USE OF ONCOLYTIC VIRUSES, ALONE OR IN COMBINATION WITH A CHECKPOINT INHIBITOR, FOR THE TREATMENT OF CANCER

Abstract

The present invention relates to the use of oncolytic viruses (e.g., talimogene laherparepvec), alone or in combination with immune checkpoint inhibitors (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 compounds such as an antibody) for the treatment of various types of cancer. Furthermore, the present invention relates to compositions and kits related to such uses of oncolytic viruses, alone or in combination with immune checkpoint inhibitors.

Description

USE OF ONCOLYTIC VIRUSES, ALONE OR IN COMBINATION WITH A CHECKPOINT INHIBITOR, FOR THE TREATMENT OF CANCER CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 USC 119(e) of United States provisional patent application number 62 / 471,875, filed on March 15, 2017, which is incorporated herein by reference. BACKGROUND OF THE INVENTION In light of advances in cancer therapy over the past few decades, the cancer mortality rate continues to decline in both men and women for the most common types of cancer, such as lung, colon, breast, and prostate cancer. This improvement in survival is likely due to progress in diagnosing certain cancers at an early stage, improvements in treatment, and the results of public health initiatives that encourage preventive measures and screening. Even so, cancer remains a major public health problem, with more than 1.6 million people diagnosed each year. Furthermore, cancer diagnoses have profound effects on patients, as well as their families and friends. In fact, cancer remains the second most common cause of death in the United States (second only to heart disease) and accounts for nearly one in four deaths. See progressreport.cancer.gov / introduction; accessed March 8, 2017. The desired goal of cancer therapy is to preferentially destroy cancer cells without harming normal cells. Various methods have been used in an attempt to achieve this goal, including surgery, radiation therapy, chemotherapy, and neolytic virus therapy. Local treatments, such as radiation therapy and surgery, offer a way to reduce tumor mass in areas of the body accessible through surgical techniques or high-dose radiation therapy. However, the primary approach to cancer treatment is chemotherapy. Chemotherapeutic agents, however, have limited effectiveness in treating many types of cancer, including many common solid tumors. This failure is due in part to drug resistance (either acquired or intrinsic) in many tumor cells. A major drawback of using chemotherapy agents is their severe side effects. These include bone marrow suppression, nausea, vomiting, hair loss, and mouth ulcers. Proposed alternative therapies include the administration of oncolytic viruses and the use of viral vectors to deliver a transgene with anticancer activity. Genetic engineering of viruses for use as oncolytic agents initially focused on using replication-incompetent viruses in an attempt to prevent virus-induced damage. non-tumor cells. A major limitation of this approach was that these replication-incompetent viruses required a helper virus to be able to integrate into and / or replicate within a host cell. The effectiveness of these viruses is limited because each replication-defective retrovirus particle can only enter a single cell and cannot productively infect others thereafter. Therefore, they cannot spread far from the producing cell and are unable to fully penetrate many tumors in vivo. More recently, genetic engineering of oncolytic viruses has focused on generating "replication-conditional" viruses in an effort to avoid systemic infection while still allowing the virus to spread to other tumor cells. Currently, the only approved oncolytic virus-based drug in the US and Europe is the talimogene laherparepvec (IMLYGIC®). The talimogene laherparepvec is an HSV-1 derived from the clinical strain JS1 (deposited in the European Cell Culture Collection (ECAAC) with accession number 01010209). In the talimogene laherparepvec, the HSV-1 viral genes encoding ICP34.5 and ICP47 have been functionally deleted. The functional deletion of ICP47 leads to earlier expression of US11, a gene that promotes viral growth in tumor cells without decreasing tumor selectivity. In addition, the sequence encoding human GM-CSF has been inserted into the viral genome at the former ICP34.5 gene sites. See, Liu et al., Gene Ther., 10: 292-303, 2003. Therapeutic combinations of oncolytic viruses and checkpoint inhibitors have been explored. For example, combinations of talimogene laherparepvec and immunotherapies (e.g., ipilimumab and pembrolizumab) are currently being explored in clinical trials in melanoma (document NCT01740297 and document NCT02263508) and head and neck squamous cell carcinoma (document NCT02626000). Checkpoint inhibitors, such as ipilimumab (an antibody against CTLA-4), pembrolizumab and nivolumab (anti-PD-1 antibodies), and atezolizumab (an anti-PD-L1 antibody), have demonstrated efficacy in a variety of tumor types. See Grosso et al., Cancer Immun., 13: 5 (2013); Pardoll, Nat Rev Cancer, 12: 252-264 (2012). and Chen et al., Immunity, 39: 1-10 (2013). However, there remains a need to further develop effective cancer therapies with reduced side effects (e.g., compared to chemotherapy). There is also a need to further develop effective cancer therapies that are effective against metastatic cancers. The present invention addresses these and other needs. SUMMARY OF THE INVENTION In one embodiment, the present invention relates to a method of treating Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer (i.e., colon cancer), melanoma, squamous cell carcinoma (e.g., squamous cell carcinoma of the head and neck), hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma by administering a therapeutically effective amount of an oncolytic virus. In some embodiments, the cancer is metastatic cancer. In some embodiments, the oncolytic virus is a herpes simplex virus. The herpes simplex virus may be herpes simplex virus 1. In some embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene.Herpes simplex virus 1 can also be modified so that: (i) it does not contain an intact ICP34.5 gene; and (ii) it does not contain an intact ICP47 gene. In further embodiments, herpes simplex virus 1 is modified so that: (i) it does not contain an intact ICP34.5 gene; (ii) it does not contain an intact ICP47 gene; and (ii) it contains a gene encoding GM-CSF (e.g., human GM-CSF). In one particular embodiment, the oncolytic virus is talimogene laherparepvec. The present invention also relates to a method of treating B-cell lymphoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma) by administering: (i) a therapeutically effective amount of an oncolytic virus; and (ii) a therapeutically effective amount of a checkpoint inhibitor. In some embodiments, the cancer is metastatic. In some embodiments, the checkpoint inhibitor is a CTLA-4 blocker (e.g., an anti-CTLA-4 antibody). In particular embodiments, the anti-CTLA-4 antibody is ipilimumab. In some embodiments, the checkpoint inhibitor is a PD-L1 blocker (e.g., an anti-PD-L1 antibody). In particular embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the checkpoint inhibitor is a PD-1 blocker (e.g., an anti-PD-1 antibody).In certain embodiments, the anti-PD-1 antibody is either nivolumab or pembrolizumab. In some embodiments, the oncolytic virus is a herpes simplex virus. The herpes simplex virus may be herpes simplex virus 1. In some embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene. Herpes simplex virus 1 may also be modified such that: (i) it does not contain an intact ICP34.5 gene; and (i) it does not contain an intact ICP47 gene. In still other embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; (i) it does not contain... 4 an intact ICP47 gene; and (iii) contains a gene encoding GM-CSF (e.g., human GM-CSF). In one particular embodiment, the oncolytic virus is talimogene laherparepvec. In one specific embodiment, the present invention also relates to a method of treating B-cell lymphoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma) by administering: (i) a therapeutically effective amount of an oncolytic virus (e.g., talimogene laherparepvec); and (ii) a therapeutically effective amount of a CTLA-4 blocker (e.g., an anti-CTLA-4 antibody such as, for example, ipilimumab). In some embodiments, the cancer is metastatic.In another embodiment, the present invention relates to a method of treating B-cell lymphoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma) by administering: (i) a therapeutically effective amount of an oncolytic virus (e.g., talimogene laherparepvec); and (ii) a therapeutically effective amount of a PD-L1 blocker (e.g., an anti-PD-L1 antibody such as, e.g., atezolizumab).In other embodiments, the present invention relates to a method of treating B-cell lymphoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma) by administering: (i) a therapeutically effective amount of an oncolytic virus (e.g., talimogene laherparepvec); and (ii) a therapeutically effective amount of a PD-1 blocker (e.g., an anti-PD-1 antibody such as, e.g., nivolumab or pembrolizumab). The present invention also relates to a method of treating B-cell lymphoma by administering: (i) a therapeutically effective amount of an oncolytic virus; and (ii) a therapeutically effective amount of a GITR agonist. In some embodiments, the cancer is metastatic B-cell lymphoma. In particular embodiments, the GITR agonist is: AMG228 (also known as 9H6v3), TRX518, MEDI1873, or MK-4166. See PCT Publication No. 2WO2015031667 and U.S. Patent 9,464,139, which are incorporated by reference in their entirety. In some embodiments, the oncolytic virus is a herpes simplex virus. The herpes simplex virus may be herpes simplex virus 1. In some embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene. The herpes simplex virus 1 may also be modified such that: (i) it does not contain an intact ICP34.5 gene; and (ii) it does not contain an intact ICP47 gene. In still other embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; (ii) it does not contain an intact ICP47 gene; and (ii) it contains a gene encoding GM-CSF (e.g., human GM-CSF). In one particular embodiment, the oncolytic virus is talimogene laherparepvec. The present invention further relates to a therapeutically effective quantity of an eneolytic virus for use in the treatment of Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma. In some embodiments, the cancer is metastatic cancer.In another aspect, the present invention relates to a pharmaceutical composition for use in a method of treating Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma, wherein the pharmaceutical composition comprises an oncolytic virus. In such embodiments, the oncolytic virus may be a herpes simplex virus. The herpes simplex virus may be herpes simplex virus 1. In some embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene.In other embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; and (ii) it does not contain an intact ICP47 gene. In still other embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; (ii) it does not contain an intact ICP47 gene; and (ii) it contains a gene encoding GM-CSF (e.g., human GM-CSF). In one particular embodiment, the oncolytic virus is talimogene laherparepvec. In other aspects, the present invention relates to a therapeutically effective amount of an oncolytic virus and a checkpoint inhibitor for use in the treatment of B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma). In some embodiments, the cancer is metastatic. In another embodiment, the present invention relates to a pharmaceutical composition for use in a method of treating B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma), wherein the pharmaceutical composition comprises a therapeutically effective amount of an oncolytic virus and a checkpoint inhibitor.In these embodiments, the checkpoint inhibitor is a CTLA-4 blocker (e.g., an anti-CTLA-4 antibody). In particular embodiments, the anti-CTLA-4 antibody is ipilimumab. In some In some embodiments, the checkpoint inhibitor is a PD-L1 blocker (e.g., an anti-PD-L1 antibody). In particular embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the checkpoint inhibitor is a PD-1 blocker (e.g., an anti-PD-1 antibody). In particular embodiments, the anti-PD-1 antibody is nivolumab or pembrolizumab. In some embodiments, the eneolytic virus is a herpes simplex virus. The herpes simplex virus may be herpes simplex virus 1. In some embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene. In other embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; and (i) it does not contain an intact ICP47 gene. In other embodiments, the herpes simplex virus 1 is modified so that: (i) it does not contain an ICP34 gene.5 intact; (i) does not contain an intact ICP47 gene; and (ii) contains a gene encoding GM-CSF (e.g., human GM-CSF). In one particular embodiment, the oncolytic virus is talimogene laherparepvec. Furthermore, the present invention relates to a therapeutically effective quantity of an oncolytic virus (e.g., talimogene laherparepvec) and a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody such as, for example, ipilimumab) for use in the treatment of B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma). In some embodiments, the cancer is metastatic cancer.In another embodiment, the present invention relates to a therapeutically effective quantity of an oncolytic virus (e.g., talimogene laherparepvec) and a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody such as, for example, atezolizumab) for use in the treatment of B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma). In another embodiment, the present invention relates to a therapeutically effective quantity of an oncolytic virus (e.g., talimogene laherparepvec) and a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as, for example, nivolumab or pembrolizumab). In some embodiments, the oncolytic virus is a herpes simplex virus. The herpes simplex virus may be herpes simplex virus 1.In some embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene. In other embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; and (ii) it does not contain an intact ICP47 gene. In still other embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; (ii) it does not contain an intact ICP47 gene; and (ii) it contains a gene encoding GM-CSF (e.g., human GM-CSF). In one particular embodiment, the oncolytic virus is talimogene laherparepvec. In another embodiment, the present invention relates to a pharmaceutical composition for use in a method of treating B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma), wherein the pharmaceutical composition comprises a therapeutically effective amount of an eneolytic virus (e.g., talimogene laherparepvec) and a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody such as ipilimumab). In some embodiments, the cancer is metastatic.In another embodiment, the present invention relates to a pharmaceutical composition for use in a method of treating B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma), wherein the pharmaceutical composition comprises a therapeutically effective amount of an oncolytic virus (e.g., talimogene laherparepvec) and a PD-L1 blocker (e.g., an anti-PD-L1 antibody such as, e.g., atezolizumab).In another embodiment, the present invention relates to a pharmaceutical composition for use in a method of treating B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma), wherein the pharmaceutical composition comprises a therapeutically effective amount of an oncolytic virus (e.g., talimogene laherparepvec) and a PD-1 inhibitor (e.g., an anti-PD-1 antibody such as, for example, nivolumab or pembrolizumab). In some embodiments, the oncolytic virus is a herpes simplex virus. The herpes simplex virus may be herpes simplex virus 1. In some embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene. In other embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an ICP34 gene.5 intact; and (ii) does not contain an intact ICP47 gene. In further embodiments, the herpes simplex virus 1 is modified so that: (i) it does not contain an intact ICP34.5 gene; (ii) it does not contain an intact ICP47 gene; and (ii) it contains a gene encoding GM-CSF (e.g., human GM-CSF). In one particular embodiment, the oncolytic virus is talimogene laherparepvec. