Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers

Abstract

Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells. We show that CD8+ T central memory cells (CD8+ T cm) can be efficiently loaded with VSV, they support intracellular virus production, and they can efficiently transfer VSV to tumor cells without compromising their own viability or antitumor reactivity. Loading VSV onto CD8+ T cm not only improves the safety compared with systemic administration of naked virus, but this approach also allows for an effective delivery of virus to its tumor target, resulting in an effective combination therapy in NSG mice bearing subcutaneous human acute myeloid leukemia (AML) tumors. We conclude that the combination of potent tumor debulking provided by the oncolytic VSV with the added effector functions afforded by the cytotoxic immune carrier cells results in a potent and safer immunotherapeutic, which can be further developed for clinical translation.

Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy

“…In this case, engineered TCR therapy, whereby T cells are engineered to express a new T cell receptor that recognizes specific antigen targets, offers an alternative option to cancer treatment. For instance, the combination of TCR transgenic CD8+ T central memory cells with oncolytic VSV results in rapid tumor necrosis and exhibits a substantial therapeutic advantage compared with control T cells [ 114 ].…”

Deriving Immune Modulating Drugs from Viruses—A New Class of Biologics

“…Whole viruses are also under investigation as new approaches to treating cancer, a field referred to as viral oncolytics, in which viruses selectively target and kill cancer cells as well as enhancing natural immune cell killing of cancer cells [5,6]. Adenoviruses, herpesviruses, measles, senecavirus and poxviruses, such as vaccinia and myxoma, are all in active development as treatments for many cancers, including multiple myeloma, melanoma, sarcomas and brain cancers such as glioblastoma multiforma (GBM) [7][8][9][10][11]. The rabbit-derived myxomavirus is one such virus now demonstrated to selectively target, infect and kill cancer cells, without infecting or killing normal, noncancerous mammalian and human cells [6].…”

Cancer Vaccines and Oncolytic Viruses Exert Profoundly Lower Side Effects in Cancer Patients than Other Systemic Therapies: A Comparative Analysis

“…Loading an oncolytic virus (e.g., vesicular stomatitis virus (VSV)) onto CD8+ central memory T cells improved safety and efficacy compared to systemic virus administration [80].…”