Cancer has always been one of the main threats to human health. To find a safe and reliable cancer treatment plan, scientists have been trying new therapeutic agents and methods for decades. The emergence of oncolytic virus (OV) provides a solution for cancer treatment. Most of these viruses have no or only slight toxicity to the human body, and they can target cancer cells through appropriate genetic modification. However, judging from the results of most preclinical experiments, OV therapeutics themselves have limited efficacy for most patients. Therefore, a thoughtful combination strategy based on an understanding of cancer biology is needed to obtain the maximum therapeutic benefit.
Fig.1 Cis versus trans combination. (Martin, 2018)
OVs can recognize and destroy cancer cells, but their mechanism of action is more complex. Current OVs in the preclinical and clinical evaluation include but are not limited to adenovirus (AdV), Coxsackie virus, herpes simplex virus (HSV), Maraba virus, Newcastle disease virus, parvovirus, reovirus, vaccinia virus (VACV) and vesicular stomatitis virus (VSV). The tumor-selective mechanism of these viruses is variable. They can achieve specific targeting through some characteristics of tumor cells that are different from normal cells, such as cancer-specific viral receptor expression, tumor cell hypermetabolism, and tumor-specific defects.
In theory, OVs are ultimately targeted cancer therapeutics because they can selectively expand themselves in the tumor environment, which can increase the therapeutic dose over time. However, when it is used as a pure oncolytic agent alone, there is a conflict between theory and clinical reality. If OVs function as a pure cell lysing agent, it is necessary to infect and kill most tumor cells, but one of the characteristics of tumor cells is their heterogeneity, and they are constructed from a mixture of normal and malignant cell types. It makes OVs difficult to infect and completely kill malignant cells that are widely spread in most patients. Fortunately, the therapeutic activity of OVs is generally not limited to its tumor oncolytic activity, but is multi-faceted, including the interaction of vascular and immune systems in the stromal cells of the tumor microenvironment and the patient's body. These interactions provide opportunities for combining orthogonal therapy to supplement OVs and improve the health status of cancer patients. In addition, many OV platforms under development can be engineered to express transgenic payloads, thereby greatly expanding their therapeutic potential.
In summary, OV therapy and the combination of OV and immunotherapy is a rapidly developing topic. The combination of OV and innovative immunomodulators (such as ICI, CAR-T cells and BiTE) promises to achieve our long-term goal of providing long-term treatment for cancer patients. But there are still some obvious obstacles and knowledge gaps that need to be overcome. For example, we need a more comprehensive understanding of the various mechanisms of OV and how they interact with the fine-tuning pathways of the immune system. At the molecular level, understanding the details of the interaction between the OV and the immune system is crucial for optimizing the combination strategy. An important example is understanding the molecular aspects of "epitope diffusion" in the context of OV therapy and how to maximize this phenomenon to enhance long-term immunotherapy attacks on tumors.
The most popular oncolytic virus combination therapy projects are as follows:
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