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Figure 1 shows the effect of intratumoral administration of talimogene laherparepvec on the tumor volume of an A-673 Ewing sarcoma in Balb / c nude mice. FIG. 2. Figure 2 shows the effect of intratumoral administration of talimogene laherparepvec on the tumor volume of an SK-N-AS neuroblastoma in Balb / c nude mice. FIG. 3. Figure 3 shows the effect of intratumoral administration of talimogene laherparepvec on the volume of a G-401 rhabdoid tumor in Balb / c nude mice. FIG. 4. Figure 4 shows the effect of intratumoral administration of talimogene laherparepvec on the tumor volume of an SJSA-1 osteosarcoma in Balb / c nude mice. FIG. 5. Figure 5 shows the effect of intratumoral administration of talimogene laherparepvec on the tumor volume of an SJCRH30 rhabdomyosarcoma in Balb / c nude mice. FIG. 6. Figure 6 shows the degree of cell growth inhibition achieved by increasing the concentrations of talimogene laherparepvec in the cell strains of LDCBG WSU-NHL (GOB subtype) and TMD8 (ABC subtype). FIG. 7. Figure 7 shows the degree of cell growth inhibition achieved by increasing the concentrations of talimogene laherparepvec in the HCT-116 (colorectal cancer) and SK-MEL-5 (melanoma) cell lines. FIG. 8. Figure 8 shows the degree of cell growth inhibition achieved by increasing the concentrations of talimogene laherparepvec in the HUT-78 (LCLT) and RPMI 8226 (multiple myeloma) cell lines. FIG. 9. Figure 9 shows the degree of cell growth inhibition achieved by increasing the concentrations of talimogene laherparepvec in the CT-26 and MC-38 cell lines (colorectal cancer). FIG. 10a-1 Figure 10a shows the effect on the volume of tumors injected into A20 tumor-bearing animals with OncoVex mGMCSF in three doses: 3x10 4 UFP, 3x10 5 UFP and 3x10 6 UFP. Figure 10b shows the effect on the volume of non-injected (contralateral) tumors in A20 tumor-bearing animals with OncoVex mGMCSF in three doses: 3x10 4 UFP, 3x10 5 UFP and 3x10 6UFP. Figure 10c shows the effect on median survival of A20 tumor-bearing animals treated with OncoVex mGM CSF in three doses: 3x10 4 UFP, 3x10 5 UFP and 3x10 6 UFP. Figures 10d and 10e show the effect of OncoVex administration mGM CSF , anti-CTLA-4 mAb and a combination of OncoVex mGM CSF and anti-CTLA-4 mAb on mouse body weight. Figure 10f shows the effect on tumor volume of injected neuro2a neuroblastoma tumor-bearing mice with OncoVex. rnGM CSF in three doses: 5x10 4 UFP, 5x10 5 UFP and 5x10 6 UFP. Figure 10g shows the effect on median survival of neuroblastoma neuro2a tumor-bearing mice treated with OncoVex mGM CSF in three doses: 5x10 4 UFP, 5x10 5 UFP and 5x10 6UFP. Figure 10h shows the effect on the volume of injected (treated) and non-injected (contralateral / untreated) tumors in neuro2a neuroblastoma tumor-bearing mice with OncoVex mGM CSF 5x10 6 UFP. Figure 10 shows the effect on the median survival of neuroblastoma neuro2a tumor-bearing mice treated with OncoVex mGMCSF 5x10 6 UFP. FIG. 11 a-11d. Figure 11a shows the effect of treating A20 tumor-bearing animals with OncoVex mGMGSF , an anti-CTLA-4 mAb, or the OncoVex combination mGM_ CSF with an anti-CTLA-4 mAb on the volume of directly injected tumors and non-injected (contralateral) tumors. Figure 11b shows the effect of treating A20 tumor-bearing animals with OncoVex mGMCSF , an anti-CTLA-4 mAb, or the OncoVex combination mGMCSFwith an anti-CTLA-4 mAb on the median survival of mice. Figure 11c shows the effect of treating A20 tumor-bearing animals with OncoVex mGMCSF , an anti-PD-L1 mAb, or the OncoVex combination mGM CSF with an anti-PD-L1 mAb on the volume of directly injected tumors and non-injected (contralateral) tumors. Figure 11d shows the effect of treating A20 tumor-bearing animals with OncoVex mGMCSF , an anti-PD-L1 mAb, or the OncoVex combination mGM CSF with an anti-PD-L1 mAb on the median survival of mice. FIG. 12a-12g. Figure 12a shows the effect of treating CT-26 tumor-bearing animals with OncoVex mGMCSF , anti-CTLA-4 mAb, or the OncoVex combination mGM CSF and an anti-CTLA-4 mAb on the volume of directly injected tumors and non-injected (contralateral) tumors. Figure 12b shows the effect of treating CT-26 tumor-bearing animals with OncoVex mGMCSF , anti-CTLA-4 mAb, or the OncoVex combination mGM CSF and an anti-CTLA-4 mAb on the median survival of mice. Figure 12c shows the effect of treating CT-26 tumor-bearing animals with OncoVex mGM CSF , anti-PD-L1 mAb or the OncoVex combination mGM CSF and an anti-PD-L1 mAb on the volume of directly injected tumors and non-injected (contralateral) tumors. Figure 12d shows the effect of treating CT-26 tumor-bearing animals with OncoVex mGM CSF , anti-PD-L1 mAb, or the OncoVex combination mGM CSF and an anti-PD-L1 mAb on the median survival of the mice. Figures 12e and 12f show the quantification of CD8 T lymphocytes +Systemic (splenic) anti-AH1 antibodies were detected by ELISpot or by dextramer staining using FACS in CT-26 tumor-bearing mice treated with OncoVex. mGM CSF CTLA-4 blockade, or the combination of OncoVex mGM CSF and CTLA-4 blockade. Figure 12g shows the quantification of CD8 T lymphocytes + Local (tumor) anti-AH1 antibodies in CT-26 tumor-bearing mice treated with OncoVex mGMCSF CTLA-4 blockade, or the combination of OncoVex mGM CSF and CTLA-4 blocking. FIG. 13a-13d. Figure 13a shows the effect of treating Nectin 1 B16F10 tumor-bearing mice with a control, OncoVex. mGMCSF CTLA-4 blockade, or the combination of OncoVex mGMCSF and CTLA-4 blockade on the volume of injected tumors. Figure 13b shows the assessment of the burden of pulmonary metastasis in Tumor-bearing mice (demonstrated by the number of lung metastases) after treatment with a control, OncoVexmGMCSF CTLA-4 blockade, or the combination of OncoVex mGMCSF and CTLA-4 blockade. Figure 13c shows the effect of treatment with control or the combination of OncoVex mGM CSF and CTLA-4 blockade on median survival in tumor-bearing mice. Figure 13d shows that macrophages were prominent both in the tumor and in dense cellular infiltrates at the tumor periphery, whereas B cells remained exclusively at the tumor periphery after treatment with the control, OncoVex. mGM CSF CTLA-4 blockade, or the combination of OncoVex mGM CSF and CTLA-4 blocking. FIG. 14. Figure 14 shows the effect of the treatment of 4T1 tumor-bearing mice with control or OncoVex mGM CSF on the volume of injected tumors. FIG. 15a and 15b. Figure 15a shows the effect of treating A20 tumor-bearing animals with OncoVex mGMCSF, anti-GITR mAb, or the OncoVex combination mGM CSF and an anti-GITR mAb on the volume of directly injected tumors and non-injected (contralateral) tumors. Figure 15b shows the effect of treating A20 tumor-bearing animals with OncoVex mGM CSF , anti-GITR mAb, or the OncoVex combination mGM CSF and an anti-GITR mAb on the median survival of mice. Figures 16a and 16b. Figure 16a shows the effect of OncoVex administration mGM CSF , anti-PD-1 mAb, and OncoVex combinations mGM CSF and anti-PD-1 mAb on mouse body weight. Figure 16b shows the effect of treating MC-38 tumor-bearing animals with OncoVex mGMCSF , anti-PD-1 mAb or the OncoVex combination mGMCSF and an anti-PD-1 mAb on the volume of directly injected tumors and non-injected (contralateral) tumors. FIG 17. Figure 17 shows the effect of treating MC-38 tumor-bearing animals with OncoVex mGM CSF , anti-PD-L1 mAb, or the OncoVex combination mGM CSF and an anti-PD-L1 mAb on the volume of directly injected tumors and non-injected (contralateral) tumors. FIG 18. Figure 18 shows the effect of treating B16F10 tumor-bearing animals with OncoVex mGMCSF , anti-PD-1 mAb, or the OncoVex combination mGMCSF and an anti-PD-1 mAb on the volume of tumors injected directly. DETAILED DESCRIPTION The section headings used in this document are for organizational purposes only and should not be interpreted as limiting the subject matter described. All references cited within the body of this descriptive report are expressly incorporated by reference in their entirety. Conventional techniques for recombinant DNA, oligonucleotide synthesis, tissue culture and transformation, protein purification, etc., can be used. Enzymatic reactions and purification techniques can be performed according to the manufacturer's specifications or as is customarily achieved in the art or as described herein. The following procedures and techniques can generally be performed according to well-known conventional methods in the art and as described in various general and more specific references cited and discussed throughout this document. See, for example, Sambrook et al., 2001, Molecular Cloning: A Laboratory Manual, 3 aed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, which is incorporated herein by reference for any purpose. Unless specific definitions are provided, the nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the field. Conventional techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery and treatment of patients. ONCOLYTIC VIRUSES As discussed herein, the present invention demonstrates that oncolytic viruses are capable of generating antitumor effects in a variety of tumor types, either alone or in combination with checkpoint inhibitors. A striking advantage of the oncolytic viruses of the present invention is that, compared to, for example, chemotherapy, the antitumor effects are accompanied by fewer severe / negative side effects. For example, in one embodiment, the present invention relates to the use of oncolytic viruses in the treatment of cancer.In another embodiment, the present invention relates to the use of oncolytic viruses to treat Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma. In another embodiment, the present invention relates to the use of a combination of an oncolytic virus and a checkpoint inhibitor to treat B-cell lymphoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma). In some embodiments, the oncolytic virus is a herpes simplex virus. The herpes simplex virus may be herpes simplex virus 1. In some embodiments, the herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene. In others In 12 embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; and (ii) it does not contain an intact ICP47 gene. In further embodiments, herpes simplex virus 1 is modified such that: (i) it does not contain an intact ICP34.5 gene; (ii) it does not contain an intact ICP47 gene; and (ii) it contains a gene encoding GM-CSF (e.g., human GM-CSF). In one particular embodiment, the eneolytic virus is talimogene laherparepvec. The talimogene laherparepvec, VHS-1 [strain JS1] ICP34.57ICP47- / hGM-CSF, (formerly known as OncoVex GM CSF), is an oncolytic immunotherapy delivered intratumorally comprising an immune-enhanced HSV-1 that selectively replicates in solid tumors. (Luí et al., Gene Therapy, 10: 292-303, 2003; U.S. Patent No. 2 7,223,593 and U.S. Patent No. 27,537,924). HSV-1 was obtained from the JS1 strain deposited in the European Cell Culture Collection (ECAAC) with accession number 01010209. In the laherparepvec thalimogene, the HSV-1 viral genes encoding ICP34.5 have been functionally deleted. Functional deletion of ICP34.5, which acts as a virulence factor during HSV infection, limits replication in non-dividing cells and renders the virus non-pathogenic. The safety of HSV with functionally suppressed ICP34.5 has been demonstrated in multiple clinical studies (MacKie et al, Lancet 357: 525-526, 2001; Markert et al, Gene Ther7: 867-874, 2000; Rampling et al, Gene Ther7: 859-866, 2000; Sundaresan et al, J. Virol 74: 3822-3841, 2000; Hunter et al, JV / ro / August; 73 (8): 6319-6326, 1999). Furthermore, ICP47 (which blocks viral antigen presentation to class I and II major histocompatibility complex molecules) has been functionally suppressed from the talimogene laherparepvec.Functional deletion of ICP47 also leads to earlier expression of US11, a gene that promotes viral growth in tumor cells without decreasing tumor selectivity. As used herein, "non-functional" viral gene means that the gene(s) are partially or completely deleted, replaced, rearranged, or otherwise altered in the herpes simplex genome such that a functional viral protein can no longer be expressed from that gene by the herpes simplex virus. The sequence encoding human GM-CSF, a cytokine involved in stimulating immune responses, has been inserted into the viral genome (at the two preceding ICP34.5 gene sites) of the thalimogene laherparepvec. The insertion of the gene encoding human GM-CSF is such that it replaces almost the entire ICP34 gene.5, ensuring that any potential recombination event between talimogene laherparepvec and wild-type virus can only result in a disabled, non-pathogenic virus and cannot result in the generation of wild-type viruses carrying the gene for human GM-CSF. The HSV thymidine kinase (TK) gene remains intact in talimogene laherparepvec, which makes the virus... 13 is sensitive to antiviral agents such as acyclovir. Therefore, acyclovir can be used to block the replication of talimogene laherparepvec, if necessary. Examples of additional HSV genes that can be modified include ICP6, the large ribonucleotide reductase subunit, involved in nucleotide metabolism and viral DNA synthesis in non-dividing cells but not in dividing cells. Thymidine kinase, responsible for phosphorylating acyclovir to acyclovir monophosphate, the virion trans-activating protein vmw65, glycoprotein H, vhs, ICP43, and the immediate early genes encoding ICP4, ICP27, ICP22, and / or ICPO can also be modified. Modifications can also be made to alter the timing of herpes simplex virus gene expression. For example, US11 can be expressed as an early gene by placing the US11 gene with the Us12 promoter, Mulvey et al. (1999) J Virology, 73: 4, 3375-3385, U.S. Patent No. US5824318, Mohr & Gluzman (1996) EMBO 15: 4759-4766. As experts in the field would appreciate, heterologous genes, such as those encoding human GM-CSF, can be inserted into the HSV viral genome, and viral genes, such as ICP34.5 and ICP47, can be functionally suppressed using homologous recombination with plasmid DNA. The talimogene laherparepvec produces a direct neolytic effect by replicating the virus within the tumor and inducing an antitumor immune response enhanced by local GM-CSF expression and the release of tumor-derived antigens through lysis. Since many cancers are present as both primary and secondary (i.e., metastatic) tumors in patients, this dual activity is beneficial as a therapeutic approach. The anticipated clinical effects include the destruction of injected tumors, the destruction of local, locoregional, and distant non-injected tumors, a reduction in the development of new metastases, a reduction in the overall progression rate and the relapse rate following treatment of the initially present disease, and prolonged overall survival. As used herein, the terms "patient" and "subject" are used interchangeably and mean a mammal, including, but not limited to, a human or non-human mammal such as a bovine, equine, canine, ovine, or feline. Preferably, the patient is a human being. Talimogene laherparepvec and OncoVex mGMCSF (a VHS-1 virus with the same genetic modifications as talimogene laherparepvec, except that human GM-CSF is replaced by murine GM-CSF) has been approved to determine its efficacy in a variety of murine tumor models in vitro (cell lineage) and in vivo and has been shown to eradicate tumors or substantially inhibit their growth at doses comparable to those 14 used in clinical studies. Non-clinical evaluation has also confirmed that GM-CSF potentiates the generated immune response, enhancing both injected and non-injected tumor responses, and that the increased surface levels of MHC class I molecules result from ICP47 suppression. The talimogene laherparepvec has been injected into normal and tumor-bearing mice to assess its safety. Overall, the virus has been well tolerated, and doses up to 1 x 10 8 UFP / doses have not shown any indication of safety problems. (See, for example, Liu et al., Gene TherlO: 292-303, 2003) Clinical trials have been or are underway in several types of advanced tumors with over 400 subjects treated with talimogene laherparepvec (see, for example, Hu et al., Clin Can Res 12: 6737-6747, 2006; Harrington et al., J Clin Oncol. 27 (15a): abstract 6018, 2009; Kaufman et al., Ann Surgic Oncol. 17: 718-730, 2010; Kaufman and Bines, Future Oncol. 6 (6): 941-949, 2010). Clinical data indicate that talimogene laherparepvec has the potential to provide overall clinical benefit to patients with advanced melanoma. In particular, a high complete response rate was achieved in stage IV melanoma (Scenzer et al., J. Clin. Oncol. 271 (12): 907-913, 2009). Furthermore, responses were observed at both injected and non-injected sites, including visceral sites. The viruses of the invention may also be derived from a herpes simplex virus 2 (HSV-2) strain or a derivative thereof. Derivatives include intertype recombinants containing DNA from both HSV-1 and HSV-2 strains. Such intertype recombinants are described in the art, for example, in Thompson et al., (1998) Virus Genes 1 (3); 275-286 and Meignier et al., (1998) J. Infect. Dis. 159; 602-614. Herpes simplex virus strains can be derived from clinical isolates. These strains are isolated from infected individuals, such as those with recurrent oral herpes. Clinical isolates can be explored to determine a desired capability or characteristic, such as enhanced replication in tumor cells and / or other cells in vitro and / or in vivo compared to conventional laboratory strains, as described in U.S. Patent Nos. 7,063,835 and 7,223,593, each of which is incorporated by reference in its entirety. In one embodiment, the herpes simplex virus is a clinical isolate from recurrent oral herpes. Viral strains of herpes simplex virus 1 include, but are not limited to, strain JS1, strain 17+, strain F and strain KOS, and strain Patton. Other examples of modified herpes simplex viruses include, but are not limited to, the Seprehvir™ (HSV1716) 17+ strain of herpes simplex virus type 1 that has a 759 bp deletion located within each copy of the BamHI fragment (0 to 0-02 and 0-81 to 0.83 map units) of the long repeat region of the VHS genome, removing a complete copy of the 18 bp DR element from the 'a' sequence and terminating 105 bp upstream of the 5' end of the immediate early gene 1 (1E), see MacLean et al., (1991) Journal of General Virology 79: 631-639). G207, an eneolytic HSV-1 derived from the wild-type HSV-1 F strain that has deletions in both copies of the major determinant of HSV neurovirulence, the ICP 34.5 gene, and an inactivating insertion of the E. coli lacZ gene at UL39, which encodes infected cell protein 6 (ICP6), see Mineta et al. (1995) NatMed. 1: 938-943. OrienXOlO, a herpes simplex virus with deletion of both copies of y34.5 and the ICP47 genes, as well as disruption of the ICP6 gene and insertion of the human GM-CSF gene, see Liu et al., (2013) World Journal of Gastroenterology 19 (31): 5138-5143. NV1020, a herpes simplex virus with the joint region of the long (L) and short (S) regions deleted, including one copy of ICP34.5, UL24 and UL56.34,35. The deleted region was replaced with a fragment of HSV-2 US DNA (US2, US3 (PK), gj and gG), see Todo, et al. (2001) Proc Natl Acad Sel USA. 98: 6396-6401. M032, a herpes simplex virus with deletion of both copies of the ICP34.5 genes and insertion of interleukin 12, see Cassady and Ness Parker, (2010) The Open Virology Journal 4:103-108. ImmunoVEX VHS-2 is a herpes simplex virus (HSV-2) that has functional deletions of the genes encoding vhs, ICP47, ICP34.5, UL43 and US5. OncoVex GALV / CDIt is also derived from the JS1 strain of HSV-1 with the genes encoding ICP34.5 and ICP47 functionally deleted and the gene encoding gibbon monkey leukemia cytosine deaminase and fusogenic glycoprotein inserted into the viral genome in place of the ICP34.5 genes. Additional examples of modified herpes simplex viruses include G47delta, G47delta IL-12, ONCR-001, GrienX-010, NSC 733972, HF-10, BV-2711, JX-594, Myb34.5, AE-618, Brainwel™ and Heapwel™. The strains of the herpes virus and how to create such strains are also disclosed in U.S. Patent Numbers US5824318; US6764675; US6,770,274; US7,063,835; US7,223,593; US7749745; US7744899; US8273568; US8420071; US8470577; WIPO Publication Numbers: W0199600007; WO199639841; WO199907394; W0200054795; W02006002394; WO201306795; Chinese Patent Numbers: CN128303, CN10230334 and CN 10230335; Varghese and Rabkin, (2002) Cancer Gene Therapy 9: 967-97 and Cassady and Ness Parker, (2010) The Open Virology Journal 4: 103-108, each of which is incorporated herein by reference. CHECKPOINT INHIBITORS Immune checkpoints are proteins that regulate certain types of immune system cells, such as T lymphocytes (which play a central role in cell-mediated immunity). While immune checkpoints help keep immune responses in check, they can also prevent T lymphocytes from destroying cancer cells. Immune checkpoint inhibitors (or simply "checkpoint inhibitors") can block the activity of the immune checkpoint protein, releasing the "brakes" on the immune system and allowing T lymphocytes to better destroy cancer cells. As used herein, the term "immune checkpoint inhibitor" or "checkpoint inhibitor" refers to molecules that reduce, inhibit, interfere with, or modulate, wholly or partially, one or more checkpoint proteins. Checkpoint proteins regulate the activation or function of T lymphocytes. