History of Oncolytic Viruses
The earliest oncolytic viruses (OVs) were actually viruses with oncolytic effects accidentally discovered by clinicians during clinical diagnosis and treatment. In 1904, The Lancet reported that a woman with chronic leukemia was unintentionally infected with the influenza virus, and her leukemia symptoms improved unexpectedly. This peculiar phenomenon made people start to realize that viruses and tumors, as two difficult-to-overcome diseases in medicine, may affect each other, and from then on, it created the precedent of virus treatment of tumors. In 1912, an Italian doctor discovered that a patient with cervical cancer had spontaneous tumor regression and shrinkage after being vaccinated with an attenuated rabies vaccine. From 1950 to 1980, people continued to try various wild-type viruses to eliminate tumors, but the treatment effect was not satisfactory, and even more serious immune reactions were produced.
Researchers have sought to enhance the oncolytic effects of a simple virus by exploring its combination with an immune checkpoint inhibitor. Recognizing that the virus infects tumor cells and produces immune checkpoint inhibitors during viral replication, the aim is to facilitate improved recognition of tumor cells by immune cells, ultimately leading to targeted tumor lysis. Advancements in genetic engineering technology have allowed researchers to move beyond the limitations of immune checkpoint inhibitors. They have even been able to incorporate chimeric-modified genes into the viral gene sequence and utilize reverse genetics technology to rescue new recombinant oncolytic virus strains. Through persistent experimentation, significant progress has been achieved in this area of research.
Immunological Mechanism of Oncolytic Virus Targeting and Killing Tumor Cells
Oncolytic viruses are promising immunotherapeutic drugs in current tumor treatment, and their antitumor activity is mediated through multiple mechanisms affecting the tumor immune cycle. The mechanism by which oncolytic viruses kill tumor cells has not been fully studied. The currently recognized mechanisms are:
1. Targeted tumor cell lysis: As a promising tumor gene therapy agent, oncolytic viruses possess a remarkable ability to replicate vigorously within tumor cells, causing their demise without a trace of replication in normal tissues - it's like a selective force of destruction. This phenomenon exposes tumor-associated antigens, which then provoke an immune response from our own body. The fact that oncolytic viruses can selectively replicate within tumor cells is of utmost importance for their noble application in tumor immunotherapy. However, it's not all black and white - some viruses have an innate inclination towards combating tumors, while others require genetic engineering to specifically target tumor cells. Once inside, the viruses cunningly exploit tumor cells' protein factories, rendering them incapable of producing enough proteins for growth. This devious interruption in normal physiological processes ultimately leads to the unraveling of tumor cells.
2. Anti-tumor immune response: Oncolytic viruses induce local and systemic specific anti-tumor immune responses. The induction of tumor-specific immune responses is a key factor for the eradication of tumors by oncolytic viruses. The therapeutic efficacy of oncolytic viruses depends on a combination of direct tumor cell lysis and indirect activation of anti-tumor immune responses. After infection with oncolytic viruses, tumor cells initiate an antiviral response composed of endoplasmic reticulum (ER) and genotoxic stress. This response leads to the upregulation of reactive oxygen species (ROS) and the production of antiviral cytokines. ROS and cytokines, especially type I interferon (IFN), are released from infected tumor cells and stimulate immune cells (antigen-presenting cells, CD8+ T cells, and natural killer (NK) cells). Oncolytic virus infection causes tumor cell death, leading to tumor lysis and subsequent release of tumor-associated antigens, progeny viruses, pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and tumor-associated antigens (TAAs), including neoantigens. These can promote adaptive immune responses by activating receptors such as Toll-like receptors (TLRs), stimulating the immune system.
A combination of an oncolytic virus with chemotherapy or immunotherapy drugs, or even multiple oncolytic virus drugs, may control tumor progression or cure tumors more effectively, and provide a potential clinical treatment option for cancer patients.
References
- Lawler S.E.; et al. Oncolytic viruses in cancer treatment: a review. JAMA Oncology. 2017, 3(6): 841-9.
- Kelly E.; Russell S.J. History of oncolytic viruses: genesis to genetic engineering. Molecular Therapy. 2007, 15(4): 651-9.
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