IFNP-NIS oncolytic virus.

9. The method of any one of claims 1-8, wherein said immune checkpoint inhibitor is a PD-1 inhibitor.

10. The method of claim 9, wherein said PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, tislelizumab, ipilimumab, tremelimumab, durvalumab, avelumab, atezolizumab, relatlimab, BMS-8, BMS-37, BMS-202, BMS-230, BMS-242, BMS-1001, BMS-1166, SB415286, vorinostat, decitabine, entitostat, JQ1, BET151, GSK5O3, panobinostat, ACY-Attorney Docket No. 07039-2370W01 / 2025-110241, azacytidine, DB36, DB71, DB15, CVN, MGCD0103, SNDX-275, IMP32, BMS986016, TSR-022, Sym023, ATIK2a, and DZNep.

11. The method of any one of claims 1-10, wherein said proteosome inhibitor is selected from the group consisting of bortezomib, carfilzomib, ixazomib, marizomib, and oprozomib.

12. The method of any one of claims 1-11, wherein said method comprises administering two or more different oncolytic viruses to said mammal.

13. The method of any one of claims 1-12, wherein said method comprises administering two or more different immune checkpoint inhibitors to said mammal.

14. The method of any one of claims 1-13, wherein said method comprises administering two or more different proteosome inhibitors to said mammal.

15. The method of any one of claims 1-14, wherein said method comprises administering an additional anti-cancer agent to said mammal, wherein said additional anti-cancer agent is selected from the group consisting of chemotherapeutic agents, targeted anti-cancer therapies, cytotoxic agents, and anti-angiogenic agents.

16. The method of any one of claims 1-15, wherein said method comprises performing an anti-cancer approach on said mammal, wherein said anti-cancer approach is selected from the group consisting of radiation therapies, adoptive cell transfer therapies, stem cell transplants, plasma exchange, and surgery.

17. A method for prolonging survival of a mammal identified as having cancer, wherein said method comprises administering, to said mammal, an oncolytic virus, an immune checkpoint inhibitor, and a proteosome inhibitor.

18. The method of claim 17, wherein said mammal is a human.

19. The method of claim 17 or claim 18, wherein said cancer is multiple myeloma.Attorney Docket No. 07039-2370W01 / 2025-11020. The method of any one of claims 17-19, wherein said cancer is relapsed refractory multiple myeloma.

21. The method of any one of claims 17-20, further comprising identifying said mammal as having said cancer.

22. The method of any one of claims 17-21, wherein said oncolytic virus is a vesicular stomatitis virus (VSV).

23. The method of claim 22, wherein said VSV encodes an interferon beta (IFN0) polypeptide or a sodium iodide symporter (NIS) polypeptide.

24. The method of claim 23, wherein said VSV is a VSV-IFNP-NIS oncolytic virus.

25. The method of any one of claims 17-24, wherein said immune checkpoint inhibitor is a PD-1 inhibitor.

26. The method of claim 25, wherein said PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, tislelizumab, ipilimumab, tremelimumab, durvalumab, avelumab, atezolizumab, relatlimab, BMS-8, BMS-37, BMS-202, BMS-230, BMS-242, BMS-1001, BMS-1166, SB415286, vorinostat, decitabine, entitostat, JQ1, BET151, GSK5O3, panobinostat, ACY-241, azacytidine, DB36, DB71, DB15, CVN, MGCD0103, SNDX-275, IMP32, BMS986016, TSR-022, Sym023, ATIK2a, and DZNep.

27. The method of any one of claims 17-26, wherein said proteosome inhibitor is selected from the group consisting of bortezomib, carfilzomib, ixazomib, marizomib, and oprozomib.

28. The method of any one of claims 17-27, wherein said method comprises administering two or more different oncolytic viruses to said mammal.

29. The method of any one of claims 17-28, wherein said method comprises administering two or more different immune checkpoint inhibitors to said mammal.Attorney Docket No. 07039-2370W01 / 2025-11030. The method of any one of claims 17-29, wherein said method comprises administering two or more different proteosome inhibitors to said mammal.

31. The method of any one of claims 17-30, wherein said method comprises administering an additional anti-cancer agent to said mammal, wherein said additional anticancer agent is selected from the group consisting of chemotherapeutic agents, targeted anticancer therapies, cytotoxic agents, and anti -angiogenic agents.

32. The method of any one of claims 17-31, wherein said method comprises performing an anti-cancer approach on said mammal, wherein said anti-cancer approach is selected from the group consisting of radiation therapies, adoptive cell transfer therapies, stem cell transplants, plasma exchange, and surgery.

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