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer: 252-264, 2012). These proteins are responsible for costimulatory or inhibitory interactions of T lymphocyte responses. Immune checkpoint proteins regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or may be derived from antibodies. Checkpoint inhibitors can include small-molecule inhibitors or antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blockade or inhibition include, but are not limited to, CTLA-4, PD-L1, PD-L2, PD-1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, and 2B4 (which belongs to the CD2 family of molecules and is expressed on all T, NK, and CD8 lymphocytes). +memory (ap)), CD160 (also called BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biological therapies, or small molecules that bind to, and block or inhibit the activity of, one or more of CTLA-4, PD-L1, PD-L2, PD-1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Cytotoxic T-cell-associated protein 4 (CTLA-4) is an immune checkpoint molecule that negatively regulates T-cell activation pathways. CTLA-4 is a negative regulator of T-cell activation. Blocking it has been shown to 17 CTLA-4 increases T lymphocyte activation and proliferation. The combination of herpes simplex virus and anti-CTLA-4 antibody aims to enhance T lymphocyte activation through two different mechanisms in order to increase the antitumor immune response to the tumor antigen released after lytic viral replication in the tumor. Therefore, the combination of herpes simplex virus and anti-CTLA-4 antibody can enhance the destruction of both injected and non-injected / distal tumors, improve the overall tumor response, and prolong overall survival, particularly when the overall survival prolongation is compared to that obtained using anti-CTLA-4 antibody alone. Programmed cell death protein 1 (PD-1) is a 288-amino-acid cell surface protein molecule expressed on T lymphocytes and pro-B cells and plays a role in their fate / differentiation. The two ligands of PD-1, PD-L1 and PD-L2, are members of the B7 family. PD-1 limits T lymphocyte activity in peripheral tissues during an inflammatory response to infection. Blocking PD-1 in vitro enhances T lymphocyte proliferation and cytokine production in response to stimulation by specific antigen targets or allogeneic cells in mixed lymphocyte reactions. A strong correlation between PD-1 expression and response to PD-1 blockade has been shown (Pardoll, Nature Reviews Cancer, 12: 252-264, 2012). PD-1 blockade can be achieved through a variety of mechanisms, including antibodies that bind to PD-1 or PD-L1. Programmed cell death ligand 1 (PD-L1), also called differentiation cluster 274 (CD274) or B7 homolog 1 (B7-H1), is a protein encoded by the CD274 gene. See Entrez Gene: CD274 CD274 molecule. PD-L1, a 40 kDa type 1 transmembrane protein that plays a role in immune suppression, binds to its receptor (PD-1) found on activated T lymphocytes, B cells, and myeloid cells to modulate cell activation or inhibition. See Chemnitz et al., Journal of Immunology, 173 (2):945-54 (2004). Other immune checkpoint inhibitors include lymphocyte activation gene 3 (LAG-3) inhibitors, such as IMP321, a soluble Ig fusion protein (Bñgnone et al., 2007, J. Immunol. 179: 4202-4211). Also included are B7 inhibitors, such as B7-H3 and B7-H4 inhibitors (e.g., the anti-B7-H3 antibody MGA271 (Loo et al., 2012, Clin. Cancer Res. July 15 (18) 3834). Another checkpoint inhibitor is TIM3 (T-cell immunoglobulin domain and mucin domain 3) (Fourcade et al., 2010, J. Exp. Med. 207: 2175-86 and Sakuishi et al., 2010, J. Exp. Med. 207: 2187-94). As further described herein, in one aspect, the present invention relates to the use of combinations of eneolytic viruses and inhibitors of 18. Checkpoint for the treatment of cancers. In another aspect, the present invention relates to pharmaceutical compositions comprising the combination of eneolytic viruses and checkpoint inhibitors. Therefore, in one aspect of the present invention, the checkpoint inhibitor is a blocker of or inhibitor of CTLA-4, PD-1, PD-L1, or PD-L2. In some embodiments, the checkpoint inhibitor is a CTLA-4 blocker or inhibitor such as tremretirumab, ipilimumab (also known as 10D1, MDX-D010), BMS-986249, AGEN-1884, and anti-CTLA-4 antibodies described in U.S. Patent Nos. 2: 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; ​​6,682,736; 6,984,720; and 7,605,238, each of which is incorporated herein by reference. In some embodiments, the checkpoint inhibitor is a PD-L1 or PD-1 blocker or inhibitor (e.g., a molecule that inhibits the interaction of PD-1 with PD-L1 and / or PD-L2 inhibitors), such as, for example, pembrolizumab (anti-PD-1 antibody), nivolumab (anti-PD-1 antibody), CT-011 (anti-PD-1 antibody), CX-072 (anti-PD-L1 antibody), 10-103 (anti-PD-L1), BGB-A333 (anti-PD-L1), WBP-3155 (anti-PD-L1), MDX-1105 (anti-PD-L1), LY-3300054 (anti-PD-L1), KN-035 (anti-PD-L1), FAZ-053 (anti-PD-L1), CK-301 (anti-PD-L1), AK-106 (anti-PD-L1), M-7824 (anti-PD-L1), CA-170 (anti-PD-L1), CS-1001 (anti-PD-L1 antibody); SHR-1316 (anti-PD-L1 antibody);BMS 936558 (anti-PD-1 antibody), BMS-936559 (anti-PD-1 antibody), atezolizumab (anti-PD-L1 antibody), AMP 224 (a PD-L2 extracellular domain fusion protein and an lgG1 antibody designed to block the PD-L2 / PD-1 interaction), MEDI4736 (durvalumab; anti-PD-L1 antibody), MSB0010718C (anti-PD-L1 antibody) and those described in U.S. Patent No. 2 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149 and the published PCT Patent applications N. 2 W003042402, WO2008156712, W02010089411, W02010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699, each of which is incorporated herein by reference. Additional anti-PD-1 antibodies include PDR-001; SHR-1210; BGB-A317; BCD-100; JNJ-63723283; PF-06801591; BI-754091; JS-001; AGEN-2034; MGD-013; LZM-009; GLS-010; MGA-012; AK-103; and genolimzumab. dostarlimab; cemiplimab; IBI-308; camrelizumab; AMP-514; TSR-042; Sym-021; HX-008; and ABBV-368. BMS 936558 is a fully human IgG4 monoclonal antibody directed against PD-1. In a phase I trial, biweekly administration of BMS-936558 in subjects with advanced, treatment-resistant malignancies showed durable partial or complete regressions. The most significant response rate was observed in subjects with melanoma (28%) and renal cell carcinoma (27%), but substantial clinical activity was also observed in subjects with non-small cell lung cancer (NSCLC), and some responses persisted for more than one year. BMS 936559 is a fully human IgG4 monoclonal antibody that targets the PD-1 ligand PD-L1. Phase I results showed that biweekly administration of this drug led to durable responses, particularly in subjects with melanoma. Objective response rates ranged from 6% to 17%, depending on the cancer type, in subjects with advanced NSCLC, melanoma, OCR, or ovarian cancer, with some subjects experiencing responses that lasted a year or more. AMP-224 is a fusion protein of the extracellular domain of the second ligand of PD-1, PD-L2, and IgG1, which has the potential to block the PD-L2 / PD-1 interaction. AMP-224 is currently in phase I trials as a monotherapy in subjects with advanced cancer. MEDI4736 is an anti-PD-L1 antibody that has demonstrated an acceptable safety profile and durable clinical activity in this dose-escalation study. Expansion into multiple cancers and development of MEDI4736 as monotherapy and in combination are ongoing. GITR AGONISTS The glucocorticoid-induced TNFR-related gene (GITR: TNFRSF18), sometimes also called an activation-inducible TNFR family member (AITR), is a receptor belonging to the TNF receptor superfamily (TNFRSF). It is activated by its affinity ligand, the GITR ligand (GITRL, TNFSF18). GITR is a type I transmembrane protein containing a cisterna-rich extracellular domain, which is characteristic of TNFR family members. The cytoplasmic domain of GITR, for example, shares close homology with certain other TNFR family members, such as 4-1BB and CD27 (Nocentini, et al., Proc. Natl. Acad. Sel., 94: 6216-6221 (1997)). GITR agonist antibodies are currently being explored as a means to expand the population of CD8+ memory effector T lymphocytes and, at the same time, promote the loss or inhibition of Tregs. The co-stimulation of responder T lymphocytes and the suppression of regulatory T lymphocyte activity mean that GITR activation results in a boosted immune response. Such activation has the potential to restore immune responses to infections and tumors. Consequently, molecules capable of activating GITR would be valuable as immunostimulatory agents in settings where triggering a boosted immune response is desirable. As further disclosed herein, in one aspect, the present invention relates to the use of combinations of eneolytic viruses and GITR agonists for the treatment of cancers. In another aspect, the present invention relates to 20 pharmaceutical compositions comprising the combination of eneolytic viruses and GITR agonists. In some implementations, the GITR agonist is AMG 228 (also called 9H6v3), TRX518, MEDI1873, MK-4166, BMS-986156, MK-1248, INCAGN01876 or GWN323. TRX518 is a humanized, iron-disabled anti-GITR monoclonal antibody that blocks GITR interaction and has been shown to act synergistically with chemotherapeutic agents in cancer models. TRX518 is currently being investigated in clinical trials, including NCT01239134 (stage III or IV malignant melanoma or other solid tumors) and NCT02628574 (advanced solid tumors). MEDI1873 is a GITR agonist (a GITR ligand IgG1 fusion protein (GITRL)) with potential immunomodulatory and antineoplastic activities. MEDI1873 is currently being investigated in clinical trials, including NCT02583165 (advanced solid tumors). MK-4166 is an anti-GITR agonist monoclonal antibody that has been shown to act synergistically with chemotherapeutic agents in cancer models. MK-4166 is currently being investigated in clinical trials, including NCT02132754 (in combination with pembrolizumab in advanced solid tumors). BMS-986156 is a monoclonal antibody anti-GITR agonist. BMS-986156 is currently being investigated in clinical trials, including NCT02598960 (as monotherapy and in combination with nivolumab in subjects with advanced solid tumors). MK-1248 is a monoclonal antibody that is an anti-GITR agonist. MK-1248 is currently being investigated in clinical trials, including NCT02553499 (as monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors). INCAGN01876 is an anti-GITR agonist monoclonal antibody. INCAGN01876 is currently being investigated in clinical trials including NCT02697591 (in subjects with advanced or metastatic solid tumors). GWN323 is a monoclonal antibody that is an anti-GITR agonist. GWN323 is currently being investigated in clinical trials, including NCT02697591 (as monotherapy and in combination with PDR001 in subjects with advanced cancer or lymphomas). METHODS OF TREATMENT FOR A DISEASE OR DISORDER The present invention also relates to methods for treating diseases or disorders, such as cancer. In some embodiments, the cancer is Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, melanoma, head and neck carcinoma, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), and cutaneous lymphoma. 21. T-cell lymphoma or multiple myeloma. In other embodiments, the cancer is B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, or breast cancer (e.g., triple-negative breast carcinoma). In some embodiments, the cancer is metastatic cancer. The term "metastatic cancer" refers to cancer that has spread from the part of the body where it started (the primary site) to other parts of the body. When cancer has spread to a new area (metastasized), it is still called the cancer of the body part where it began. For example, colon cancer that has spread to the pancreas is called "metastatic colon cancer to the pancreas," as opposed to pancreatic cancer. Treatment is also based on where the cancer originated. If colon cancer spreads to the bones, it is still colon cancer, and the appropriate doctor will recommend treatments that have been shown to fight metastatic colon cancer. The present invention also relates to the use of combinations of eneolytic viruses and checkpoint inhibitors for the treatment of cancers. In some embodiments, the cancer is Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, melanoma, head and neck carcinoma, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma. In other embodiments, the cancer is B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma). In some embodiments, the cancer is metastatic cancer. The present invention also relates to a method of treating diseases or disorders, such as cancer, by administering: (i) a therapeutically effective amount of an eneolytic virus; and (ii) a therapeutically effective amount of a GITR agonist. In particular embodiments, the cancer is B-cell lymphoma. In other embodiments, the GITR agonist is AMG 228, TRX518, MEDI1873, or MK-4166. The oncolytic virus can be any of those described herein. In some embodiments, the oncolytic virus is a herpes simplex virus (e.g., herpes simplex virus 1). In other embodiments, herpes simplex virus 1 is modified so that it does not contain an intact ICP34.5 gene. In other embodiments, herpes simplex virus 1 is modified so that it does not contain an intact ICP34.5 gene and does not contain an intact ICP47 gene. In still other embodiments, herpes simplex virus 1 is modified so that it does not contain an intact ICP34.5 gene and does not contain an ICP47 gene. 22 intact and contains a gene encoding GM-CSF (e.g., human GM-CSF). In one specific embodiment, the eneolytic virus is talimogene laherparepvec. A checkpoint inhibitor can be any molecule that blocks or inhibits inhibitory pathways of the immune system. For example, the following checkpoint molecules can be blocked or inhibited: CTLA-4, PD-L1, PD-L2, PD-1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, and 2B4 (which belongs to the CD2 family of molecules and is expressed on all NK, I, and CD8 T lymphocytes). +(a|3) memory), CD160 (also referred to as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Examples of checkpoint inhibitors include binding proteins (e.g., antibodies or antigen-binding fragments thereof), biological therapies, or small molecules, which bind to, and block or inhibit the activity of one or more of CTLA-4, PD-L1, PD-L2, PD-1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160, and CGEN-15049. In some embodiments, the checkpoint inhibitor is a blocker or inhibitor of CTLA-4, PD-1, PD-L1, or PD-L2. Examples of CTLA-4 inhibitors include tremretirumab, ipilimumab (also known as 10D1, MDX-D010), BMS-986249, AGEN-1884, and anti-CTLA-4 antibodies described in U.S. Patent No. 2: 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; ​​6,682,736; 6,984,720; and 7,605,238, each of which is incorporated herein by reference.Examples of molecules that inhibit the interaction of PD-1 with PD-L1 and / or PD-L2 inhibitors include pembrolizumab (anti-PD-1 antibody), nivolumab (BMS 936558; anti-PD-1 antibody), CT-011 (anti-PD-1 antibody), BMS 936558 (anti-PD-1 antibody), BMS-936559 (anti-PD-L1 antibody), CX-072 (anti-PD-L1 antibody), 10-103 (anti-PD-L1), BGB-A333 (anti-PD-L1), WBP-3155 (anti-PD-L1), MDX-1105 (anti-PD-L1), LY-3300054 (anti-PD-L1), KN-035 (anti-PD-L1), FAZ-053 (anti-PD-L1), and CK-301. (anti-PD-L1), AK-106 (anti-PD-L1), M-7824 (anti-PD-L1), CA-170 (anti-PD-L1), CS-1001 (anti-PD-L1 antibody), SHR-1316 (anti-PD-L1 antibody), atezolizumab (anti-PD-L1 antibody), AMP 224 (a PD-L2 extracellular domain fusion protein and an lgG1 antibody designed to block the PD-L2 / PD-1 interaction), MEDI4736 (durvalumab; anti-PD-L1 antibody), MSB0010718C (avelumab; anti-PD-L1 antibody) and those described in U.S. Patent No. B7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149 and the published PCT Patent applications N. s : W003042402, WO2008156712, W02010089411, W02010036959, WO2011066342, WO2011159877. Additional anti-PD-1 antibodies include PDR-001; SHR-1210; BGB-A317; BCD-100; JNJ-63723283; PF-06801591; BI-754091; JS-001; AGEN-2034; MGD-013; LZM-009; GLS-010; MGA-012; AK-103; genolimzumab; dostarlimab; cemiplimab; IBI-308; camrelizumab; AMP-514; TSR-042; Sym-021; HX-008; and ABBV-368. In particular embodiments, the present invention relates to a combination of an eneolytic virus and an anti-PD-1 antibody, an eneolytic virus and an anti-PD-L1 antibody, or an eneolytic virus and an anti-CTLA-4 antibody. In specific embodiments, the eneolytic virus is talimogene laherparepvec. In many cases, cancer is present in patients as a primary tumor (i.e., a tumor that grows at the anatomical site where tumor progression began and advanced to produce a cancerous mass) and as a secondary tumor or metastasis (i.e., the spread of a tumor from its primary site to other parts of the body). The eneolytic viruses of the present invention can be effective in treating tumors through a lytic effect and a systemic immune effect. For example, in the context of talimogene laherparepvec, the virus physically lyses