FIGURE 4.

Combining Oncolytic Virus (OV) therapy with other immunotherapy strategies. Since OV acts at the first step of the cancer-immunity cycle, releasing DAMPs, PAMPs and TAAs, its association with additional interventions aiming to establish an antitumor response is favored. The induction of ICD leads to recruitment and activation of antigen-presenting cells (APCs), which can increase the efficiency of vaccine-based approaches (especially peptide vaccines) and generate a stronger T cell response. Immune Checkpoint Inhibitors (ICIs) can increase activation of T cells during priming (here represented by anti-CTLA-4 mAb) and also increase T-cell effector activity in the tumor (i.e., anti-PD-(L)1 mAbs) following OV-induced immune cell infiltration. Agonist monoclonal antibodies (mAbs) are also an interesting intervention to increase T cell activation against TAAs (released after oncolytic therapy) by recognizing and activating costimulatory T cell receptors (i.e., 4-1 BB). Targeted therapy can also potentiate the immune responses to target tumor cells by increasing the effector activity of the innate immune system, including NK cell-mediated ADCC, macrophage-mediated ADCP and complement-mediated CDC. It is important to note that the cytotoxic activity of innate immune cells increases antigen release and, consequently, T cell recruitment. Virotherapy can also increase efficiency of Adoptive Cell Therapy (ACT), here represented by CAR T cells, by promoting a pro-inflammatory microenvironment, enabling T cells enhanced functions and leading to a higher recognition and elimination of tumor cells even in solid tumors. Therapy using bi-specific antibodies, such as BiTEs, can also be enhanced by oncolytic therapy as OVs precondition tumors in terms of T cell recruitment and activation. Finally, cytokines can act at many key steps of the process, such as antigen presentation and T cell priming, activation and recruitment. Furthermore, these factors have an important role at maintaining a favorable microenvironment for the survival of activated immune cells and the sustainment of the immune response. ICD, Immunogenic Cell Death; TAA, Tumor-Associated Antigen; DAMPs, Damage-Associated Molecular Pattern; PAMPs, Pathogen-Associated Molecular Pattern; NK, Natural killer; CTLA-4, Cytotoxic T-Lymphocyte-Associated protein 4; PD-1, Programmed cell Death protein 1; PD-L1, Programmed cell Death Ligand 1; CAR, Chimeric Antigen Receptor; BiTEs, Bi-specific T-cell Engagers; ADCC, Antibody-Dependent Cell-mediated Cytotoxicity; ADCP, Antibody-Dependent Cellular Phagocytosis; CDC, Complement-Dependent Cytotoxicity. Created with BioRender.com.