The Viral Frontier

During the late 19th century, cancer patients were observed to go into remission after being accidentally exposed to viral infections. Although the underlying reasons for this occurrence were unclear at the time, these early observations heralded the concept of cancer treatment through different viral strains.

The eventual shift to virus-based cancer strategies became apparent in the early 20th century, when patients grappling with leukemia experienced remission following viral infections. The medical community took note of these cases, leading to the proposition of harnessing viruses for cancer treatment. By the mid-20th century, reports emerged detailing the use of oncolytic viruses, notably adenovirus, to combat cancer progression. In 1956, 30 women with advanced cervical carcinoma were intentionally infected with adenovirus. Of this cohort, around 70 percent exhibited tumor necrosis, demonstrating not only negligible side effects but also target-specific efficacy.

Delving into viruses
 

Since then, the scientific community has learned significantly more about viruses and cancer. Viruses threaten cancer cells in two ways; firstly by enhancing the immune response against it, and secondly by directly targeting the cancer cell. The reason for the progression of most cancers is that they go undetected by our immune system. Viruses help the tumor microenvironment to shift from the cold phase (absence of immune-related defense mechanisms) of advanced progressive cancers to the hot phase (activation of immunological mechanisms). 

Oncolytic viruses initiate infection in tumor cells by binding to their cell surface receptors, such as CXADR, CD46, and desmoglein-2 via a fiber knob. Subsequently, the virus is internalized through interaction between the penton proteins of the virus and integrins on the tumor cell (1). Once integrated into the host genome, the viral genome triggers the transcription of viral proteins, leading to the generation of numerous viral progeny. These progeny continue to infect tumor cells by disrupting their cell membrane, creating a cyclical process.

Viral replication and infection activates the immune system at the tumor site. This involves increased copies of viral genomes eliciting a response from the immune system through pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Consequently, natural killer cells and adaptive immune cells, such as helper and cytotoxic T cells, are activated (2). The immune activation then alleviates immune suppression in the tumor microenvironment, showcasing polyfunctional antiviral responses that extend beyond viruses to include the identification and targeting of tumor cells.

The release of PAMPs and DAMPs activates on-site dendritic cells (DCs), upregulating genetic markers like CD86 and CD83, dendritic cell maturation. Mature DCs process and present virus- and tumor-associated antigens to circulating T cells, attracting them to the tumor site. T-cell activation enables B cells to release antibodies that attach to the surface of tumor cells, rendering them susceptible to phagocytosis or antibody-dependent cellular cytotoxicity (ADCC) by macrophages and NK cells.

These immune cells release factors such as IFN γ, perforins, and granzymes, which contribute to the elimination of both infected and non-infected tumor cells. The persistent oncolytic viral infection also enhances the expression of class I human leukocyte antigen in tumor cells, heightening their vulnerability to CD8+ T cells (3). 

The modification solution
 

To ensure safety, enhance tumor specificity, and minimize potential adverse effects related to viruses, modifications have been made to these viruses to ensure transcriptional control of selective viral proteins. For instance, the selective deletion of the E1A gene results in the production of an abnormal E1A protein, which hinders healthy virus-infected cells from entering the S phase, effectively blocking viral replication in normal body tissues. Further modifications have been implemented by introducing therapeutic genes, such as thymidine kinase and cytosine deaminase, into viral genomes. When modified viral-infected tumor cells are coupled with the administration of drugs like 5-fluorocytosine and ganciclovir, it enables tumor cells to generate cytotoxic compounds, essentially becoming the cause of their own demise (4).

Another significant alteration involves the insertion of the transgene granulocyte-macrophage colony-stimulating factor into the viral genome. This modification leads to the efficient and active recruitment, as well as on-site maturation, of DCs and T cells within the tumor microenvironment. This process is associated with the release of tumor-associated antigens after oncolysis, contributing to a more robust and targeted immune response against the tumor.

Though data suggests promising results in the treatment of advanced-stage cancers by using oncolytic viral therapy, there still is a need to design strategies with increased tumor-control effects and reduced possible adverse outcomes. The overall efficiency of the use of viruses for cancer immunotherapy also needs to be elucidated through advanced clinical trials. 

With the continuous effort of scientists and the medical community, I expect that oncolytic viral therapy will become part of future multi-therapeutic approaches for cancer treatment.