Armed oncolytic viruses: A kick-start for anti-tumor immunity

Abstract

Oncolytic viruses (OVs), viruses that specifically result in killing tumor cells, represent a promising class of cancer therapy. Recently, the focus in the OV therapy field has shifted from their direct oncolytic effect to their immune stimulatory effect. OV therapy can function as a "kick start" for the antitumor immune response by releasing tumor associated antigens and release of inflammatory signals. Combining OVs with immune modulators could enhance the efficacy of both immune and OV therapies. Additionally, genetic engineering of OVs allows local expression of immune therapeutics, thereby reducing related toxicities. Different options to modify the tumor microenvironment in combination with OV therapy have been explored. The possibilities and obstacles of these combinations will be discussed in this review.

Keywords: Immune therapy; Oncolytic viruses; Transgenes.

Graphical abstract

Fig. 1

The immunosuppressive tumor micro environment. (A) Tumor cells (orange) and stromal cells (pink) secrete immune suppressive molecules, which inhibit the maturation of APCs. Maturated APCs migrate to the lymph node to activate the adaptive immune system. (B) As a result, activated T cells migrate to the tumor driven by a chemokine gradient. However, the secretion of chemokines is lowered in the tumor resulting in reduced T cell infiltration. (C) T cells that enter the TME to target the tumor cells are inhibited by immune suppressive receptors expressed by the tumor, stromal cell, but also immune suppressed APCs. (D) Tregs and MDSCs are recruited to the TME, which secrete more immune suppressive molecules and inhibit the T cell response even further.

Fig. 2

Combining oncolytic viral therapy with immune modulators. (A) Weak immunogenic tumor cells in an immunosuppressive TME are infected by oncolytic viruses (green) armed with immune modulators. (B) Tumor cells start secreting viral induced cytokines and chemokines, but also the immune modulators, which improves the immune activation. As a result, immune cells start to infiltrate the TME. (C) Occasionally, the virus will induce an immunogenic cell death. The TAAs and immune stimulating environment will result in the maturation of APCs. (D) The APCs will activate the adaptive immune system upon which T cells will start infiltrating the tumor attracted by the secreted chemokines. Possible activity of immune suppressive ligands, such as PD-L1, will be prevented by the circulating immune checkpoint inhibitors resulting in clearance of the tumor.