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Dr. Corinna Fiorotti
Posted by Dr. Corinna Fiorotti Cell Therapy, Gene Therapy, Viruses

Pushing the ‘Viral Envelope’: The Power of Oncolytic Viruses as Immunotherapy

Pushing the ‘Viral Envelope’: The Power of Oncolytic Viruses as Immunotherapy

The notion that viruses can fight cancer dates back as early as the 1900s, when doctors observed that cancer patients would sometimes experience rapid remission, at least temporarily, following a viral infection. The development of cancer-killing oncolytic viruses (OVs) as a form of immunotherapy began in earnest in the 1980s, and to date there have been three OV therapies approved and registered for cancer therapy. The first OV approval by a national regulatory agency came in 2004 with Rigvir®, a genetically unmodified ECHO-7 strain enterovirus approved in Lativa for the treatment of skin melanoma. In 2005, a genetically modified oncolytic adenovirus, H101, was approved in China for the treatment of head and neck cancer. In 2015, talimogene laherparepvec (OncoVex, T-VEC), an oncolytic herpes simplex virus type 1 (HSV-1) modified to express GM-CSF and used for the treatment of advanced inoperable melanoma, became the first OV approved in the US and Europe and subsequently brought the promise of OV therapies back into the spotlight.

An OV is defined as a virus that selectively infects and lyses cancer cells while not affecting healthy cells of the organism. Two groups of viruses are mainly being investigated for use in virotherapy. First, unmodified viruses that have natural selectivity to tumor cells and are non-pathogenic in humans. Secondly, genetically modified viruses with those genes that are needed for replication in normal tissue modified or deleted, but with retained ability to replicate in cancer cells (i.e., adenovirus, herpes simplex virus, vesicular stomatitis virus).

Today, further advances in genetic editing technology like CRISPR-Cas9 have provided more capability to genetically modify OVs for specific cancer cell targeting, pushing the ‘viral envelope’ in their therapeutic capabilities to address critical oncological conditions.

‘Bursting’ with Benefits

Oncolytic viruses have many appealing properties for cancer immunotherapy. OV selectively replicate in and kill cancer cells, subsequently spreading within a tumor without harming normal tissue. Cancer cells often have impaired anti-viral defenses and oncolytic virus therapies aim to exploit this weakness. OVs mediate their antitumor effect through a dual mechanism of action by having a direct lytic effect on tumor cells and also by stimulating host anti-tumor adaptive immune responses. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumor. This not only kills the cell itself but also causes it to release immune-stimulating tumor antigens that can elicit local immune responses (which can eliminate any remaining uninfected tumor cells nearby) and systemic immune responses (which can eliminate any remaining tumor cells throughout the patient’s body).

Engineering Added Potency

CRISPR-Cas9 is making it fast and feasible to delete key portions of the viral genome required for an oncolytic virus to replicate in healthy cells, meaning that even potentially pathogenic viruses can now be manipulated for use as safe therapies. Through viral gene editing it is also possible to incorporate tumor-specific promoter elements for improved selectivity in delivery of therapeutic payloads to cancer cells. For instance, in OVs that use the oncolytic herpes simplex virus and oncolytic vaccinia virus as vectors, researchers have found that the deletion of thymidine kinase (TK) via CRISPR technology increases the virus’ ability to target cancer cells among healthy ones. In addition, scientists have found that arming these types of OVs with therapeutic cytokines, such as granulocyte/macrophage-colony stimulating factor (GM-CSF), enhance anti-tumor immune responses.

Another promising path being explored is using immune checkpoint inhibitors (ICIs) in combination with oncolytic virus therapies. Some tumors can manipulate immune checkpoint pathways to inhibit immune activation, making them resistant to the body’s native immune system. ICIs aim to disengage these “brakes” thereby exposing the tumor’s T lymphocytes to attack. OVs can alert the immune system to previously undetected cancer cells, jump-starting a response by transforming a “cold” tumor microenvironment with low circulating immune effector cells into a “hot” environment with increased immune cell and cytokine infiltration. This augments the efficacy of ICIs, which work best in “hot” environments, by sensitizing the tumor to subsequent treatment with checkpoint inhibitor therapy.

OVs can be also further modified to selectively deliver therapeutic transgenes to the tumor microenvironment to enhance their anti-tumor potency or boost an anti-tumor immune response. OVs also have the potential to synergize with chimeric antigen receptor (CAR) T cells by helping them simultaneously overcome some of the multiple barriers found in solid tumors. All these characteristics make OVs excellent potential partners to synergize with current and emerging immunotherapies.

Powerful Promise Demands Deep Bioanalysis

As oncolytic therapies continue to become more targeted and potent, the complex interactions between the tumor, its microenvironment, the virus, and the host immune response must be carefully evaluated and monitored. From determining optimal virus structure to assessing potential side effects – particularly unwanted immune responses against the large number of viral non-self-peptides and the immune responses that may occur from stimulating the immune system to action – sponsors need a partner fully versed in the contemporary methods, regulations, and platforms involved in the bioanalysis of this complex modality for cancer treatment.

How the Scientists at BioAgilytix Can Help

BioAgilytix is equipped with the deep expertise and premier platform suite needed to deliver robust, reliable results for a wide range of oncolytic virotherapy assessments including assays for PK/PD, biodistribution, immunogenicity, viral shedding, and CMC testing. If you have a development program involving an oncolytic virus alone or in a combination therapy, I invite you to reach out to our scientific team to discuss how we can help.

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