Harnessing oncolytic viruses for cancer immunotherapy to improve treatment outcomes

Frontiers JournalsAug 6 2024

Oncolytic virus (OV)-based immunotherapy has emerged as a promising strategy for cancer treatment, offering a unique potential to selectively target malignant cells while sparing normal tissues. However, the immunosuppressive nature of tumor microenvironment (TME) poses a substantial hurdle to the development of OVs as effective immunotherapeutic agents, as it restricts the activation and recruitment of immune cells.

This review elucidates the potential of OV-based immunotherapy in modulating the immune landscape within the TME to overcome immune resistance and enhance antitumor immune responses. The authors examine the role of OVs in targeting specific immune cell populations, including dendritic cells, T cells, natural killer cells, and macrophages, and their ability to alter the TME by inhibiting angiogenesis and reducing tumor fibrosis. Additionally, the authors explore strategies to optimize OV-based drug delivery and improve the efficiency of OV-mediated immunotherapy. In conclusion, this review offers a concise and comprehensive synopsis of the current status and future prospects of OV-based immunotherapy, underscoring its remarkable potential as an effective immunotherapeutic agent for cancer treatment.

Oncolytic virus (OV)-based immunotherapy leverages the natural or genetically modified abilities of viruses to selectively infect and destroy cancer cells while stimulating the immune system's response to malignancies. The US FDA's approval of T-VEC in 2015 and G47Δ in 2021 for melanoma and glioblastoma, respectively, underscores the therapeutic potential of OVs.

The mechanisms by which OVs exert their antitumor effects are multifaceted. They include direct oncolysis, induction of immunogenic cell death pathways such as apoptosis and necroptosis, activation of innate and adaptive immune responses, and modulation of the tumor microenvironment (TME). The TME, characterized by immunosuppressive elements and physical barriers, poses a significant challenge to effective cancer immunotherapy. However, OVs have shown the capacity to counteract the immunosuppressive TME by promoting the infiltration and activation of immune cells such as T cells and dendritic cells (DCs).

Innovative approaches in OV-based immunotherapy involve arming these viruses with immune-stimulatory genes, such as those encoding cytokines and chemokines, to enhance the recruitment and activation of immune cells within the TME. Additionally, OVs can be engineered to express immune checkpoint inhibitors and bispecific T cell engagers (BiTEs), further augmenting the immune response against cancer.

The success of OV therapy is contingent upon the ability to overcome various challenges, including improving viral infection and replication within tumor cells, modulating the suppressive TME, and addressing therapeutic resistance. Strategies to enhance these aspects include genetic engineering to improve viral tropism and the use of combination therapies with other immunotherapies or conventional treatments.

Clinical trials are actively exploring the combination of OVs with other therapeutic modalities, such as chemotherapy, radiotherapy, and immune checkpoint inhibitors, to maximize therapeutic efficacy. The results from these trials are promising, indicating an enhanced objective response rate when OVs are combined with immunotherapies like ipilimumab.

Despite the advancements, the full realization of OVs' potential in cancer therapy requires addressing several issues. These include enhancing the efficiency of viral entry and replication within tumor cells, overcoming the host's antiviral defenses, and developing strategies to modulate the TME to facilitate a more robust immune response.

In conclusion, OV-based immunotherapy represents a promising frontier in cancer treatment, with the capacity to reshape the immune landscape within the TME and enhance the overall effectiveness of cancer therapies. Continued research and development are essential to optimize the clinical utility of OVs and to overcome the existing challenges in this field.