Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression

Oncolytic virotherapy (OV) is an emerging class of immunotherapeutic drugs. Their mechanism of action is two-fold: direct cell lysis and unmasking of the cancer through immunogenic cell death, which allows the immune system to recognize and eradicate tumours. Breast cancer is the most common cancer in women and is challenging to treat with immunotherapy modalities because it is classically an immunogenically “cold” tumour type. This provides an attractive niche for OV, given viruses have been shown to turn “cold” tumours “hot,” thereby opening a plethora of treatment opportunities. There has been a number of pre-clinical attempts to explore the use of OV in breast cancer; however, these have not led to any meaningful clinical trials. This review considers both the potential and the barriers to OV in breast cancer, namely, the limitations of monotherapy and the scope for combination therapy, improving viral delivery and challenges specific to the breast cancer population (e.g., tumour subtype, menopausal status, age).

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Mechanisms that allow vaccination against an oncolytic vesicular stomatitis virus-encoded transgene to enhance safety without abrogating oncolysis

Scientific Reports ◽

10.1038/s41598-021-94483-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Amanda W. K. AuYeung ◽

Robert C. Mould ◽

Ashley A. Stegelmeier ◽

Jacob P. van Vloten ◽

Khalil Karimi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vesicular Stomatitis Virus ◽

Cell Response ◽

Viral Infections ◽

T Cell Response ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Cell Immunity ◽

Vesicular Stomatitis

AbstractVaccination can prevent viral infections via virus-specific T cells, among other mechanisms. A goal of oncolytic virotherapy is replication of oncolytic viruses (OVs) in tumors, so pre-existing T cell immunity against an OV-encoded transgene would seem counterproductive. We developed a treatment for melanomas by pre-vaccinating against an oncolytic vesicular stomatitis virus (VSV)-encoded tumor antigen. Surprisingly, when the VSV-vectored booster vaccine was administered at the peak of the primary effector T cell response, oncolysis was not abrogated. We sought to determine how oncolysis was retained during a robust T cell response against the VSV-encoded transgene product. A murine melanoma model was used to identify two mechanisms that enable this phenomenon. First, tumor-infiltrating T cells had reduced cytopathic potential due to immunosuppression. Second, virus-induced lymphopenia acutely removed virus-specific T cells from tumors. These mechanisms provide a window of opportunity for replication of oncolytic VSV and rationale for a paradigm change in oncolytic virotherapy, whereby immune responses could be intentionally induced against a VSV-encoded melanoma-associated antigen to improve safety without abrogating oncolysis.

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716 Cell-based virotherapy for targeting cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0716 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A758-A758

Author(s):

Duong Nguyen ◽

Alberto Gomez ◽

Forrest Neuharth ◽

Ashley Alamillo ◽

Thomas Herrmann ◽

...

Keyword(s):

Stem Cells ◽

Vaccinia Virus ◽

Cancer Cells ◽

Neutralizing Antibodies ◽

Immune Cell ◽

Human Cancer ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Adaptive Immune ◽

Immune Barriers

BackgroundOncolytic virotherapy has been recognized as a promising new therapy for cancer for decades but only few viruses have been approved worldwide. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers making oncolytic virus clinically inefficient. To overcome this obstacle, we utilized adipose-derived stem cells (AD-MSC) loaded with tumor selective CAL1 oncolytic vaccinia virus to generate a new therapeutic agent called SNV1 (SuperNova-1).MethodsCAL1 vaccinia virus was tested for its ability to replicate and selectively kill various human cancer cell lines in vitro and in vivo. Additionally, CAL1 was loaded into adipose-derived mesenchymal stem cells to generate SuperNova1 (SNV1). Both CAL1 and SNV1 were tested for their ability to kill cancer cells in the presence of active complement and neutralizing antibodies in cell culture as well as in mice. Immune cell infiltration of the treated and untreated tumors was analyzed by flow cytometry.ResultsCAL1 showed preferential amplification and killed various tested human (PC3, FaDu, MDA-MB-231, RPMI) and mouse cancer cells (CT26, EMT6, TRAMP-C2, RM1). In animals, CAL1 caused tumor regression in PC3 and CT26 mouse models without signs of toxicity. SNV1 significantly enhanced protection of CAL1 virus from clearance by the immune system as compared to naked CAL1 virus, leading to higher therapeutic efficacy in animals. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations. Importantly, we documented a decreased frequency of Tregs, and improved effector to Treg ratios, which was associated with inhibition of tumor growth at the treated tumor site and also at distant untreated sites.ConclusionsCAL1 is potentially used as an oncolytic agent. In addition, SNV1 cell-based platform protects and potentiates oncolytic vaccinia virus by circumventing humoral innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. Particularly, SNV1 provided instantly active viral particles for immediate infection and simultaneous release of therapeutic proteins in the injected tumors.

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Oncolytic virotherapy for multiple myeloma

Expert Opinion on Biological Therapy ◽

10.1517/14712598.8.4.463 ◽

2008 ◽

Vol 8 (4) ◽

pp. 463-473 ◽

Cited By ~ 10

Author(s):

Amaalia E Stief ◽

J Andrea McCart

Keyword(s):

Multiple Myeloma ◽

Oncolytic Virotherapy

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