Oncolytic virus (OV) therapy is an emerging novel oncology treatment that selectively replicates in and destroys tumor cells while leaving normal cells unharmed. Thus, in recent years, strategies have shifted toward the development of viral vectors to enhance the immune response within the tumor or to modulate tumor neovascularization, tumor metabolism, and other aspects of the tumor to counteract the malignant tumor microenvironment (TME).
Recently, a study titled "Inhibition of Tumor Metastasis by Liquid Nitrogen-Shocked Tumor Cells with Oncolytic Viruses Infection" was published in Advanced Materials by the lab of Professor Zhen Gu from the College of Pharmacy at Zhejiang University. The paper gives a thorough introduction to OV therapy, delving into the basics of how OV functions in the setting of complicated tumor microenvironments. The latest developments in genetic engineering methodologies for constructing multifunctional OVs are also discussed in depth by the researchers.
In contrast to conventional radiotherapy theories, OVs precisely lyse cancer cells by interacting with specific cellular receptors, exploiting tumor suppressor gene defects, downregulating antiviral pathways in tumor cells, or designing viral vectors with specific gene knockouts. Due to the characteristics of viral vectors and tumor cell types, most of them can trigger immunogenic cell death, release tumor-associated antigens, and trigger antitumor immune responses. However, it cannot be ignored that antiviral immunity can be triggered at the same time as infection initiation. Therefore, the selection and design of viral vectors are diverse and flexible, taking into account the balance between viral, TME, and host immunity. Regarding the activation of tumor immunity, OV seems to be superior to immune checkpoint inhibitors (ICIs) and other targeted drugs, as ICIs specifically target immune checkpoints, whereas small molecule drugs target only a certain molecule.
In the context of OVs, a broader range of antitumor immune activities will be evoked to combat the tumor, such as the release of tumor-associated antigens (TAAs) during tumor lysis, immune activation, increased immune cell recognition and killing capacity, and reversal of the immunosuppressive microenvironment. OVs can also help modulate TME abnormalities such as neovascularization, tumor metabolism, and the rigid extracellular matrix barrier brought about by tumor stromal cells, compared to other therapeutic approaches that have limited effect.
Numerous experiments and clinical trials have been carried out with naturally occurring OVs such as eutherovirus and blistering stomatitis virus by scientists so far. As most researchers have found, OV is well suited for combination strategies compared to single-modality therapies because of the complexity of the mechanisms involved in OV progression in the complex environment of tumors. The development of combinatorial approaches for implementing antitumor agents produces synergistic or additional antitumor benefits, for which clinical validation through well-designed and statistically sound clinical trials is required.
These adjuvant drugs are ideal for use in combination with OV since it is a highly adaptable treatment that introduces critical variables impacting tumor immunity directly into the TME. In fact, OV in combination has shown the best results in most preclinical investigations. Other therapies that work synergistically with OV include immune checkpoint inhibitors, ACT therapy, cytotoxic chemotherapy, or targeted agents.
Challenges
The most prevalent route of administration for OV is intra-tumor injection. But there are drawbacks to this method, such as
Intra-tumor drug delivery requires penetration, which can cause bleeding and local metastases if not done carefully.
Difficulty in puncturing deep tumor tissue due to technical limitations significantly limits the number of patients who can benefit.
The potential for eliminating circulating viruses through neutralizing antibodies, which calls for competent and experienced professionals to handle and administer the medicine.
Furthermore, the research and development of OV lyophilized formulations are challenging.
As with other forms of anticancer treatment, OV therapy faces the seemingly insurmountable challenge of tumor heterogeneity. Although combining BiTE or TriTE with OV in a novel way is appealing, it is possible that other combinations will prove more fruitful in the long run. But at the moment, single treatments are used in about two-thirds of clinical trials.
In order to get the best possible results, it is important to take into account not only the kind and stage of cancer, but also the mechanism of each therapy, and to choose agents that functionally compensate for each other. Researchers' hopes for the future of personalized and precision medicine rest on better knowledge of the anti-tumor mechanism of OV and the active development of related experiments.