Oncolytic virotherapy: basic principles, recent advances and future directions

Abstract

Oncolytic viruses (OVs) have attracted growing awareness in the twenty-first century, as they are generally considered to have direct oncolysis and cancer immune effects. With the progress in genetic engineering technology, OVs have been adopted as versatile platforms for developing novel antitumor strategies, used alone or in combination with other therapies. Recent studies have yielded eye-catching results that delineate the promising clinical outcomes that OVs would bring about in the future. In this review, we summarized the basic principles of OVs in terms of their classifications, as well as the recent advances in OV-modification strategies based on their characteristics, biofunctions, and cancer hallmarks. Candidate OVs are expected to be designed as "qualified soldiers" first by improving target fidelity and safety, and then equipped with "cold weapons" for a proper cytocidal effect, "hot weapons" capable of activating cancer immunotherapy, or "auxiliary weapons" by harnessing tactics such as anti-angiogenesis, reversed metabolic reprogramming and decomposing extracellular matrix around tumors. Combinations with other cancer therapeutic agents have also been elaborated to show encouraging antitumor effects. Robust results from clinical trials using OV as a treatment congruously suggested its significance in future application directions and challenges in developing OVs as novel weapons for tactical decisions in cancer treatment.

Fig. 1

Stronger oncolytic immunogenicity of engineered OVs. ① When OVs cleave tumor cells, the viral progeny, TSAs, PAMPs, as well as DAMPs are released simultaneously, triggering ICD. ② Meanwhile, innate immunity is initiated, as DCs and NK cells collaborate for tumor clearance. ③ TSAs ingested by APCs soon migrate into lymph nodes, where T cells are activated, which infiltrate primary and metastatic foci to perform adaptive immunity. ④ In addition, engineered OVs are strengthened with the ability to break through ECM barriers, yielding inflammatory factors and chemokines, even reversing the immunosuppressive characteristic of TME. ⑤ In a collaborative effort, the engineered OVs may transform the immunologically “cold” tumor into “hot” tumor, also exerting an upgraded and more powerful antitumor immunity. Created with BioRender.com

Fig. 2

a Schematic diagram showing the mechanism of EphA2-TEA-VV EphA2-TEA-VV has been designed to express BiTE that targets EphA2 expressed on lung cancer cells and CD3 on T cells to stimulate T cells directly without antigen presentation by APCs. b CD19t for improving target identification and tumor control of CD19 CAR-T oVV was designed to express CD19 on the surface of infected tumor cells before oncolysis, which helps CD19 CAR T cells to probe and attack those CD19-marked tumor cells that could not be recognized and targeted essentially. Created with BioRender.com

Fig. 3

Three OV-engineered examples of ICIs expressing for reversing immunosuppression ICI-armed OVs infect tumor cells, subsequently releasing ICIs into TME to take effect. ① VG161 expresses PD-L1 blockade. ② CF-33-hNIS-antiPDL1 produces bioactive anti-PD-L1 antibody. ③ ONCR-177 secretes both anti-PD-1 VHH-Fc and anti-CTLA-4 mAbs. These strategies are used to block immune checkpoints and cooperate with OVs to enhance antitumor immunity. Created with BioRender.com

Fig. 4

a OV-modification strategies against antiviral immune responses. ① Expression of TAP-1 inhibitor to limit antiviral CTLs for BV49.5. ② Expression of CDH1 to protect against NK cytotoxicity during the early stage of OV treatment. ③ Modification on enveloped membrane sites of VV (A27L, H3L, L1R and D8L) to restrict NAbs. b The possible mechanism of antitumor immunity benefiting from antiviral immune responses induced by OVs OV-induced antiviral immunological events may create an inflammatory TME. Besides that, IFN-γ produced by antiviral CD4⁺ T cells approves some DCs to cross-present specific epitopes to CTLs, resulting in ICD and more elicited TSAs that can reinforce antitumor immune responses. Created with BioRender.com

Fig. 5

Different strategies of OV engineering for anti-angiogenesis and the possible induced phenotype of TME. ① Some OVs have been modified to attack tumor-associated endothelial cells, while the immunosuppressive TME provide a perfect niche for “cold” tumor development. ② Normalizing the tumor vasculature may promote immune cell infiltration and OV diffusion, giving rise to “hot” tumors. Created with BioRender.com

Fig. 6

a The TOP 20 distribution of transgenes in clinical trials until 2022 b The TOP 20 distribution of indications in clinical trials until 2022