Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells

Zhang, Tiantian; Kordish, Dennis H.; Suryawanshi, Yogesh R.; Eversole, Robert; Kohler, Steven L.; Mackenzie, Charles D.; Essani, Karim

doi:10.2174/1568009617666170630143931

Cited by 12 publications

(15 citation statements)

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“…For recombinant virus replication, OMK cells were infected as described previously. Expression of the IL-2 and FliC transgenes was previously confirmed [3,5]. TPV/∆66R/mIL-2 was previously tested for efficacy in an immunodeficient (IDt) animal model bearing human melanoma xenografts in our lab [12].…”

Section: Cells Viruses and Reagentsmentioning

confidence: 98%

“…Cell viability was tested both prior to injection and post injection with 0.4% (w/v) trypan blue dissolved in PBS-A to ensure that >90% of the cell population was and remained viable through the procedure. Once tumors became visible, volumes were measured with digital Vernier calipers using the formula ((length × width × height) × (π/6)) in mm 3 . When 1 of the 2 transplanted tumors reached the range of 120 mm 3 -180 mm 3 , mice were randomly assigned into 1 of 8 possible treatment groups, half being IDt and the others receiving adoptive transfer of splenocytes.…”

Section: Virotherapy Of Human Melanoma Xenografts In Balb/c Nude Micementioning

confidence: 99%

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Multiple Administration Routes, Including Intramuscular Injection, of Oncolytic Tanapoxvirus Variants Significantly Regress Human Melanoma Xenografts in BALB/c Nude Mice Reconstituted with Splenocytes from Normal BALB/c Donors

Monaco,

Idris,

Filpi

et al. 2023

Genes

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Human melanoma is the most aggressive form of skin cancer and is responsible for the most deaths of all skin cancers. Localized tumors, and those which have limited spread, have 5-year survival rates of over 90%, with those numbers steadily rising over the past decade. However, metastatic melanomas have a sharp decrease in 5-year survival rates and are still an area of need for new, successful therapies. Immuno-oncolytic viruses (OVs) have emerged as a promising class of immunovirotherapy that can potentially address this disease. The Food and Drug Administration in the United States has approved one oncolytic herpes simplex virus expressing granulocyte-macrophage colony-stimulating factor (Talimogene Laherparepvec) for the treatment of metastatic melanoma, and others could soon follow for this and other cancers. In previous studies, Tanapoxvirus (TPV) recombinants expressing mouse interleukin-2 (mIL-2) and another expressing bacterial flagellin from Salmonella typhimurium (FliC) have demonstrated anti-tumor efficacy in nude mouse models. TPV replicates only in humans and monkeys, including tumor cells, which makes the use of syngeneic tumor models impossible for the study of this OV in a standard immunocompetent system. In this study, TPV/Δ66R/mIL-2 and TPV/Δ2L/Δ66R/FliC were tested for their ability to treat human melanoma xenografts (SK-MEL3) in a BALB/c nude mouse model reconstituted with splenocytes from genetically compatible, normal BALB/c donor mice. Two SK-MEL3 tumors were transplanted into each flank of BALB/c nude mice, and the larger tumor was treated intratumorally (IT) with virus or mock injection. In one set of animals, mice received adoptive transfers of splenocytes from BALB/c mice on day 4 to reconstitute their immune systems and allow for adaptive immune responses to occur in a xenograft model. Direct IT injection of TPV/Δ66R/mIL-2 led to significantly greater rates of tumor regression compared to reconstituted control (RC) mice in the primary and distant tumor sites, whereas TPV/Δ2L/Δ66R/FliC treatment led to significantly greater rates of tumor regression in distant tumor sites only. A second experiment used TPV/Δ66R/mIL-2 to test whether TPV could be administered intravenously (IV), intramuscularly (IM), or both routes simultaneously to exert similar anti-tumor effects in an indirectly treated tumor. A single SK-MEL3 tumor was transplanted into one flank of BALB/c nude mice and was treated either into the tail vein, the nearest rear leg to the tumor, or both. All mice then received adoptive transfers of splenocytes in the same way as previously described on day 4 and received an additional TPV treatment on day 14. The results demonstrated that TPV/Δ66R/mIL-2 treatment IV or IM had significantly greater rates of tumor regression than RC-treated mice but failed to exert this effect when both routes were used simultaneously. Data obtained through these experiments support the continued development of Tanapoxvirus for the treatment of human melanoma and using immune reconstitution to create intact adaptive immunity in a xenograft context, which can allow other tropism-limited OVs to be studied against human cancers.