tumor cells, causing the death of the primary tumor cells.Furthermore, [1] lysis of tumor cells releases tumor-derived antigens that are subsequently recognized by the immune system; and [2] GM-CSF production aids in the induction of an antitumor immune response: both mechanisms are thought to lead to a systemic immune response whereby the immune system can recognize and attack both primary and secondary tumors / metastases. In embodiments where the neolytic virus is combined with a checkpoint inhibitor, the checkpoint inhibitor is thought to further potentiate the systemic immune response by enhancing sensitization and reducing the inhibitory effect of immune checkpoint proteins on immune system cells, such as T lymphocytes.Furthermore, in embodiments where the eneolytic virus is combined with a GITR agonist, the GITR agonist is believed to further enhance the systemic immune response by expanding the population of CD8+ effector memory T lymphocytes and promoting the loss or inhibition of Tregs. Accordingly, the present invention contemplates the treatment of primary tumors, metastases (i.e., secondary tumors), or both with an eneolytic virus (e.g., talimogene laherparepvec) alone or in combination with a checkpoint inhibitor. In some embodiments, the treatment methods or uses described herein do not include radiation therapy or a combination therapy with radiation. In other embodiments, the treatment methods or uses described herein do not include chemotherapy (i.e., chemical agents or drugs, typically small-molecule compounds, that are selectively destructive to malignant cells and tissues), such as cisplatin, or a combination therapy with chemotherapy (e.g., cisplatin). In other embodiments 24 Furthermore, the treatment methods or uses described herein do not include treatment with a combination of radiation and a chemotherapy agent (e.g., cisplatin). The methods of the present invention can be used to treat several different stages of cancer. Most staging systems include information on whether the cancer has spread to nearby lymph nodes, where the tumor is located in the body, the cell type (e.g., squamous cell carcinoma), whether the cancer has spread to a different part of the body, the tumor size, and the tumor grade (i.e., the level of cellular abnormality, the likelihood that the tumor will grow and spread). For example, Stage 0 refers to the presence of abnormal cells that have not spread to nearby tissue—that is, cells that may become cancerous. Stage I, Stage II, and Stage III cancer refer to the presence of cancer. The higher the stage, the larger the cancerous tumor and the more it has spread to nearby tissues. Stage IV cancer is cancer that has spread to distant parts of the body.In some embodiments, the methods of the present invention can be used to treat metastatic cancer. PHARMACEUTICAL COMPOSITIONS The present invention also relates to pharmaceutical compositions comprising eneolytic viruses or comprising a combination of eneolytic viruses and checkpoint inhibitors. The pharmaceutical composition may contain formulation materials to modify, maintain, or preserve, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or penetration of the composition.Pharmaceutically active agents can be administered to a patient via various routes, including, for example, orally or parenterally, such as intravenously, intramuscularly, subcutaneously, intraorbitally, intracapsularly, intraperitoneally, intrarectally, intracisternally, intratumorally, intravascularly, intradermally, or by passive or facilitated absorption through the skin using, for example, a skin patch or transdermal iontophoresis, respectively. In one embodiment, the oncolytic virus (e.g., talimogene laherparepvec) is injected into the tumor (i.e., via intratumoral injection). In another embodiment, the checkpoint inhibitor (e.g., an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody) is administered systemically (e.g., intravenously). A practitioner may determine the dosage and duration of treatment in accordance with any aspect of this disclosure. For example, a practitioner may monitor patients to determine whether treatment should be initiated. 25. Treatment may be continued, interrupted, or resumed. An effective amount for a particular patient may vary depending on factors such as the condition being treated, the patient's general health, and the method, route, and dose of administration. The physician, using established parameters of the technique, determines the appropriate dose. An effective amount of a pharmaceutical composition to be used therapeutically will depend, for example, on the therapeutic context and objectives. A practitioner will appreciate that the appropriate dosage levels for treatment will therefore vary, depending in part on the delivered molecule, the indication for which the binding agent molecule is used, the route of administration, and the patient's size (body weight, body surface area, or organ size) and condition (age and general health status). Consequently, the clinician may titrate the dose and modify the route of administration to achieve the optimal therapeutic effect. Clinical studies have demonstrated that talimogene laherparepvec can be injected directly into cutaneous, subcutaneous, or lymph node lesions that are visible, palpable, or can be injected under ultrasound guidance. Thus, in one respect, pharmaceutical compositions comprising talimogene laherparepvec are administered by intralesional injection. Talimogene laherparepvec is currently provided in 1 ml single-use vials in fixed dosage concentrations: 10 6 ufp / ml for initial dosage and 10 8 FFU / mL for subsequent dosing (Reske, et al. J Immunol, 2008. 180 (11): p. 7525-36). The volume injected may vary depending on the tumor type. For example, talimogen laherparepvec is administered by intratumoral injection in cutaneous, subcutaneous, and lymph node tumors at a dose of up to 4.0 mL of 10 6plaque-forming units / ml (PFU / ml) on day 1 of week 1 followed by a dose of up to 4.0 ml of 10 8 UFP / ml on day 1 of week 4 and every 2 weeks (± 3 days) thereafter. In another embodiment, talimogene laherparepvec is administered by intratumoral injection into injectable cutaneous, subcutaneous, and lymph node tumors at a dose of up to 4.0 ml of 10 6 plaque-forming units / ml (PFU / ml) on day 1 of week 1 followed by a dose of up to 4.0 ml of 10 7 UFP / ml on day 1 of week 4 and every 2 weeks (± 3 days) thereafter. The recommended volume of talimogen laherparepvec to be injected into the tumor or tumors depends on the size of the tumor or tumors and can be determined according to the injection volume guideline in Table 1 (and as shown in patent application PCT / US2013 / 057542, which is incorporated herein by reference). Table 1. Talimogene Laherparepvec injection volume guidelines based on tumor size Tumor size (longest dimension) Maximum injection volume > 5.0 cm 4.0 ml > 2.5 cm to 5.0 cm 2.0 ml > 1.5 cm to 2.5 cm 1.0 ml > 0.5 cm to 1.5 cm 0.5 ml < 0.5 cm 0.1 ml Generally, all reasonably injectable lesions should be injected with the maximum available dosage volume on a single dosing occasion. On each treatment day, it is recommended to prioritize injections as follows: any new injectable tumors that have appeared since the last injection; by tumor size, starting with the largest tumor; and any previously injectable tumors that are now injectable. The compositions of the present invention may comprise one or more additional components, including a physiologically acceptable vehicle, excipient, or diluent. For example, the compositions may comprise one or more of a buffer, an antioxidant such as ascorbic acid, a low molecular weight polypeptide (e.g., having fewer than 10 amino acids), a protein, an amino acid, a carbohydrate such as glucose, sucrose, or dextrins, a chelating agent such as EDTA or glutathione, a stabilizer, and an excipient. Acceptable diluents include, for example, neutral buffered saline or saline mixed with specific serum albumin. Preservatives such as benzyl alcohol may also be added. The composition may be formulated as a lyophilized powder using appropriate excipient solutions (e.g., sucrose) as diluents. In certain embodiments, the checkpoint inhibitor is administered at 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, or any combination of these doses. In certain embodiments, the checkpoint inhibitor is administered once a week, twice a week, three times a week, once every two weeks, or once a month. In certain embodiments, the checkpoint inhibitor is administered as a single dose, in two doses, in three doses, in four doses, in five doses, or in six or more doses. In certain embodiments, the anti-PD-1 antibody is administered by injection (e.g., subcutaneously or intravenously) at a dose of approximately 1 to 30 mg / kg, for example, approximately 5 to 25 mg / kg, approximately 10 to 20 mg / kg, approximately 1 to 5 mg / kg, or approximately 3 mg / kg. The dosing schedule may vary, for example, from once a week to once every 2, 3, or 4 weeks. In one embodiment, the anti-PD-1 antibody is administered at a dose of approximately 10 to 20 mg / kg every two weeks. In one embodiment, the anti-PD-1 antibody molecule, for example, nivolumab, is administered intravenously at a dose of approximately 1 mg / kg to 3 mg / kg, for example, approximately 1 mg / kg, 2 mg / kg, or 3 mg / kg, every two weeks. In another embodiment, the anti-PD-1 antibody molecule, for example, nivolumab, is administered intravenously at a dose of approximately 2 mg / kg at 3-week intervals. In yet another embodiment, nivolumab is administered in an amount of approximately 1 mg / kg to 5 mg / kg, for example, 3 mg / kg, and can be administered over a period of 60 minutes, approximately once a week to once every 2, 3, or 4 weeks. In one embodiment, the anti-PD-1 antibody molecule, for example, pembrolizumab, is administered intravenously at a dose of approximately 1 mg / kg to 3 mg / kg, for example, approximately 1 mg / kg, 2 mg / kg, or 3 mg / kg, every three weeks. In another embodiment, the anti-PD-1 antibody molecule, for example, pembrolizumab, is administered intravenously at a dose of approximately 2 mg / kg at 3-week intervals. In yet another embodiment, the anti-PD-1 antibody molecule, for example, pembrolizumab, is administered intravenously at a dose of approximately 100 mg / kg to 300 mg / kg, for example, approximately 100 mg / kg, 200 mg / kg, or 300 mg / kg, every three weeks. In one embodiment, the anti-PD-1 antibody molecule, for example, pembrolizumab, is administered intravenously at a dose of approximately 200 mg / kg at 3-week intervals. In certain embodiments, the anti-CTLA-4 antibody (e.g., ipilimumab) is administered by injection (e.g., subcutaneously or intravenously) at a dose of approximately 3 mg / kg IV every 3 weeks for a maximum of 4 doses; approximately 3 mg / kg IV every 6 weeks for a maximum of 4 doses; approximately 3 mg / kg IV every 12 weeks for a maximum of 4 doses; approximately 10 mg / kg IV every 3 weeks for a maximum of 4 doses; or Approximately 10 mg / kg IV every 12 weeks for a maximum of 4 doses. In certain realizations, the anti-CTLA-4 antibody (e.g., tremelimumab) is administered by injection (e.g., subcutaneously or intravenously) at a dose of approximately 10 mg / kg every 4 weeks; or approximately 15 mg / kg every 3 months. In certain embodiments, the anti-PD-L1 antibody (e.g., atezolizumab) is administered by injection (e.g., subcutaneously or intravenously) at a dose of approximately 1200 mg IV every 3 weeks until disease progression or unacceptable toxicity. Therefore, in one embodiment, the present invention relates to a pharmaceutical composition for use in a method of treating Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (by 28. For example, diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, breast cancer (for example, triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma, wherein the pharmaceutical composition comprises an eneolytic virus. In another embodiment, the present invention relates to a pharmaceutical composition for use in a method of treating B-cell lymphoma (for example, diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (for example, triple-negative breast carcinoma), wherein the pharmaceutical composition comprises a therapeutically effective amount of an eneolytic virus and a checkpoint inhibitor.In further embodiments, the present invention relates to a pharmaceutical composition for use in a method of treating B-cell lymphoma, wherein the pharmaceutical composition comprises a therapeutically effective amount of an eneolytic virus and a GITR agonist. In other embodiments, the present invention relates to a therapeutically effective quantity of an eneolytic virus for use in the treatment of Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma. In further embodiments, the present invention relates to a therapeutically effective quantity of an eneolytic virus and a checkpoint inhibitor for use in the treatment of B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma).In further embodiments, the present invention relates to a therapeutically effective quantity of an oncolytic virus and a GITR agonist for use in the treatment of B-cell lymphoma. In some embodiments, the oncolytic virus is a herpes simplex virus (e.g., herpes simplex virus 1). In other embodiments, herpes simplex virus 1 is modified so that it does not contain an intact ICP34.5 gene. In other embodiments, herpes simplex virus 1 is modified so that it does not contain an intact ICP34.5 gene and does not contain an intact ICP47 gene. In still other embodiments, herpes simplex virus 1 is modified so that it does not contain an intact ICP34.5 gene, does not contain an intact ICP47 gene, and contains a gene encoding GM-CSF (e.g., human GM-CSF). In one specific embodiment, the oncolytic virus is talimogene laherparepvec. In embodiments where the pharmaceutical composition comprises a checkpoint inhibitor, the checkpoint inhibitor may be any of those discussed herein. For example, the checkpoint inhibitor may be a CTLA-4 blocker, a PD-L1 blocker, or a PD-1 blocker. The CTLA-4 blocker may be an anti-CTLA-4 antibody such as, for example, ipilimumab. The PD-L1 blocker may be an anti-PD-L1 antibody such as, for example, atezolizumab. The PD-1 blocker may be an anti-PD-1 antibody such as, for example, nivolumab or pembrolizumab. In some implementations, the GITR agonist is AMG 228, TRX518, MEDI1873 or MK-4166. In some embodiments, the pharmaceutical compositions described herein are not used in conjunction with radiation or in combination with radiation therapy. In other embodiments, the pharmaceutical compositions described herein do not include chemotherapeutic agents (e.g., cisplatin). In still other embodiments, the pharmaceutical compositions described herein are not used in combination with radiation and a chemotherapeutic agent (e.g., cisplatin). KITS In another aspect, the present invention relates to kits comprising [1] the eneolytic virus, optionally in combination with a checkpoint inhibitor; and [2] instructions for administration to patients. For example, a kit of the present invention may comprise an eneolytic virus (e.g., talimogene laherparepvec) and instructions (e.g., in a package insert or label) for treating a cancer patient. In some embodiments, the cancer is metastatic cancer. In another embodiment, the kit of the present invention may comprise an eneolytic virus (e.g., talimogene laherparepvec), a checkpoint inhibitor (e.g., an anti-PD-1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody), and instructions (e.g., in a package insert or label) for treating a cancer patient. In another aspect, the present invention relates to kits comprising [1] the eneolytic virus, optionally in combination with a GITR agonist; and [2] instructions for administration to patients. In other embodiments, the kit of the present invention may comprise an eneolytic virus (e.g., talimogene laherparepvec), a GITR agonist (e.g., AMG 228 (also known as 9H6v3), TRX518, MEDI1873, or MK-4166), and instructions (e.g., in a package insert or label) for treating a cancer patient. In some embodiments, the kit comprising talimogene laherparepvec includes instructions (e.g., in a leaflet or label) for administration by intratumoral injection at a dose of up to 4.0 ml of 10 6 UFP / ml on day 1 of week 1 followed by a dose of up to 4.0 ml of 10 8UFP / ml on day 1 of week 4 and every 2 weeks thereafter (e.g., until complete response). In some embodiments, the kit comprising talimogene laherparepvec includes instructions (e.g., in a package insert or label) for administration by intratumoral injection at a dose of up to 4.0 ml of 10 6 UFP / ml on day 1 of week 1 followed by a dose of up to 4.0 ml of 10 7 UFP / ml on day 1 of week 4 and every 2 weeks thereafter (e.g., until full response). In embodiments where the kit comprises an anti-PD-1 antibody, the kit includes instructions (e.g., in a package insert or label) for intravenous administration at the doses described herein. Examples of anti-PD-1 antibodies include pembrolizumab and nivolumab. In embodiments where the kit comprises an anti-PD-L1 antibody, the kit includes instructions (e.g., in a package insert or label) for intravenous administration at the doses described herein. Examples of anti-PD-L1 antibodies include atezolizumab. In embodiments where the kit comprises an anti-CTLA-4 antibody, the kit includes instructions (e.g., in a package insert or label) for intravenous administration at the doses described herein. Examples of anti-CTLA-4 antibodies include ipilimumab. In embodiments where the kit includes a GITR agonist, the kit includes instructions (e.g., in a package insert or label) for intravenous administration at the doses described herein. Examples of anti-GITR antibodies include AMG 228, TRX518, MEDI1873, or MK-4166. In another embodiment, a method for manufacturing the kits of the present invention is provided. In some embodiments, the kits described herein are not used in conjunction with radiation or in a combination therapy with radiation. In other embodiments, the kits described herein do not include chemotherapeutic agents (e.g., cisplatin). In still other embodiments, the kits described herein are not used in treatment with a combination of radiation and a chemotherapeutic agent (e.g., cisplatin). EXAMPLES The following examples are provided to illustrate specific embodiments or features of the present invention and are not intended to limit its scope. EXAMPLE 1 THE THALIMOGEN LAHERPAREPVEC EXHIBITS ANTITUMOR ACTIVITY AGAINST A RANGE OF TUMOR TYPES IN AN IN VIVO MOUSE MODEL This example demonstrates that administering the talimogene laherparepvec to tumor-bearing mice leads to tumor destruction. The antitumor efficacy of talimogene laherparepvec was evaluated in several mouse xenograft studies in Balb / c nude mice. Tumor cells (human pediatric Ewing sarcoma A-673, human pediatric rhabdomyosarcoma SJCRH30, human pediatric rhabdoid tumor G-401, human pediatric neuroblastoma SK-N-AS, or human pediatric osteosarcoma SJSA-1) were implanted into the right flank of each mouse by subcutaneous injection. In each case, 5 x 10 6 1x10 7 cells in 100-200 pl of 50% matrigel / 50% DMEM in mice. Tumor measurements were obtained twice weekly. Treatment with talimogene laherparepvec began when tumors reached an average diameter of 4–6 mm. Three doses of talimogene laherparepvec (5 x 10) were administered. 