As the two-year anniversary of the Covid-19 pandemic nears and viral variants capture daily news headlines, we all deeply understand the devastation viruses can cause. They invade our bodies and communities and can turn our world upside down. Yet with “virus” and “vaccine” now a part of our everyday lives and lexicon, we should not overlook the inverse potential of viruses and their power to treat our most challenging diseases.
While counterintuitive in concept, the approach is not new. Spurred by repeated observations of tumor regressions following natural virus infection over the past century, researchers have made progress toward harnessing the natural or engineered ability of viruses to infect, replicate in, and destroy tumor cells without damaging healthy cells—for example, using herpes to treat melanoma, among others. Originally, we believed this direct cancer-killing effect was the major mechanism of action and, accordingly, these viruses were called “oncolytic,” essentially acting as self-amplifying cytotoxic agents. Today, we know this is only one aspect of the strength these viruses hold.
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Johanna Kaufmann Johanna K. Kaufmann, PhD, Executive Vice President of Oncology at Codagenix, leads the company’s efforts in developing virotherapeutic candidates for breast cancer and other solid tumors. Codagenix is a clinical-stage biotechnology company committed to building the world's most agile, adaptable, and powerful vaccine platform to discover and develop prophylactic viral vaccines and immunotherapies […]
Creating cancer-fighting viruses
Cancer cells have evolved survival mechanisms to fly under the radar of the immune system, with relatively small immunogenic differences compared to healthy cells. Oncolytic viruses, however, have the power to make the tumor more visible to the immune system and mark the area of attack. It is this anti-tumor immune activation that has the potential to induce long-term responses in patients. Immunotherapy has revolutionized cancer care over the past two decades, and viruses are well suited to further increase its impact. Thus, oncolytic viruses are among the most exciting emerging therapeutic modalities. With their favorable safety profile, evidence for clinical efficacy, and low cost of production, they hold promise to improve patient care with broad accessibility.
The typical process to design a virotherapy for cancer treatment requires selection of a virus species that is harmless to humans or, more frequently, engineering of pathogenic viruses to make them safe for use by ensuring they selectively infect cancer cells, but not healthy cells. This process often reduces the immune-stimulatory potency of the virus, which is, in turn, compensated for by transgene expression. In addition, cancer is not a one-size-fits-all disease, challenging drug developers to find the most effective virus for a specific tumor type and making oncolytic virus discovery a time- and resource-intensive endeavor.
Fortunately, emergent platform technologies enable us to select, rationally design, and optimize existing viruses that specifically target a tumor of interest, sometimes even avoiding the necessity for transgene expression. These innovative approaches help expedite the discovery of novel virotherapeutics for cancer types of high unmet need.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
Combating breast cancer with the flu
One such disease is breast cancer—the second leading cause of death in women. In 2020 alone, more than 2 million patients worldwide were diagnosed with the disease. It is also among the most difficult cancers to treat with immunotherapy, largely due to heterogeneity across breast cancer subtypes and low visibility to the immune system. As we innovate to improve outcomes for these patients, influenza virus may provide some answers. In fact, the same traits that make having the flu so undesirable—its potent ability to infect and stimulate robust immune responses—position it as an ideal virotherapeutic candidate to treat cancer. Influenza viral particles include molecules that recognize a specific glycosylation pattern that is upregulated on the surface of breast cancer cells, enabling preferential targeting to prime cancer-fighting immune responses. And if a patient has had the flu or received flu shots in the past, their pre-existing immunity may give them a head start in fighting disease, as immune memory cells can quickly recognize the virus and allow for improved cross-priming of an anti-tumor response.
But how can we give patients the flu without giving patients the flu? The answer lies in viral attenuation.
Exploiting the genetic code to develop better treatments
One avenue for unlocking the enormous potential of viruses as cancer-fighting agents is codon deoptimization. This AI-assisted approach systematically exchanges hundreds of codons in the viral genome with those less frequently used in human cells. This slows viral translation and renders the virus unable to efficiently replicate in healthy cells, while retaining all outward immune-stimulatory characteristics of the original virus. In the case of cancer-targeting viruses, attenuation through deoptimization offers enhanced safety, as the recoded virus can still selectively replicate in tumor cells that have shut off their innate immune response and other mechanisms cells use to abort viral infection.
Importantly, the codon modifications yield a genetically stable phenotype that is incapable of reversion to a more infectious form and is compatible with efficient, large-scale manufacturing in selected cell lines. By leveraging this method and combining it with other emerging or established technologies, we can expand virotherapy access to more patients and boost the effectiveness of other treatment modalities as part of rationally designed combination regimens.
This technology not only leads to an influenza-based therapy for breast cancer but is applicable to other virus-tumor pairs, bringing us one step closer to maximizing the transformational potential of cancer immunotherapy.
As the height of flu season looms while we continue to battle Covid-19, let this be an encouraging reminder of the good that can come from the viruses we so often fear.
Photo: Main_sail, Getty Images
Johanna K. Kaufmann, PhD, Executive Vice President of Oncology at Codagenix, leads the company’s efforts in developing virotherapeutic candidates for breast cancer and other solid tumors. Codagenix is a clinical-stage biotechnology company committed to building the world's most agile, adaptable, and powerful vaccine platform to discover and develop prophylactic viral vaccines and immunotherapies for cancer.