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Section: Cells Viruses and Reagentsmentioning

confidence: 98%

Section: Virotherapy Of Human Melanoma Xenografts In Balb/c Nude Micementioning

confidence: 99%

Multiple Administration Routes, Including Intramuscular Injection, of Oncolytic Tanapoxvirus Variants Significantly Regress Human Melanoma Xenografts in BALB/c Nude Mice Reconstituted with Splenocytes from Normal BALB/c Donors

Monaco,

Idris,

Filpi

et al. 2023

Genes

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“…1. Expression of immunomodulatory transgenes such as IL-2, for enhancing antitumor efficacy and survival ( 18 ). Additionally, IL-12 also possesses anti-cancer activity and inhibits tumor angiogenesis.…”

Section: Augmentation By Transgene Expressionmentioning

confidence: 99%

Oncolytic immunovirotherapy for high-grade gliomas: A novel and an evolving therapeutic option

et al. 2023

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Glioblastoma is one of the most difficult tumor types to manage, having high morbidity and mortality with available therapies (surgery, radiotherapy and chemotherapy). Immunotherapeutic agents like Oncolytic Viruses (OVs), Immune Checkpoint Inhibitors (ICIs), Chimeric Antigen Receptor (CAR) T cells and Natural Killer (NK) cell therapies are now being extensively used as experimental therapies in the management of glioblastoma. Oncolytic virotherapy is an emerging form of anti-cancer therapy, employing nature’s own agents to target and destroy glioma cells. Several oncolytic viruses have demonstrated the ability to infect and lyse glioma cells by inducing apoptosis or triggering an anti-tumor immune response. In this mini-review, we discuss the role of OV therapy (OVT) in malignant gliomas with a special focus on ongoing and completed clinical trials and the ensuing challenges and perspectives thereof in subsequent sections.

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“…Several OVs have been designed to express immunostimulatory cytokines, such as IL-2 [123][124][125], IL-12 [126,127], IL15Rα-IL15 fusion protein [128], IL-4 [129], GM-CSF [130,131] and chemokines [132,133], which have shown promising results in pre-clinical studies in malignant glioma tumor models; however, this review focuses on OVs that are in clinical studies. At least two OVs, M032-and DNX-2440-expressing immunostimulatory proteins to potentiate anti-tumor immune responses are currently in clinical trials in malignant glioma patients.…”

Section: Changing the Tumor Landscape: From Cold To Hotmentioning

confidence: 99%

“…Oncolytic virotherapy uses two main approaches to achieve the higher levels of pro-inflammatory factors in the TME: (1) engineering OVs to express immunostimulatory proteins and (2) the administration of immune stimulators and OVs in combination. Several OVs have been designed to express immunostimulatory cytokines, such as IL-2 [ 123 , 124 , 125 ], IL-12 [ 126 , 127 ], IL15Rα-IL15 fusion protein [ 128 ], IL-4 [ 129 ], GM-CSF [ 130 , 131 ] and chemokines [ 132 , 133 ], which have shown promising results in pre-clinical studies in malignant glioma tumor models; however, this review focuses on OVs that are in clinical studies. At least two OVs, M032- and DNX-2440-expressing immunostimulatory proteins to potentiate anti-tumor immune responses are currently in clinical trials in malignant glioma patients.…”

Section: Challenges In Treating Malignant Glioma With Oncolytic Virusmentioning

confidence: 99%

Oncolytic Viruses for Malignant Glioma: On the Verge of Success?

Suryawanshi

Schulze

2021

Viruses

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Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking and chemo- and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors, and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated the ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood–brain barrier, the immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to (1) optimize delivery of oncolytic viruses beyond the blood–brain barrier; (2) trigger inflammatory immune responses in and around tumors; and (3) use multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.

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Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells

Abstract: We conclude that TANVΔ66R/mIL-2 is potentially therapeutic for human melanomas in the absence of T cells, and IL-2 expression resulted in an overall increase of therapeutic efficacy.

Cited by 12 publications

References 0 publications

Multiple Administration Routes, Including Intramuscular Injection, of Oncolytic Tanapoxvirus Variants Significantly Regress Human Melanoma Xenografts in BALB/c Nude Mice Reconstituted with Splenocytes from Normal BALB/c Donors

Multiple Administration Routes, Including Intramuscular Injection, of Oncolytic Tanapoxvirus Variants Significantly Regress Human Melanoma Xenografts in BALB/c Nude Mice Reconstituted with Splenocytes from Normal BALB/c Donors

Oncolytic immunovirotherapy for high-grade gliomas: A novel and an evolving therapeutic option

Oncolytic Viruses for Malignant Glioma: On the Verge of Success?

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