4 , 5x10 5, or 5x10 6 UFP / dose, dose volume of 50 pills) with three days between intratumoral injections. Body weights, general clinical observations, and tumor measurements were obtained twice weekly. Animals were euthanized when tumor weight exceeded 10% of body weight. In these experiments, the talimogene laherparepvec showed antitumor efficacy against all cell lines tested, with an inhibition of tumor growth of 65-112% and evidence of complete regression in 3-30% of animals across all tumor types. EWING SARCOMA Mice carrying Ewing sarcoma A-673 tumor were therapeutically treated with talimogene laherparepvec at 5x10 4 , 5x10 5 , or 5x10 6UFP / dose. Talimogene laherparepvec was administered by intratumoral injection once daily on days 8, 11, and 14 of the study (Figure 1, red arrows). Tumors were measured 2–3 times per week. Results are expressed as the mean tumor volume of the group in mm³ 3 ± standard error of the mean as a function of time in days where day 0 is the day of tumor inoculation (n = 10 per group, except as indicated for the vehicle control group on days 16, 20 and 23). The asterisk indicates p < 0.0001 for all talimogene laherparepvec groups with respect to the vehicle control on study day 23. The results are shown in Figure 1. NEUROBLASTOMA SK-N-AS neuroblastoma tumor-bearing mice were therapeutically treated with talimogene laherparepvec at 5x10 4 , 5x10 5 , or 5x10 6 UFP / dose. Talimogen was administered. 32 laherparepvec units were administered by intratumoral injection once daily on days 6, 9, and 12 of the study (Figure 2, red arrows). Tumors were measured 2–3 times per week. Results are expressed as the mean tumor volume of the group in mm³ 3 ± standard error of the mean as a function of time in days where day 0 is the day of tumor inoculation (n = 10 per group, except as indicated for the 5x10 group 4 UFP / dose on days 18, 20, and 23). The asterisk indicates p < 0.0001 for the 5x10 groups 6 and 5x10 5 PFU / dose and p = 0.0001 for the 5x10 group 4 UFP / dose with respect to formulation buffer control on study day 23. The results are shown in Figure 2. RHABDOID TUMOR Mice carrying the G-401 rhabdoid tumor were therapeutically treated with the talimogene laherparepvec at 5x10 4 , 5x10 5 , or 5x10 6UFP / dose. Talimogene laherparepvec was administered by intratumoral injection once daily on days 14, 17, and 20 of the study (Figure 3, red arrows). Tumors were measured 2–3 times per week. Results are expressed as the mean tumor volume of the group in mm³ 3 ± standard error of the mean as a function of time in days where day 0 is the day of tumor inoculation (n = 10 per group, except where indicated). The asterisk indicates p < 0.0001 for all talimogen laherparepvec dose groups with respect to the vehicle control on study day 40. The results are shown in Figure 3. OSTEOSARCOMA Mice carrying SJSA-1 osteosarcoma tumors were therapeutically treated with the talimogene laherparepvec at 5x10 4 , 5x10 5 , or 5x10 6 UFP / dose. Talimogene laherparepvec was administered by intratumoral injection once daily on days 9, 12, and 15 of the study (Figure 4, red arrows). Tumors were measured 2–3 times per week. Results are expressed as the mean tumor volume of the group in mm³ 3 ± standard error of the mean as a function of time in days where day 0 is the day of tumor inoculation (n = 10 per group). The results are shown in Figure 4. RHABDOMYOSARCOMA Mice carrying SJCRH30 rhabdomyosarcoma tumors were therapeutically treated with talimogene laherparepvec at 5x10 4 , 5x10 5 , or 5x10 6 UFP / dose. Talimogene laherparepvec was administered by intratumoral injection once daily on days 8, 11, and 14 of the study (Figure 5, red arrows). Tumors were measured 2–3 times per week. Results are expressed as the mean tumor volume of the group in mm³ 3 ± standard error of the mean as a function of time in days where day 0 is the day of tumor inoculation (n = 10 per group, except as indicated for the 5x10 group4 UFP / dose on days 26, 30 and 33 and for the 5x10 group 6 UFP / dose on days 30 and 33). The asterisk indicates p < 0.0001 for all talimogen laherparepvec dose groups with respect to vehicle control on day of 33 study 26 (the last day of study in which all control animals were in study). The results are shown in Figure 5. EXAMPLE 2 THE THALIMOGEN LAHERPAREPVEC INHIBITS THE GROWTH OF A RANGE OF HUMAN TUMOR TYPES IN CELL-BASED ASSAYS DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL OR DLBCL) Several LDCBG cell strains (SU-DHL-2, OCI-LY-3, TMD8, RI-1 (ABC subtype) and WSU-NHL (GCB subtype)) were cultured in a 96-well plate at 5,000 cells per well and incubated overnight at 37 eC. For each cell strain, talimogene laherparepvec was serially diluted (serial dilutions of 1:4) in nine wells, starting at an MOI of 100. After a 72-hour incubation, the number of remaining cells in each well was quantified using the CelITiter-Glo Luminescent Cell Viability Assay (Promega, Madison, Wl). The talimogene laherparepvec was effective in 14 of 21 DLBCL cell lines at an MOI below 100. Five cell lines (SU-DHL-2, OCI-LY-3, TMD8, RI-1 (ABC subtype), and WSU-NHL (GCB subtype)) showed the greatest sensitivity with an MOI IC50 of or below 1 (Table 2). Conversely, OCI-LY-1, KARPAS422, WSU-DLCL2, SU-DHL-4, SU-DHL-10, and OCI-LY-7 (all GCB subtypes) showed resistance to talimogene laherparepvec up to an MOI of 100 (Table 2). Cell growth inhibition was maximal in most cell strains that showed sensitivity to an MOI IC50 below 1. Figure 6 shows the degree of cell growth inhibition achieved by increasing the concentrations of talimogene laherparepvec in the LDCBG WSU-NHL (GCB subtype) and TMD8 (ABC subtype) cell strains.These results demonstrate that treating DLBCL cell lines with talimogene laherparepvec results in strong inhibition of DLBCL tumor cell growth. Table 2: MOI IC50 for 21 LDCBG cell strains representing ABC and GCB subtypes. Cell line Indication IC50 of MOI DOHH2 DLBCL >100 FARAGE DLBCL 16,769 DB DLBCL 11,746 SU-DHL-4 DLBCL >100 VAL DLBCL 3,582 RCK-8 DLBCL 6,058 RI-1 LDCBG 1.053 OCI-LY-7 LDCBG >100 SU-DHL-10 LDCBG >100 U2938 LDCBG 10.044 WSU-DLCL2 LDCBG >100 WSU-NHL LDCBG 0.520 KARPAS 422 LDCBG >100 SU-DHL-6 LDCBG 9.970 OCI-LY-10 DLBCL 15.012 TMD8 DLBCL 0.580 OCI-LY-1 DLBCL >100 OCI-LY-3 DLBCL 0.300 OCI-LY-19 DLBCL 52.799 SC-1 DLBCL 6.766 SU-DHL-2 DLBCL 0.231 ADDITIONAL SOLID TUMORS Various cell strains from solid tumors (melanoma, non-small cell lung carcinoma, colorectal cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, and triple-negative breast carcinoma) were cultured in a 96-well plate at 2,000–10,000 cells per well and incubated overnight at 37°C. For each cell strain, talimogene laherparepvec was serially diluted (1:4 serial dilutions) in nine wells, starting at an MOI of 100. After a 72-hour incubation, the number of remaining cells in each well was quantified using ATP-Lite (Perkin Elmer, Waltham, MA). Talimogene laherparepvec was effective against all 13 melanoma and carcinoma cell lines tested. All cell lines tested showed an MOI IC50 below 1 (Table 3). Figure 7 shows the degree of cell growth inhibition achieved by increasing talimogene laherparepvec concentrations in the HCT-116 (colorectal cancer) and SK-MEL-5 (melanoma) cell lines. These results demonstrate that treatment of melanoma, non-small cell lung carcinoma, colorectal cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, and triple-negative breast carcinoma cell lines with talimogene laherparepvec results in strong inhibition of tumor cell growth. Table 3: MOI Cl50 for 13 cell lines representing a diversity of solid tumor indications. LYMPHOMA Cell lineage Indication MOI CI50 SK-MEL-5 Melanoma 0.051 M24met Melanoma 0.225 A375 Melanoma 0.1 A549 NSCLC 0.218 SK-CO-1 Colorectal 0.145 HT-29 Colorectal 0.135 HCT-116 Colorectal 0.072 FADU CCECC 0.0133 CAL 27 CCECC 0.004 SNU-182 Hepatocellular 0.03 SNU-620 Gastric 0.162 MDA-231 Breast 0.19 Cal-51 Breast 0.56 T-cell lymphocyte (LCLT) and myeloma .TRIPLE (MM) LCLT and MM cell lines were cultured in a 96-well plate at 2,000-10,000 cells per well and incubated overnight at 37 S C. For each cell strain, talimogene laherparepvec was serially diluted (serial dilutions of 1:4) in nine wells, starting at an MOI of 100. After a 72-hour incubation, the number of remaining cells in each well was quantified using ATP-Lite (Perkin Elmer, Waltham, MA). The talimogene laherparepvec was effective against all five cell lines tested (Table 4). Multiple myeloma cell lines showed greater sensitivity than cutaneous T-cell lymphoma cell lines. Figure 8 shows the degree of cell growth inhibition achieved by increasing talimogene laherparepvec concentrations in the HUT-78 (LCLT) and RPMI 8226 (multiple myeloma) cell lines. These results demonstrate that the treatment of cutaneous T-cell lymphoma cell lines is effective against multiple myeloma. T lymphocytes (LCLT) and multiple myeloma (MM) with talimogene laherparepvec results in strong inhibition of tumor cell growth. Table 4: MOI Cl5o for 2 cutaneous T-cell lymphoma cell lines and three multiple myeloma cell lines. Cell lineage Indication MOI CI50 HUT-78 LCLT 0.961 HUT-102 LCLT 19.22 KMS-12-BM MM 0.56 RPMI8226 MM 0.037 NCI-H929 MM 0.03 EXAMPLE 3 THE TALIMOGEN LAHERPAREPVEC INHIBITS THE GROWTH OF A DIVERSITY OF MURINE TUMOR CELL STRAINS IN CELL-BASED ASSAYS Murine melanoma, colorectal carcinoma, and B-cell lymphoma cell lines were plated in a 96-well plate at 2,000–10,000 cells per well and incubated overnight at 37°C. a C. For each cell strain, talimogene laherparepvec was serially diluted (serial dilutions of 1:4) in nine wells, starting at MOI of 100. After a 72-hour incubation, the number of remaining cells in each well was quantified using ATP-Lite (Perkin Elmer, Waltham, MA). The talimogene laherparepvec was effective against 4 of the 5 cell lines tested (Table 5). The melanoma cell line B16F10 demonstrated resistance to talimogene laherparepvec. This resistance is mediated by the lack of entry receptors for herpes simplex virus type 1, as previously described by Miller et al., Molecular Therapy, 3 (2): 160-168 (2001). The Cloudman CL M3 (melanoma), CT-26, and MC-38 (colorectal cancer) cell lines showed similar sensitivity, with an IC50 of MOI ~ 0.2. Figure 9 shows the degree of cell growth inhibition achieved by increasing talimogene laherparepvec concentrations in the CT-26 and MC-38 (colorectal cancer) cell lines.These results demonstrate that treatment of murine tumor cell lines (melanoma, colorectal carcinoma, and B-cell lymphoma) with talimogene laherparepvec results in strong inhibition of tumor cell growth. Table 5: MOI IC50 for 5 murine cell strains. Cell lineage Indication MOI CI50 Cloudman CL M3 Melanoma 0.17 B16F10 Melanoma > 100 A20 B-cell lymphoma 2.00 CT-26 Colorectal 0.22 MC-38 Colorectal 0.12 EXAMPLE 4 ONCOVEX mGM CSF INHIBITS THE GROWTH OF LYMPHOMA BY CELL NEUROBLASTOMA TUMORS IN A MOUSE MODEL A20 tumor cells were injected subcutaneously into the right and left flanks of female BALB / c mice (2x10 6 cells) on day 0. Tumor volume (mm³) 3 The tumors were measured using electronic calipers twice a week (every two weeks). Once the tumors reached an average of approximately 100 mm3 Mice were randomized into groups (10 mice per group) so that the mean tumor volume (on both flanks) and the variability of tumor volume at baseline were uniform between treatment groups. Mice received three intratumoral injections of OncoVex. mGMCSF (3x10 4 - 3x10 6 UFP / dose) or vehicle on days 10, 13 and 16. Clinical signs, body weight changes and survival were measured (mice were removed from the study when tumors reached 800 mm 3 ) 2-3 times per week until the end of the study. The treatment of A20 tumor-bearing animals with OncoVex mGMCSF This resulted in 100% complete regression of all tumors injected directly at the three doses: 3x10 4 UFP, 3x10 5 UFP and 3x10 6UFP (Figure 10a). Contralateral tumors showed no response to the 3x10 dose 4 UFP, 50% inhibition of tumor growth at a dose of 3x10 5 UFP and 100% inhibition of tumor growth at a dose of 3x10 6 UFP (Figure 10b). Median survival increased significantly in the 3x10 dose groups 5 UFP (p = 0.0054) and 3x10 6 UFP (p = 0.0004) compared with the vehicle (38 days vs. 21 days, respectively – Figure 10c). No reduction in body weight was observed, indicating that the treatments under investigation were safe and tolerable (Figures 10d and 10e). Table 6 shows the percentage of subjects who were tumor-free in each group. In addition, mice carrying neuroblastoma neuro2a tumors were treated with OncoVex mGMCSF 5x10 4 , 5x10 5 , or 5x10 6 UFP / dose (n = 10 per group). It was administered OncoVex mGM CSF by intratumoral injection once daily on study days 10, 13, and 16 (Figure 101). Injected tumors were measured twice weekly. Results are presented as individual tumor volume in mm³ 3 based on time in days, where day 0 is the day of tumor inoculation. Median survival increased significantly in the 5x10 groups 4 UFP / dose (p = 0.0056), 5x10 5 UFP / dose (p <0.0001) and 5x10 6 UFP / dose (p <0.0001) compared to the vehicle (Figure 10g). The effect of treatment with OncoVex was also evaluated. mGMCSF on uninjected ("untreated") tumors in neuro2a neuroblastoma tumor-bearing mice. Neuro2a tumor cells were implanted subcutaneously in the right and left flanks of female A / J mice (1x10 6 cells) on day 0. Tumor volume (mm³) 3The tumors were measured using electronic calipers twice a week (every two weeks). Once the tumors reached an average of approximately 100 mm 3 Mice were randomized into groups (10 mice per group) so that the mean tumor volume (on both flanks) and the variability of tumor volume at baseline were uniform between treatment groups. Mice received three intratumoral injections of OncoVEX. mGMCSF (5x10 6 UFP / dose) or vehicle on days 10, 13, and 16 on the right side ("treatment" side). Tumor volume and survival (mice were withdrawn from the study when tumors reached 800 mm³) 3 on both sides) were measured twice a week until the end of the study (Figure 10h). Treatment of Neuro2a tumor-bearing animals with OncoVEX mGMCSFThis resulted in complete regression in 8 / 10 directly injected tumors (Figure 10h). Contralateral uninjected ("untreated") tumors showed marked retardation of tumor growth (Figure 10h). Median survival increased significantly in the OncoVEX-treated groups. mGM CSF , compared to the vehicle (32 days vs 18 days, p < 0.0001, Figure 10). These results demonstrate that the treatment of B-cell lymphoma and established neuroblastoma tumors with OncoVex mGMCSF In an in vivo mouse model, it resulted in strong inhibition of tumor growth. Antitumor activity was observed in directly injected tumors (presumably through oncolysis and immune response) and in contralateral, non-injected tumors in the same host (presumably through adaptive immune response). Table 6. MEDIAN SURVIVAL GROUP CENSORED SUBJECTS SUBJECTS WITHOUT TUMOR SUBJECTS WITHOUT TUMOR Contralateral Injected Vehicle 21 0 1 / 10 1 / 10 OncoVex mGM_ CSF 3x10 4 UFP 28 0 8 / 10 0 / 10 OncoVex mGM_ CSF 3x10 5 UFP 38 0 9 / 10 5 / 10 OncoVex mGM_ CSF 3x10 6 UFP 38 0 10 / 10 5 / 10 EXAMPLE 5 A COMBINATION OF ONCOVEX mGMCSF And CTLA-4 or PD-L1 blockade inhibits B-cell lymphoma tumor growth in a model of MOUSE A20 tumor cells were injected subcutaneously into the right and left flanks of female BALB / c mice (2x10 6 cells) on day 0. Tumor volume (mm³) 3 The tumors were measured using electronic calipers twice a week (every two weeks). Once the tumors reached an average of approximately 100 mm 3The animals were randomized into groups (10 mice per group) so that the mean tumor volume (on both flanks) and the variability of tumor volume at baseline were uniform between the treatment groups. The animals then received three intratumoral injections of OncoVex. mGMCSF (5x10 6 UFP / dose) alone or in combination with intraperitoneal injections of anti-PD-L1 mAb or anti-CTLA-4 mAb. Clinical signs, body weight changes and survival were measured (mice were withdrawn from the study when tumors reached 800 mm 3 ) 2-3 times per week until the end of the study. The treatment of A20 tumor-bearing animals with OncoVex mGMCSF , an anti-CTLA-4 mAb or the OncoVex combination mGMCSFTreatment with an anti-CTLA-4 mAb resulted in complete regression of all directly injected tumors (Figure 11a). Tumors treated with intraperitoneal anti-CTLA-4 alone (both flanks) showed approximately 50% inhibition of tumor growth. Contralateral tumors showed some effects consistent with OncoVex. mGM CSF alone, while the combination of OncoVex mGM_ CSF The anti-CTLA-4 mAb resulted in regression of all tumors and led to complete cures in 9 / 10 mice. Median survival increased significantly in the anti-CTLA-4 mAb group compared to the OncoVex group. mGMCSF and the combination of the anti-CTLA-4 mAb group and the OncoVex group mGMCSF versus vehicle. In addition, a significant increase in median survival was measured in the combination group compared to a single agent alone (p = 0.012 vs OncoVex). mGMCSF(p = 0.001 vs. anti-CTLA-4 mAb). Median survival was 25.5 days for the vehicle group, 36.5 days for the OncoVex group mGM CSF