Engineering strategies to enhance oncolytic viruses in cancer immunotherapy

Abstract

Oncolytic viruses (OVs) are emerging as potentially useful platforms in treatment methods for patients with tumors. They preferentially target and kill tumor cells, leaving healthy cells unharmed. In addition to direct oncolysis, the essential and attractive aspect of oncolytic virotherapy is based on the intrinsic induction of both innate and adaptive immune responses. To further augment this efficacious response, OVs have been genetically engineered to express immune regulators that enhance or restore antitumor immunity. Recently, combinations of OVs with other immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptors (CARs), antigen-specific T-cell receptors (TCRs) and autologous tumor-infiltrating lymphocytes (TILs), have led to promising progress in cancer treatment. This review summarizes the intrinsic mechanisms of OVs, describes the optimization strategies for using armed OVs to enhance the effects of antitumor immunity and highlights rational combinations of OVs with other immunotherapies in recent preclinical and clinical studies.

Fig. 1

A timeline of important milestones in the development of oncolytic virus as a cancer therapy

Fig. 2

Mechanisms of oncolytic virus (OV) action. a Direct oncolysis: new viral particles are released from OV-lysed tumor cells to infect unaffected tumor cells. Moreover, exosomes derived from OV-infected tumors contain OVs and can exhibit high tumor tropism. b Antitumor immunity: immunogenic cell death (ICD) induced by OV exposure leads to the release of multiple molecules, including pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), tumor-associated antigens (TAAs) and tumor-associated neoantigens (TANs). The identification of PAMPs/DAMPs through pattern recognition receptors (PRRs) in cancer or immune cells triggers the expression of proinflammatory cytokines such as type I interferons (IFNs), interleukin (IL)-1β, IL-6, IL-12, TNF-α, granulocyte macrophage colony-stimulating factor (GM-CSF), and chemokines such as CCL2, CCL3, CCL5 and CXCL10. Chemokines recruit neutrophils and macrophages to infection sites, and these cytokines stimulate the activity of innate immune cells such as NK cells and DCs, which further stimulate the production of IFNs, TNF-α, IL-12, IL-6, and chemokines, resulting in the amplification of the initial innate response and turning immunologically “cold” tumors into “hot” tumors. Type I IFNs increased the levels of MHC class I and II molecules and costimulatory molecules such as CD40, CD80, and CD86 on the surface of DCs. The released TAAs and TANs are processed and ultimately presented on the APC surface in complex with MHC molecules. Multiple cytokines and chemokines contribute to the recruitment and activation of antitumor CD8⁺ T cells and B cells

Fig. 3

Armed oncolytic virus (OV) enhances antitumor activity. a There are numerous means to prove the lytic activity of OVs, some of which might be more immunogenic and prime antiviral adaptive immune responses. b The administration of OV-expressing chemokines promotes the secretion of chemokines into the tumor microenvironment (TME), which increases T-cell trafficking to tumors. The secretion of cytokines induced by OVs maintains T-cell survival and expansion. c Armed OVs can provide local antigen targets for chimeric antigen receptor T-cell therapy (CAR T) cells or human leukocyte antigen (HLA)/costimulation molecules directed to T-cell receptor (TCR)-T cells. Furthermore, OVs expressing bispecific T-cell engagers (BiTEs) are capable of overcoming antigen heterogeneity and inducing tumor cell death. d Immune checkpoint inhibitors (ICIs) or mini bodies and immunosuppressive ligands locally delivered by armed OVs reverse T-cell exhaustion