The oncolytic virus ∆PK has multi-modal anti-tumor activity
Oncolytic viruses (OVs) are an emerging cancer therapeutic based on tumor cell lysis by replicating virus and the resulting release of cellular proteins [viz. tumor-associated antigens (TAAs)], which modulate tumor immunogenic cell death (ICD). OVs have a near complete absence of serious adverse events. Unfortunately, clinical efficacy is limited, apparently due to their relatively poor tumor penetration, failure to eradicate tumor-initiating cancer stem cells (CSCs), and inability to alter the strongly immunosuppressive tumor microenvironment. Current strategies to overcome these limitations include the selection of distinct virus platforms, the introduction of an inflammatory cytokine gene and the use of combinatorial therapy. However, clinical efficacy is a delicate balance of forces, between: (i) effective OV replication and virus clearance by the induced antiviral immunity, (ii) antitumor immunity and factors promoting tumor growth, and (iii) immune stimulation and the immunosuppressive nature of the tumor microenvironment. Therefore, altering any one of these parameters may counteract the positive effect of the other parameters and the development of OVs with multi-modal death-inducing activity is the increasingly recognized therapeutic goal.
We developed ∆PK, a Herpes simplex virus type 2 (HSV-2) OV with multi-modal oncolytic activity (Fig. 1) and superior clinical efficacy. Indeed, complete remission was seen in 87.5% of mice bearing human melanoma at 5 months after the last ΔPK injection and survival was 100%. ∆PK is deleted in a protein kinase gene (ICP10PK), which controls both virus growth in normal cells and cell survival, a unique regulatory process which is not conserved in the closely related HSV-1. While ICP10PK deletion reduces virus growth, it also triggers multiple programmed cell death (PCD) pathways (caspases-3,-7, calpain, and autophagic cell death) and restores expression of the tumor suppressor function (H11/HspB8) thereby further stimulating apoptosis. The activated PCD pathways provide distinct and independent cell killing mechanisms, increasing tumor penetration and efficient CSC lysis in both melanoma and breast cancer.
The multi-modal oncolytic activity of ∆PK also includes inhibition of the tumor immunosuppressive microenvironment and ICD. ∆PK inhibits tumor secretion of the immunosuppressive cytokine IL-10 while increasing the secretion of multiple pro-inflammatory cytokines (TNF-a, IL-6, GM-CSF and IL-1b), which counteract immunosuppression. IL-10 down-regulation is through activation of JNK/AP-1 pathways. Its loss blocks recruitment of immune inhibitory T cells (Tregs) and stimulates immune-mediated tumor cell killing through upregulation of MICA, the ligand for the activating receptor NKG2D that is expressed on cytotoxic T and natural killer (NK) cells. TNF-a, IL-6 and GM-CSF upregulation is through the activation of Toll-like receptor factor 2 (TLR2)/NF-kB pathways; IL-1b through pyroptosome-dependent caspase-1 activation. TNF-a and GM-CSF are independently associated with improved efficacy of virotherapy. IL-1b induces robust and durable primary and secondary CD4+ T cell responses and IL-6 enhances cytotoxic T cell responses and therapeutic immunity by counteracting Tregs-mediated immunosuppression. Moreover, ∆PK inhibits expression of the negative T cell function regulator CTLA-4 that is constitutively expressed by melanoma cells in order to maintain immune tolerance. It also inhibits IL-18, a pro-inflammatory cytokine that is expressed by breast cancer cells and is involved in tumor cell migration and escape from immune surveillance (Fig. 1). Significantly, ∆PK was well tolerated in phase I clinical trials in which it was shown to inhibit immunosuppressive CD4+Th2 cells while inducing the overriding CD4+ Th1 cells. The clinical efficacy of ∆PK in other tumor types is currently under investigation.
Departments of Pharmacology and Microbiology and Immunology
University of Maryland, School of Medicine
Baltimore, Maryland, USA
The oncolytic virus ΔPK has multimodal anti-tumor activity.
Aurelian L, Bollino D, Colunga A
Pathog Dis. 2016 Jul