Oncolytic virotherapy: new weapon for breast cancer treatment

Abstract

The recent introduction of viruses as a weapon against cancer can be regarded as one of the most intriguing approaches in the context of precision medicine. The role of immune checkpoint inhibitors has been extensively studied in early and advanced cancer stages, with extraordinary results. Although there is a good tolerability profile, especially when compared with conventional chemotherapy, severe immune-related adverse events have emerged as a potential limitation. Moreover, there are still treatment-resistant cases and thus further treatment options need to be implemented. Several in vitro and in vivo studies have been conducted and are ongoing to develop oncolytic viruses (OVs) as a tool to modulate the immune system response. OVs are attenuated viruses that can kill cancer cells after having infected them, producing microenvironment remodelling and antitumour immune response. The potential of oncolytic virotherapy is to contrast the absence of T cell infiltrates, converting 'cold' tumours into 'hot' ones, thus improving the performance of the immune system. Breast cancer, the second most common cause of cancer-related deaths among women, is considered a 'cold' tumour. In this context, oncolytic virotherapy might well be considered as a promising strategy. This review summarises the current status, clinical applications and future development of OVs, focusing on breast cancer treatment.

Keywords: BC; OVs; immunotherapy.

Figure 1.. Immunoediting. The three phases of the cancer immunoediting process: elimination, equilibrium and escape. In tumour elimination (left), which often occurs in early tumour development, highly antigenic tumour clones are recognised and eliminated by both innate and adaptive immune systems. In the equilibrium phase (middle), the tumour and the adaptive immune system coexist. Tumour escape (right) occurs when there is poor antigenic expression, immunosuppressive cytokines, MDSCs, and expression of negative regulatory receptors. Various forms of immunotherapy aim to shift the balance from escape and equilibrium to elimination. Treg: T regulatory; MDSCs: Myeloid Derived Suppressor Cells; MCH I: Major Histocompatibility Complex Class I. The figure was modified from Servier Medical Art, http://smart.servier.com/.

Figure 2.. Oncolytic viruses make tumours ‘hot’. ‘Cold’ tumours poorly infiltrated by immune cells and have low expression of PD-L1 on cancer cells surface, and for this reason, the response to ICI therapy is inefficient (left panel). Oncolytic virotherapy promotes strong antiviral immune response accompanied by the production of cytokines, such as IFN type I that stimulates PD-L1 expression on the surface of cancer cells, and chemokines, like CCL3 and CCL4, attract immune cells expressing PD-1 or CTLA-4. These events make tumour ‘hot’, and when ICIs are administered subsequently, they can bind to their respective targets on either cancer or immune cells (right panel). NK: Natural killer; PD-1: Programmed death-1; PD-L1: Programmed death ligand-1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; IFN I: Interferon type I; CCL3/4: Chemokine (C-C motif) ligand 3 or 4. The figure was modified from Servier Medical Art, http://smart.servier.com/.

Figure 3:. Mechanism of oncolytic virus immunotherapy. Oncolytic viruses infect cancer cells and induce the immunogenic cell death and release of infectious viral progeny that infect nearby cancer cells. Tumour-associated antigens and cellular DAMPs, such as CRT, HMGB1 and cellular ATP, stimulate the host antitumour immune responses. Cellular detection of viral infection and the products of oncolysis trigger the rapid activation of host antiviral responses and influx of immune cells that mediate the destruction of residual infected and uninfected tumour cells. The direct recognition and killing of tumour cells is primarily mediated by natural killer cells of the innate immune system and tumour antigen-specific CD8+ cytotoxic and CD4+ helper T lymphocytes of the adaptive immune system. The effects of OVs reflect on MDSCs, TAMs and Treg cells inhibition and modify the suppressive microenvironment altering the cytokine milieu (red lines) OVs: oncolytic viruses; ATP: adenosine triphosphate; HMGB1: high mobility Group Box 1; CRT: calreticulin; DAMPs: damage-associated molecular pathways; CD: cluster differentiation; TLR4: Toll-like receptor 4; P2RX7: Purin 2 Receptor X7; DC: dendritic cell; MCH I: major histocompatibility complex Class I; Treg: T regulatory; TAMs: tumour-associated microenvironment; MDSCs: myeloid-derived suppressor cells. The figure was modified from Servier Medical Art, http://smart.servier.com/.