and 32 for the anti-CTLA-4 mAb group. Median survival for the combination group remained indefinite after day 40, at which point 9 out of 10 mice showed no signs of tumor. (Figure 11 by Table 7a). Table 7a. MEDIAN SURVIVAL GROUP TUMOR-FREE SUBJECTS Injected TUMOR-FREE SUBJECTS Contralateral Control 25.5 0 / 10 0 / 10 OncoVex mGMCSF 5x10 e UFP 36.5 10 / 10 4 / 10 mAb mCTLA-4 30 pig 32 4 / 10 1 / 10 OncoVex mGMCSF + mAb mCTLA-4 undefined 9 / 10 9 / 10 The treatment of A20 tumor-bearing animals with OncoVex mGMCSF , an anti-PD-L1 mAb or the OncoVex combination mGM CSFTreatment with an anti-PD-L1 mAb resulted in complete regression of all directly injected tumors (Figure 11c). Tumors treated only with intraperitoneal anti-PD-L1 mAb (both flanks) showed no effect on tumor growth. Contralateral tumors showed some effects consistent with OncoVex. mGM CSF alone, while the combination of OncoVex mGM_ CSF The anti-PD-L1 mAb resulted in regression of all tumors and led to complete cures in 10 / 10 mice. Median survival increased significantly in the OncoVex groups. mGMCSF and combination versus vehicle. In addition, a significant increase in median survival was measured in the combination group compared to anti-PD-L1 mAb alone. A strong trend in overall survival was also observed when compared the combination with OncoVex mGMCSF although no statistical significance was observed (p = 0.067 vs. OncoVex) mGMCSF(p = 0.0013 vs. anti-PD-L1 mAb). Median survival was 23 days for the vehicle group, 48 days for the OncoVex group mGM CSF and 26 days for the anti-PD-L1 mAb group. Median survival for the combination group remained indefinite after day 40, at which point 10 out of 10 mice showed no signs of tumor. (Figure 11d and Table 7b). Table 7b MEDIAN SURVIVAL GROUP CENSORED SUBJECTS NON-TUMORIS SUBJECTS Injected NON-TUMORIS SUBJECTS Not Injected Vehicle 22.5 0 1 2 OncoVex mGMCSF 3x10 5 UFP 46 0 6 3 PD-L1 (MIH5) 25 1* 1 1 Undefined Combo 0 10 10 These results demonstrate that the treatment of B-cell lymphoma tumors established in an in vivo mouse model with OncoVex mGMCSFIn combination with PD-L1 or CTLA-4 blockade, it results in better inhibition of tumor growth compared to either agent alone. Antitumor activity was observed in directly injected tumors (presumably through oncolysis and immune response) and in contralateral, non-injected tumors in the same host (presumably through adaptive immune response). EXAMPLE 6 ONCOVEX mGM ~ CSF WHETHER ALONE OR IN COMBINATION WITH LOCKING CTLA-4 or PD-L1 inhibits the growth of colorectal tumors in a mouse model CT-26 tumor cells were injected subcutaneously into the right and left flanks of female BALB / c mice (2x10 6 cells) on day 0. Tumor volume (mm³) 3 The tumors were measured using electronic calipers twice a week (every two weeks). Once the tumors reached an average of approximately 100 mm 3The animals were randomized into 4 groups (10 mice per group) so that the average tumor volume (on both flanks) and the variability of tumor volume at the start of treatment were uniform between the treatment groups. The animals were then 42 administered: a) PBS + IgG control; b) OncoVex mGMCSF + control IgG; c) PBS + anti CTLA-4 mAb, or PBS + anti PD-L1 mAb; or d) OncoVex mGMCSF + anti-CTLA-4 mAb, or OncoVex mGM_ CSF + anti-PD-L1 mAb. Clinical signs, body weight changes and survival were measured (mice were withdrawn from the study when tumors reached 800 mm 3 ) 2-3 times per week until the end of the study. The treatment of CT-26 tumor-bearing animals with OncoVex mGMCSFAnti-CTLA-4 mAbs or a combination thereof resulted in tumor growth inhibition in approximately 75% of all directly injected tumors by day 20 (data not shown). Contralateral tumors did not respond to OncoVex. mGM CSF OncoVEX alone showed approximately 25% tumor growth inhibition, while approximately 75% inhibition was observed in the anti-CTLA-4 mAb and combination groups. Median survival was significantly increased in the anti-CTLA-4 mAb and combination groups compared to the vehicle alone (Figure 12b). Median survival was 20 days for the vehicle and 22 days for OncoVEX. mGM CSF and 41 days for the anti-CTLA-4 group. Median survival for the combination group was greater than 50 days and remained indefinite when the experiment was stopped. Median survival in the combination groups was significantly longer than in the OncoVex groups. mGMCSF(p = 0.0001) or anti CTLA-4 mAb (p = 0.0031) alone. (Figure 12b and Table 8a). Table 8a. MEDIAN SURVIVAL GROUP TUMOR-FREE SUBJECTS Injected TUMOR-FREE SUBJECTS Contralateral Control 20 0 / 10 0 / 10 OncoVex mGMCSF 5x10® UFP 22 1 / 10 0 / 10 mAb mCTLA-4 30 pg 41 2 / 9 2 / 9 OncoVex mGMCSF + mAb mCTLA-4 undefined 10 / 10 6 / 10 Treatment of CT-26 tumor carrier animals with OncoVex mGMCSF or the combination of OncoVex mGM CSF Anti-PD-L1 mAb resulted in approximately 75% inhibition of tumor growth in all directly injected tumors by day 18 (data not shown). Intraperitoneal injection with anti-PD-L1 mAb had little effect on tumor growth (in both flanks). Contralateral tumors showed no response to OncoVex mGM CSFor anti-PD-L1 mAb alone, while ~75% tumor growth inhibition was observed in the combination group (Figure 12c). Median survival was significantly increased in the combination group compared to any single agent (p = 0.012 vs. OncoVex). mGMCSF (p = 0.007 vs. anti-PD-L1 mAb). Median survival was 21 days for the vehicle and anti-PD-L1 mAb groups, and 23 days for OncoVex. mGMCSF , and 34 days for the combination group. (Figure 12d and Table 8b). Table 8b. MEDIAN SURVIVAL GROUP TUMOR-FREE SUBJECTS Injected TUMOR-FREE SUBJECTS Contralateral Control 21 0 0 OncoVex mGMCSF 5x10 6 UFP 23 1 0 PD-L1 (MIH5) 300 pig 21 0 0 OncoVex mGMCSF + PD-L1 (MIH5) 34 5 1 These results demonstrate that the treatment of established colorectal tumors in an in vivo mouse model with: 1) OncoVex mGM CSF ; 2) a combination of OncoVex mGI * CSFand anti-CTLA-4 blockade; or 3) a combination of OncoVex mGM CSF and anti-PD-L1 blockade, resulting in strong inhibition of tumor growth. Antitumor activity was observed in tumors injected directly (presumably through oncolysis and immune response) with: 1) OncoVex mGMCSF ; 2) a combination of OncoVex mGM CSF and anti-CTLA-4 blockade; and 3) a combination of OncoVex mGM CSF and anti-PD-L1 blockade. Antitumor activity was observed in contralateral tumors not injected into the same host (presumably through adaptive immune response) with: 1) a combination of OncoVex mGM CSF and anti-CTLA-4 blockade; and 2) a combination of OncoVex mGM CSF and anti-PD-L1 blocking. To better understand the antitumor activity of the OncoVex combination mGM CSF and the anti-CTLA-4 blockade, the ability of: 1) OncoVex was evaluated mGMCSF 2) anti-CTLA-4 blockade; and 3) a combination of OncoVex mGMCSFand anti-CTLA-4 blockade to release tumor antigens and stimulate specific antitumor T lymphocyte responses. They coated 96-well ELISpot plates with a nitrocellulose filter base (Millititer HA; Millipore, Temecula, CA) with a purified anti-IFN-γ antibody (2 pg / ml). Splenocytes (8x10) were incubated 5 ) of CT-26 tumor-bearing mice treated with OncoVex mGMCSF , anti-CTLA-4 mAb or combination on day 10 with control peptides (GFP) or the AH1 peptide (SPSYVYHQF) at a final concentration of 1 pM for 20 hours at 37 2 degrees. The AH1 peptide is an immunodominant Ag derived from the envelope protein (gp70) of the endogenous murine leukemia virus presented by the L molecule d of MHC class I (25). Spots were numbered using a CTLS6 Fluorospot analyzer (CTL, Shaker Heights, OH). CD8 T lymphocyte quantification +Systemic (splenic) anti-AH1 antibodies, detected by ELISpot or dextramer staining using FACS, showed a significant increase in AH1-reactive T lymphocytes in OncoVex-treated mice. mGMCSF CTLA-4 blockade or the combination of OncoVex mGM CSF and CTLA-4 blockade (Figure 12e, 12f). Quantification of CD8 T lymphocytes + Local (tumor-mediated) anti-AH1 antibodies showed a significant increase only in the combination group. A significant decrease in Tregs was also observed in the CT-26 model. This effect was greater in combination with CTLA-4 blockade (Figure 12g). This experiment demonstrates that the combination of OncoVex mGM CSF and the anti-CTLA-4 blockade leads to an increase in the presence of effector cells and a decrease in the presence of regulatory T lymphocytes, which in turn leads to an increase in the effectiveness of the combination over any single compound. EXAMPLE 7 ONCOVEX mGM CSF, ALONE OR IN COMBINATION WITH CTLA-4 BLOCKADE, INHIBITS MELANOMA TUMOR GROWTH IN A MOUSE MODEL B16F10 cells (5x10) were injected 4 - resistant to lysis by OncoVex mGMCSF due to the lack of an HSV-1 entry receptor) intravenously on day 0. On day 2, mouse Nectin 1 transfected B16F10 melanoma cells (sensitive to OncoVex lysis) were injected. mGMCSF ) subcutaneously in the right flank of female BL6 mice. The tumor volume (mm³) 3 The size was measured using electronic calipers twice a week (every two weeks). Once the subcutaneous tumors reached an average of approximately 100 mm 3The animals were randomized into four groups (10 mice per group) so that the mean tumor volume and tumor volume variability at baseline were uniform across treatment groups. The animals received three intratumoral injections of OncoVex. mGMCSF (5x10 6 UFP / dose), four intraperitoneal injections of anti-CTLA-4 mAb, a combination of three intratumoral injections of OncoVex mGM CSF (5x10 6 UFP / dose) with four intraperitoneal injections of anti-CTLA-4 mAb or vehicle alone. Clinical signs, body weight changes, and survival were measured (mice were withdrawn from the study). 45 when the tumors reached 800 mm 3 ) 2-3 times per week until the end of the study. Treatment of Nectin 1 B16F10 tumor-bearing mice with OncoVex mGM_ CSF or the combination of OncoVex mGMCSFand anti-CTLA-4 mAb resulted in ~85% and 99% inhibition of subcutaneous tumor growth, respectively. No inhibition was observed with anti-CTLA-4 mAb alone (Figure 13a). Assessment of lung metastasis burden showed that the combination of OncoVex mGMCSF and the anti-CTLA-4 mAb was significantly more effective than any treatment alone (p = 0.0008 vs OncoVex mGM_ CSF p = 0.0007 versus anti-CTLA-4 mAb) for inhibiting lung metastasis (Figure 13b). Median survival was significantly increased in the combination group compared to the vehicle group (p < 0.0001). Median survival was 30 days for the vehicle group and 46 days for the OncoVex group. mGM CSF plus anti-CTLA-4 mAb (Figure 13c and Table 9). Table 9. Group (n = 10) Treatment Tumors mDS (days) 1 Control IV Lung only 30 2 OncoVex mGMCSF + CTLA-4 SC and lung 46 These results demonstrate that the treatment of established melanoma tumors in an in vivo mouse model with OncoVex mGMCSF or the combination of OncoVex mGM CSF and anti-CTLA-4 mAb results in strong inhibition of tumor growth. These results also show that the combination of OncoVex mGMCSF The anti-CTLA-4 mAb shows a significantly more robust systemic antitumor effect compared to either treatment alone, as evidenced by the combination's ability to inhibit lung metastases. Antitumor activity was observed in directly injected tumors (presumably through oncolysis and immune response) and in contralateral, non-injected tumors in the same host (presumably through adaptive immune response). It was also observed that lung tumors in the vehicle groups, OncoVex mGM CSFAnd anti-CTLA-4 mAb showed uncommon T and B lymphocytes scattered at the tumor periphery and mild intratumoral macrophages. Interestingly, the tumors in the OncoVex combination group mGMCSF Anti-CTLA-4 mAbs showed prominent T lymphocytes in the periphery of the tumor, as well as T lymphocyte infiltration into the tumor in varying numbers. Macrophages were prominent both in the tumor and in the 46 dense cellular infiltrates in the periphery of the tumor. B cells remained exclusively in the periphery of the tumor (Figure 13d and data not shown). These results from lung tumor immune infiltration indicate that the combination of OncoVex mGMCSF and CTLA-4 blockade can convert poorly infiltrated B16F10 metastases (i.e., "cold" tumors) into well infiltrated B16F10 metastases (i.e., "hot" tumors). EXAMPLE 8 ONCOVEX mGM CSFINHIBITS THE GROWTH OF TRIPLE-NEGATIVE BREAST CARCINOMA TUMORS IN A MOUSE MODEL 4T1 tumor cells were injected subcutaneously into the right flanks of female BALB / c mice (2x10 6 cells) on day 0. Tumor volume (mm³) 3 The tumors were measured using electronic calipers twice a week (every two weeks). Once the tumors reached an average of approximately 100 mm 3 The animals were randomized into four groups (10 mice per group) so that the mean tumor volume and tumor volume variability at baseline were uniform across the treatment groups. The animals then received three intratumoral injections of OncoVex. mGM CSF (5x10 4 , 5x10 5 , or 5x10 6UFP / dose) or vehicle. Clinical signs, body weight changes, and survival were measured (mice were removed from the study when tumors reached 800 mm 3 ) 2-3 times per week until the end of the study. The treatment of animals carrying 4T1 tumors with OncoVex mGM CSF This resulted in approximately 75% inhibition of tumor growth in the 5x10 group. 6 UFP / dose (p < 0.0001). Doses of 5x10 4 and 5x10 5 from OncoVex mGM CSF They did not result in any medial inhibition of tumor growth (Figure 14). These results demonstrate that the treatment of established triple-negative breast carcinoma tumors with OncoVex mGMCSF It produces a strong inhibition of tumor growth. The antitumor activity was measured only in directly injected tumors. EXAMPLE 9 ONCOVEX mGMCSF, EITHER ALONE OR IN COMBINATION WITH A GITR AGONIST, INHIBITS THE GROWTH OF B-CELL LYMPHOMA TUMORS IN A MOUSE MODEL A20 tumor cells were injected subcutaneously into the right and left flanks of female BALB / c mice (2x10 6 cells) on day 0. Tumor volume (mm³) 3 The tumors were measured using electronic calipers twice a week (every two weeks). Once the tumors reached an average of approximately 100 mm 3 The animals were randomized into 4 groups (10 mice per group) so that the mean tumor volume (on both flanks) and the variability of tumor volume at the start of treatment were uniform across the treatment groups. The animals were then 47 administered OncoVex mGMCSF or a combination of OncoVex mGMCSFand anti-GITR mAb. Clinical signs, body weight changes and survival were measured (mice were withdrawn from the study when tumors reached 800 mm 3 ) 2-3 times per week until the end of the study. Tumors treated with intraperitoneal anti-GITR mAb resulted in a 30% cure rate (both injected and contralateral). OncoVex mGMCSF It cured 6 / 10 (60%) of the injected tumors, while contralateral tumors showed a modest response with no cures. The OncoVex combination mGM CSF The anti-GITR mAb produced regression of all tumors (both injected and contralateral) and led to complete cures in 7 / 10 mice. See Figure 15a. Median survival increased significantly in the anti-GITR mAb group compared to the OncoVex group. mGM CSF and the OncoVex combination group mGMCSFand anti-GITR mAb, compared to the vehicle. In addition, a significant increase in median survival was measured in the OncoVex group. mGM CSF and the anti-GITR mAb combination group versus a single agent alone (p < 0.0001 vs OncoVex mGM CSF (p = 0.039 vs. anti-GITR mAb). Median survival was 24 days for the vehicle group, 26 days for the OncoVex group mGM CSF and 43 for the anti-GITR mAb group. Median survival for the combination group remained indefinite after day 49, at which point 7 out of 10 mice showed no signs of tumor. See Figure 15b and Table 10. Table 10. Median Survival Group Tumor-Free Subjects Injected Tumor-Free Subjects Contralateral Control 24 0 / 10 0 / 10 OncoVex mGM_ CSF 3x10 5 UFP 26 6 / 10 0 / 10 mAb mGITR 100 ug 43 4 / 10 3 / 10 OncoVex mGM ' CSF + mAb undefined 8 / 10 7 / 10 mGITR These results demonstrate that the treatment of B-cell lantern tumors with OncoVex mGMCSF and a combination of the OncoVex group mGMCSF and anti-GITR mAb results in strong inhibition of tumor growth. EXAMPLE 10 STUDY EVALUATING THE ONCOVEX COMBINATION muGM CSF WITH PD-1 INHIBITION IN A MOUSE MODEL OF COLON (COLORRECTAL) ADENOCARCINOMA (MC-38) This study was designed to evaluate the tolerability and antitumor activity of OncoVex. muGM CSF PD-1 inhibition or the combination of OncoVex muGMCSF and PD-1 inhibition in an MC-38 mouse tumor model. C57BL / 6 mice were inoculated with syngeneic MC-38 tumor cells in the right and left flanks. Ten days post-inoculation, the tumors averaged 5 mm in diameter (60 mm²). 