Oncolytic Virus Combination Therapies-with Immune Checkpoint Blockade
With the deepening of research on the immune system, the development of multiple immune checkpoint inhibitors has provided new ideas for cancer treatment. In recent years, oncolytic virus (OV) has become another advantageous medical tool for cancer cells. Currently, popular OV vector platforms include adenovirus, reovirus, vaccinia virus, herpes virus and coxsackievirus. These viruses not only lyse cells to kill cancer, but also cause huge changes in the tumor immune microenvironment. Preclinical and clinical data indicate that oncolytic carriers can induce anti-tumor immunity and significantly increase the infiltration of immune cells into the local tumor microenvironment. These changes can lay the foundation for the subsequent release of checkpoint inhibitors, because they are most effective in environments with large lymphocyte infiltration. Obviously, OV and checkpoint inhibitors will continue to develop as a combination therapy for multiple cancers in the future.
Fig.1 Combining oncolytic vectors and checkpoint inhibitors. (Larocca, 2018)
Immune Checkpoint Inhibitors for Cancer Treatment
The emergence of immunotherapy is a huge advancement in the field of cancer treatment. Some immunotherapies have shown significant therapeutic effects on melanoma, lung cancer, and multiple intra-abdominal malignancies. In particular, a class of drugs called checkpoint inhibitors has attracted great interest from researchers and clinicians. These antibodies block negative regulators of T cell function (immune checkpoints), thereby increasing T cell activation. For example, ipilimumab is a monoclonal antibody that inhibits cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and is currently approved for the treatment of melanoma. In addition, the principle of combining therapeutic agents with complementary mechanisms has also been applied to checkpoint suppression of a series of malignant tumors including gastrointestinal and soft tissue cancers. The combined treatment of ipilimumab and nivolumab in patients with advanced melanoma can significantly improve the overall survival rate (58% vs 34%) compared with ipilimumab alone.
Combination of Immune Checkpoint Inhibitors and OVs
When there is a large amount of lymphocyte infiltration, the therapeutic effect of checkpoint suppression is most effective, and this is not always the case for a given tumor. Genetically engineered oncolytic viruses can generally target specific tumor cells more accurately, while minimizing damage to surrounding normal tissues. This advantage makes it easy to combine with other anti-cancer drugs. Besides, the characteristics of OV to change the tumor microenvironment are exactly what is needed for checkpoint suppression therapy. Multiple studies have shown that local oncolytic virus injections can regulate tumor-specific CD8+ T cell responses, making distant tumors more and more susceptible to immune checkpoint inhibitor treatment. Several ongoing clinical trials are using these two types of cancer therapeutics combined treatment regimens, and their efficacy has been proven in preclinical data.
Reference
- Larocca, C. J.; Warner, S. G. Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials. Clinical and translational medicine. 2018, 7.1: 35.