As part of an article series on anti-cancer gene therapy, Ici Beyrouth addresses, in this third and final part, the topic of oncolytic virus-based immunotherapy as a promising therapeutic breakthrough. Jean-François Fonteneau, researcher in immunology at the Cancer Research and Integrated Immunology Center of Nantes-Angers elaborates on this topic.
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Nowadays, more so than ever, biotechnological revolutions in the field of immuno-oncology have paved the way for the emergence of new curative treatments against an array of hitherto incurable cancers. Oncolytic viruses are a new class of biological drugs that have now been added to the vast therapeutic arsenal against cancer. These viruses, whether natural or recombinant, selectively infect and kill tumor cells, while sparing normal ones.
This oncolytic viral therapy also stimulates the body’s immune defenses, creating as a result a more physiological anti-cancer immunity. This strategy is far from being in its early stages. While the first official clinical trial testing an oncolytic virus was reported in 1949, case reports have been suggesting, since the mid-19th century, that naturally occurring microbial infections in cancer patients can sometimes lead to a temporary regression of tumor load.
The developments of immunotherapy
The potential therapeutic role of microorganisms was established by William Coley -regarded today as the “father of immunotherapy”-, in the late 1890s. In fact, a review of hospital records led him to the case of a patient with spontaneous regression of facial sarcoma following a bacterial skin infection (known as erysipelas) caused by Streptococcus pyogenes. The American researcher and oncologist suspected that the infection was somehow responsible for this “miraculous” recovery. Determined to put his theory to the test, he infected one of his patients with inoperable sarcoma with a mixture of live and inactivated S. pyogenes.
A few months later, he found out that the tumor had indeed regressed, before completely disappearing. This strategy, therefore, established the beginnings of a new anti-cancer therapeutic approach: immunotherapy. Over the coming years, William Coley refined his concoction and administered it to hundreds of patients with various sarcomas and carcinomas.
From bacteria to viruses
Despite his moderately encouraging results, Coley was accused of charlatanism and his treatments were rejected by the American Cancer Society. Towards the end of the 20th century, a deeper understanding of the immune system was a game changer, giving Dr. Coley the recognition he deserved.
Later on, from 1949 onward, numerous clinical trials were undertaken in order, this time around, to test viral therapeutic vaccines. Thereby, live viruses (such as West Nile virus, adenovirus lysates, and the Urabe strain of the mumps virus) have been deliberately injected into cancer patients: promising results were reported, but potentially serious side effects were identified, especially in immunocompromised patients with leukemia or lymphoma.
Soon thereafter, alongside the rise of molecular biology, scientific research focused on genetically modified viruses, which are less pathogenic for humans, such as live attenuated vaccines. Over the past three decades, gene therapies based on oncolytic viruses have revolutionized the field of medical oncology.
Promising breakthrough
Antitumor viral therapy is based on the use of oncolytic viruses which will replicate only in tumor cells and kill them in an immunogenic way”, explains to Ici Beyrouth Jean-François Fonteneau, researcher at the Cancer and Integrated Immunology Research Center at Nantes-Angers. “This immunogenic death will thenceforth activate the patient’s immune system not only against the virus, but also against the tumor cells”, continues the French researcher. Therefore, this viral therapy is a form of immunotherapy, and it constitutes a promising breakthrough in oncology research.
On the other hand, in addition to killing tumor cells and activating the antitumor immune response, Jean-François Fonteneau discloses that oncolytic viruses can be modified by the addition of a gene that allows the production of a therapeutic protein in the tumor during virus replication.
“The first research in viral therapy was developed following the Second World War, after having discovered that rare cases of cancer patients were recovering after having caught a viral infection” he says. However, advances in molecular biology engineering had to take place (beginning of the 21st century) before the first generation of oncolytic viruses could be tested in clinical trials. “One of these viruses, T-vec, a herpes virus modified to target tumor cells, was approved in 2015, in Europe and the United States, for the treatment of metastatic melanoma”, indicates the immunologist who between 1999 and 2003, joined the laboratory of Professor Ralph Steinman, winner of the 2011 Nobel Prize for Medicine.
However, Jean-François Fonteneau points out that T-vec is seldom used because other immunotherapeutic drugs, known as immune checkpoint inhibitors (antibodies aimed at removing the inhibition of some of the patient’s immune defenses against tumor cells) proved to be more effective. “More recently, in June 2021, a modified herpes virus, G47delta, was temporarily approved in Japan for the treatment of glioblastoma (brain cancer)”, he adds.
New generations
Genetic manipulation of the viral genome has helped the development of new generations of oncolytic viruses. These molecular modifications have therefore allowed attenuating pathogenicity of the virus, improving target selectivity, reducing adverse effects, and even inserting exogenous therapeutic genes into the virus genome. In this respect, the immunology researcher notes that first-generation oncolytic viruses, which had reached advanced stages in clinical trials or had even been approved (such as T-vec), were often modified to produce GM-CSF, a protein that stimulates the immune system. “A whole new generation of oncolytic viruses producing more effective therapeutic proteins than GM-CSF is in preparation. This is one of the main challenges of this therapeutic approach”, reveals Jean-François Fonteneau. In fact, according to several scientific studies, the immune responses triggered by oncolytic viruses are not powerful enough, especially for weakly immunogenic or immunosuppressive solid tumors.
In a study published in October 2020, in the Journal for Immunotherapy of Cancer, Macedo et al. analyzed 97 clinical trials testing oncolytic viruses on 3,233 patients. According to the published results, the mean objective response (i.e., the percentage of patients with a partial or complete response to treatment within a certain period of time) in these studies was 9%. Considerable work is currently underway to optimize viral vectors through genetic engineering to improve immunogenicity (the ability to induce an immune response). “For example, the company Transgene is currently testing in France a modified vaccinia virus (virus linked to the one of smallpox) in patients suffering from colon cancer, during a phase I clinical trial, underlines Jean-François Fonteneau. They added a gene that allows the virus to produce an enzyme in the tumor that transforms a non-toxic pro-drug into an extremely toxic drug. This allows two things to happen: the effect of the drug is concentrated in the tumor, and there is fewer exposure of healthy tissue”. M. Fonteneau’s team is also studying, along with Frederic Tangy’s team from the Institut Pasteur, the vaccine strain of the measles virus, which has oncolytic activity against several types of cancer.
Overall, with the continuous advances in biotechnology, gene therapy based on oncolytic viruses is increasingly being developed in an attempt to treat various tumors. Finally, it is essential to mention that numerous cases of total remission have been reported in patients with lymphomas after having contracted Covid-19. According to various case reports, this finding could point towards a strong oncolytic effect of SARS-CoV-2.