3 of tumor volume) and the animals were assigned to 6 groups (n = 10 / group). OncoVEX was administered. muGM CSF (5x106 UFP / dose) or buffered formulation control administered intratumorally to right-sided tumors once daily every three days for a total of three doses. Left-sided tumors did not receive injection. Anti-mouse PD-1 (clone RMP1-14, BioXCell) or isotype control antibody (rat IgG2a, clone 2A3, BioXCell) was administered intraperitoneally at 1 mg / dose or 300 pg / dose twice weekly, beginning on study day 10 and ending on study day 30 (7 doses administered). Tumor volumes of injected (right side) and non-injected (left side) tumors, body weight, and general clinical observations were collected 2–3 times weekly. Animals were euthanized if the total tumor volume (right + left) reached the IACUC mandatory cutoff of >10% of body weight or if the animals showed signs of distress. Peripheral blood was drawn on days 14 and 20 of the study (4 and 10 days, respectively, after the start of dosing) for immunophenotyping analysis.After red blood cell lysis, white blood cells were stained for the following markers: CD3, CD4, CD8, CD25, CD49b (NK marker), FoxP3, GITR, PD-1 and PD-L1 and analyzed by flow cytometry. All animals survived throughout the experiment and showed no evidence of adverse health effects associated with the treatment, as evidenced by body weight (Figure 16a) or survival, and no adverse clinical signs were identified in the daily health check examinations. A slightly lower body weight in the treated groups compared to the control groups is attributed to more aggressive tumor growth in the control animals compared to the treated animals, as discussed below. Inhibition of tumor growth was observed in response to monotherapy treatment with the anti-mPD-1 antibody (at both test doses of 300 pg and 1 mg per dose) or with OncoVEX muGMCSF (Figure 16b). Table 11 summarizes the number of animals that were tumor-free (regressions) at the end of the experiment on the right (injected side) or left (non-injected side) flanks. While the activity of a single agent with either of the agents was limited to 10–20% complete regression in injected tumors (and no complete regression in non-injected tumors), the combination led to 80–90% regression in injected tumors (and complete regressions in 10–20% of non-injected tumors). These data indicate that combination therapy with OncoVEX muGMCSF and anti-PD-1 led to substantially improved tumor clearance in the MC-38 mouse tumor model. Table 11. Number of animals with complete regressions Group Injected Tumors Non-injected Tumors Vehicle + Isotype 0 / 10 0 / 10 OncoVEX muGMCSF + Isotype 2 / 10 0 / 10 Vehicle + anti-PD-1 (1 mg) 1 / 10 0 / 10 Vehicle + anti-PD-1 (300 pg) 1 / 10 0 / 10 OncoVEX muGMCSF + anti-PD-1 (1 mg) 8 / 10 2 / 10 OncoVEX muGM CSF + anti-PD-1 (300 pg) 9 / 10 1 / 10 These results demonstrate that OncoVex mGMCSF , either alone or in combination with PD-1 blockade, inhibits the growth of MC-38 colorectal tumors. EXAMPLE 11 ONCOVEX COMBINATION EVALUATION STUDY muGMCSF PD-L1 INHIBITION IN A MOUSE MODEL OF COLON (COLORRECTAL) ADENOCARCINOMA (MC-38) This study was designed to evaluate the tolerability and antitumor activity of OncoVEX muGMCSF PD-L1 inhibition or the combination of OncoVEX muGM CSF and PD-L1 inhibition in an MC-38 mouse tumor model. MC-38 tumor cells were injected subcutaneously into the right and left flanks of female C57BL / 6 mice on day 0. The tumor volume (mm³) 3 The tumors were measured using electronic calipers twice a week (every two weeks). Once the tumors reached an average of approximately 100 mm 3 The animals were randomized into 4 groups (10 mice per group) so that the average tumor volume (on both flanks) and the variability of tumor volume at the start of treatment administration were uniform between the treatment groups. OncoVex was administered. mGMCSF (5x10 6 UFP / dose) or formulation buffer control via intratumoral route (on the right side of the animal) every three days for a total of three injections, alone or in combination with 50 intraperitoneal injections of anti-PD-L1 mAb (MIH5 clone, mouse IgG1) or a control IgG1 (mAbs were administered four times in total). Uninjected tumors (contralateral; on the left side of the animal) were not injected. Clinical signs, body weight changes, and survival were measured (mice were removed from the study when tumors reached 800 mm²). 3 ) 2-3 times per week until the end of the study. All animals survived throughout the experiment and showed no evidence of adverse health effects associated with the treatment, as demonstrated by body weight, and no adverse clinical signs were identified in daily health check examinations. Inhibition of tumor growth was observed in response to monotherapy treatment with OncoVex. mGMCSF or anti-PD-L1 mAb in injected and contralateral tumors (Figure 17), while the combination of OncoVex mGMCSFand anti-PD-L1 mAb produced regression of all injected tumors and 7 out of 10 non-injected tumors (Figure 17). EXAMPLE 12 ONCOVEX COMBINATION EVALUATION STUDY muGMCSF WITH PD-1 INHIBITION IN A MOUSE MELANOMA TUMOR MODEL (B16F10) This study was designed to evaluate the tolerability and antitumor activity of OncoVEX muGM CSF PD-1 inhibition or the combination of OncoVEX muGM CSF and the inhibition of PD-1 in a B16F10 melanoma tumor model in mice. Genetically engineered B16F10 tumor cells expressing mNectin were injected subcutaneously into the right flank of female C57BL / 6 mice on day 0. The tumor volume (mm³) 3 The tumors were measured using electronic calipers twice a week (every two weeks). Once the tumors reached an average of approximately 100 mm 3The animals were randomized into 4 groups (10 mice per group) so that the mean tumor volume and tumor volume variability at the start of treatment were uniform across the treatment groups. OncoVex was administered. mGM CSF (5x10 6 UFP / dose) or buffered formulation control intratumorally three times every three days, alone or in combination with intraperitoneal injection of anti-PD-1 mAb (Clone 29F1A12, mouse IgG1) or an IgG1 control (mAbs were dosed four times in total). Clinical signs, body weight changes, and survival were measured (mice were withdrawn from the study when tumors reached 800 mm²). 3 ) 2-3 times per week until the end of the study. All animals survived throughout the experiment and showed no evidence of adverse health effects associated with the treatment, as demonstrated by body weight, and no adverse clinical signs were identified in daily health check examinations. Inhibition of tumor growth was observed in response to monotherapy treatment with OncoVex monotherapy. mGMCSF (3 out of 10 mice showed tumor regression), while monotherapy with anti-PD-1 mAb had no inhibitory effect on tumor growth (Figure 18). The OncoVex combination mGMCSF and anti-PD-1 mAb produced regression in 5 out of 10 injected tumors (Figure 18), demonstrating that the combination of OncoVex mGM CSF and anti-PD-1 mAb has superior antitumor activity compared to monotherapy. EXAMPLE 13 MULTICENTER, UNBLINDED, PHASE 1 DOSE REDUCTION STUDY TO EVALUATE THE SAFETY AND EFFICACY OF TALIMOGEN LAHERPAREPVEC IN PEDIATRIC SUBJECTS WITH ADVANCED NON-CENTRAL NERVOUS SYSTEM TUMORS WHO ARE SUSCEPTIBLE TO DIRECT INJECTION This example describes a phase 1, multicenter, open-label dose-tapping study to evaluate the safety and efficacy of Talimogene Laherparepvec in pediatric subjects with advanced non-central nervous system tumors who are amenable to direct injection. See the U.S. National Institutes of Health website (clinicaltrials.gov), study identifier: NCT 02756845 (incorporated herein by reference). The main objective of the study is to determine the safety and tolerability of talimogene laherparepvec, evaluated by the incidence of dose-limiting toxicities (DLTs), in pediatric subjects with advanced non-Central Nervous System (CNS) tumors who are susceptible to direct injection. The talimogene laherparepvec will be administered to approximately 18 to 36 pediatric subjects with advanced non-CNS tumors who are amenable to direct injection. The pediatric subjects will generally be enrolled in cohorts stratified by age and baseline herpes simplex virus type 1 (HSV-1) serologic status (3 to 6 subjects / cohort). TLDs will be assessed based on 3 to 6 subjects evaluable for TLDs within each cohort. The primary outcome measure is to determine the safety and tolerability of talimogene laherparepvec, as assessed by the incidence of dose-limiting toxicities (DLTs), in pediatric subjects with advanced non-central nervous system (CNS) tumors amenable to direct injection. Secondary outcome measures are (1) to assess the antitumor activity of the talimogene laherparepvec, evaluated by overall response rate (ORR), duration of response (DDR), time to response (TDR), time to progression (TDP), progression-free survival (PFS) using modified immune-related response criteria that mimic response assessment criteria in solid tumors (CRri-CERETS), and overall survival (OS), and (2) to assess the association between 52 granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors / subunits in archived tumor tissue and clinical outcomes (safety endpoints and efficacy endpoints such as TRG, DDR, TDR, TDP, SSP and SG). INCLUSION CRITERIA: • The subject's legally acceptable representative has given informed consent / assent when the subject is legally too young to provide informed consent / assent and the subject has given written consent in accordance with local regulations and / or guidelines before any specific study activity / procedure began. • Male or female subjects aged 0 to < 18 years at the time of informed consent / assent • They must be willing to present a local HSV-1 serological status within the 28 days prior to enrollment • Histologically or cytologically confirmed non-CNS solid tumor that recurred after standard therapy or for which no standard therapy is available • Presence of measurable lesions (defined by CRri-CERETS) or non-measurable lesions defined by modified CRri-CERETS • The subject must be a candidate for intralesional injection, defined as one or more of the following: at least 1 injectable lesion > 10 mm in diameter longer than multiple injectable lesions that together have a diameter longer than > 10 mm NOTE: Visceral injuries are not eligible for injection. Additionally, bone injuries are not eligible for injection unless there is a soft tissue component that is suitable for injection. • Performance status: Karnofsky > 70% for children 12 to < 18 years old; Lansky Play Scale > 70% for children 0 to < 12 years old; Life expectancy > 4 months from the date of registration • Proper organic function as defined below: Hematological (without the need for hematopoietic growth factor) absolute neutrophil count (ANC) > 1.0 x 10 9 / L platelet count > 75 x 10 9 / L hemoglobin > 8 g / dl (without need for supportive transfusions) Renal serum creatinine < 1.5 x upper limit of normal (ULN) for age OR creatinine clearance > 60 ml / min / 1.73m 2for a subject with creatinine levels > 1.5 x ULN for age. (Note that creatinine clearance does not need to be determined if baseline serum creatinine is < 1.5 x ULN for age. Creatinine clearance should be determined according to institutional criteria.) Hepatic Serum bilirubin < 1.5 x ULN for age or direct bilirubin < ULN for age for a subject with a total bilirubin level > 1.5 x ULN for age Aspartate aminotransferase (AST) < 2.5 x ULN for age or < 5 x ULN for age for a subject with liver metastases Alanine aminotransferase (ALT) < 2.5 x ULN for age or < 5 x ULN for age of the subject with liver metastasis Coagulation international normalization ratio (INR) or prothrombin time (PT) < 1.5 x ULN for age partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) < 1.5 x ULN for age • Women of childbearing age must have a negative urine or serum pregnancy test 72 hours before dosing. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. EXCLUSION CRITERIA • Diagnosis of leukemia, non-Hodgkin lymphoma, Hodgkin's disease, or other hematologic malignancy • Bone marrow radiotherapy 6 weeks before enrollment OR 3 months before enrollment if previous radiotherapy was received to the craniospinal axis or to at least 60% of the pelvis; 2 weeks before enrollment if local palliative radiotherapy was received • CNS tumor or clinically active brain metastases • primary ocular or mucosal melanoma • History or evidence of giant congenital melanocytic nevus, dysplastic nevus syndrome, or xeroderma pigmentosum • History of another malignant disease in the last 5 years with the following exception: malignancy treated with curative intent and with no known active disease present and has not received chemotherapy for > 5 years prior to enrollment and the physician believes that they have a low risk of recurrence • History or evidence of active autoimmune disease requiring systemic treatment (i.e., with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. • Evidence of clinically significant immunosuppression such as the following: primary immunodeficiency state such as disease of severe combined immunodeficiency simultaneous opportunistic infection Subjects receiving systemic immunosuppressive therapy (> 2 weeks prior to enrollment), including doses of oral corticosteroids (with the exception of maintenance physiological replacement), will not be excluded from the study. Subjects requiring intermittent use of inhalation corticosteroids or local injection of corticosteroids will not be excluded from the study. • Active herpetic skin lesions or previous complications of herpetic infection (e.g., herpetic keratitis or encephalitis) • Previous treatment with thalimogene laherparepvec or any other eneolytic virus • Previous treatment with a tumor vaccine • Requires intermittent or chronic treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent topical use • Prior chemotherapy, radiotherapy, or biological cancer therapy within 28 days prior to enrollment, or failure to recover to a Common Terminology Criteria for Adverse Events (CTCEA) grade 1 or better from an adverse event due to cancer therapy administered more than 28 days prior to enrollment • Currently receiving treatment in another investigational device or drug study, or less than 28 days since completing treatment in another investigational device or drug study(s). Other research procedures are excluded while participating in this study. • Major surgery < 28 days before registration • It is expected that the patient will require other cancer therapy during the study, with the exception of local palliative radiation treatment. • Have acute or chronic hepatitis B or hepatitis C virus infection or received treatment with nucleotide analogues such as those used in the treatment of hepatitis B virus (e.g., lamivudine, adefovir, tenofovir, telbivudine, and entecavir), ribavirin, or interferon alpha within 12 weeks of starting study treatment. • Known or suspected human immunodeficiency virus (HIV) infection • Vaccine made with live microbes received within 28 days prior to registration • Antiplatelet or anticoagulant medications are not permitted in the 7 days prior to the injection of talimogen laherparepvec except for low doses of heparin necessary to maintain the patency of the venous catheter • Female subjects who are pregnant or breastfeeding or planning to become pregnant during study treatment and up to 3 months after the last dose of talimogene laherparepvec • Female subject of childbearing age who is unwilling to use an acceptable method or methods of effective contraception during study treatment and for 3 months after the last dose of talimogene laherparepvec. Note: Acceptable methods of effective contraception are defined in the informed consent / assent form. Where required by local laws and regulations, additional country-specific contraceptive requirements may be outlined in a country-specific protocol supplement at the end of the Protocol Appendix section. • Sexually active individuals and their partners who do not wish to use a male or female latex condom to prevent possible viral transmission during sexual contact for the duration of treatment and for 30 days after treatment with talimogene laherparepvec • The subject has a known sensitivity to any of the products or components to be administered during dosing • Subject who is likely to be unavailable to complete all study visits or procedures required by the protocol, and / or to comply with all required study procedures to the best of the subject's and investigator's knowledge • History or evidence of any psychiatric disorder, substance abuse, or any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to the subject's safety or interfere with the assessment, procedures, or completion of the study • Subjects who are unwilling to minimize exposure with their blood or other body fluids to individuals at increased risk of HSV-1-induced complications (immunocompromised individuals, HIV-positive individuals, pregnant women, or children under 1 year of age) during treatment with talimogene laherparepvec and up to 28 days after the last dose of talimogene laherparepvec According to the inclusion and exclusion criteria, the talimogene laherparepvec will be administered by intralesional injection only in injectable cutaneous, subcutaneous, lymph node, and other non-visceral tumors. Therefore, the anticipated eligible tumor types for this study are as follows: • Bone sarcoma: Ewing sarcoma and osteosarcoma • Soft tissue sarcoma: Rhabdomyosarcoma and non-rhabdomyosarcomatous soft tissue sarcoma • Neuroblastoma • Melanoma The first dose of talimogene laherparepvec will be up to 4.0 ml of 10 6 UFP / ml administered on day 1. The second injection, up to 4.0 ml of 10 8 UFP / ml (or up to 4.0 ml of 10 6UFP / ml for a reduced-dose cohort), will be administered 21 (+3) days after the initial injection (i.e., not earlier than day 22, but should not be delayed more than 3 days past the 21-day time point). All subsequent injections, up to 4.0 ml of 10 8 UFP / ml (or up to 4.0 ml of 10 6UFP / ml (for a reduced-dose cohort) will be administered every 14 (± 3) days. The treatment cycle interval may be increased due to toxicity. The maximum volume of talimogene laherparepvec administered at any dose is 4.0 ml for any single lesion and in any treatment. The recommended volume of talimogene laherparepvec to be injected into the tumor(s) depends on the size of the tumor(s) and will be determined according to the injection volume guideline in Table 12. It is recommended that each lesion receive the maximum possible amount to be injected, given the tumor's characteristics, at each visit before proceeding to the next lesion, using the prioritization model below and the injection volume guideline based on tumor size. Table 12. Laherparepvec talimogene injection volume guideline based on tumor size Tumor size (longest dimension) Maximum injection volume > 5.0 cm 4.0 ml > 2.5 cm to 5.0 cm 2.0 ml > 1.5 cm to 2.5 cm 1.0 ml > 0.5 cm to 1.5 cm 0.5 ml < 0.5 cm 0.1 ml On each day of treatment, the prioritization of injections is recommended from the as follows: 1. Any new injectable tumor that has appeared since the last injection. 2. By tumor size, starting with the largest tumor 3. Any tumor previously seen during tumor assessment that was too small to inject and has now become large enough to inject Subjects will be treated with talimogene laherparepvec until they have achieved a complete response (CR), no injectable tumors are present, progressive disease (PD) is confirmed by modified CRri-CERETS, study treatment intolerance occurs, 24 months have passed since the date of the first dose of talimogene laherparepvec, alternative cancer therapy is required, or the study is completed, whichever occurs first. Due to the mechanism of action, subjects may experience growth in existing tumors or the development of new tumors before the maximum clinical benefit of talimogene laherparepvec is reached. Therefore, modified CRri-CERETS will be used to assess response.

Claims

NOVELTY OF THE INVENTION Having described the present invention as above, it is considered novel and, therefore, the contents contained in the following are claimed as property: CLAIMS 1. A method of treating Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, melanoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma by administering a therapeutically effective amount of an eneolytic virus.

2. The method of claim 1, wherein said oncolytic virus is a herpes simplex virus.

3. The method of claim 1 or 2, wherein said oncolytic virus is talimogene laherparepvec.

4. A method of treating B-cell lymphoma, colorectal cancer, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma) by administering: (i) a therapeutically effective quantity of an oncolytic virus; and (i) a therapeutically effective amount of a checkpoint inhibitor.

5. The method according to claim 4, wherein said checkpoint inhibitor is a CTLA-4, PD-L1 or PD-L1 blocker.

6. The method of claim 4 or 5, wherein said oncolytic virus is a herpes simplex virus.

7. The method of claim 6, wherein said herpes simplex virus is talimogene laherparepvec.

8. A therapeutically effective amount of an oncolytic virus for use in the treatment of Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-small cell lung carcinoma, colorectal cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma, or multiple myeloma.

9. A pharmaceutical composition for use in a method of treating Ewing sarcoma, neuroblastoma, rhabdoid tumor, osteosarcoma, rhabdomyosarcoma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), non-allergic lung carcinoma small cell carcinoma, colorectal cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, gastric carcinoma, breast cancer (e.g., triple-negative breast carcinoma), cutaneous T-cell lymphoma or multiple myeloma, wherein said pharmaceutical composition comprises an eneolytic virus.

10. The oncolytic virus of claim 8 or 9, wherein said oncolytic virus is a herpes simplex virus.

11. The oncolytic virus of claim 10, wherein said herpes simplex virus is talimogene laherparepvec.

12. A therapeutically effective amount of an oncolytic virus and a checkpoint inhibitor for use in the treatment of B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma).

13. A pharmaceutical composition for use in a method of treating B-cell lymphoma (e.g., diffuse large B-cell lymphoma), colorectal cancer, squamous cell carcinoma of the head and neck, or breast cancer (e.g., triple-negative breast carcinoma), wherein said pharmaceutical composition comprises a therapeutically effective amount of an oncolytic virus and a checkpoint inhibitor.

14. The checkpoint inhibitor of claim 12 or 13, wherein said checkpoint inhibitor is a CTLA-4, PD-1 or PD-L1 blocker.

15. The oncolytic virus of claim 13 or 14, wherein said oncolytic virus is a herpes simplex virus.

16. The oncolytic virus of claim 15, wherein said herpes virus simple is talimogene laherparepvec.