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The virus in question has been genetically modified to selectively infect cancer cells and eliminate them. It does not attack healthy cells. This treatment, called CF33-hNIS (or Vaxinia), has already shown its full potential in animal models of colon cancer, and preclinical models of lung, breast, ovarian and pancreatic cancer. It will soon be tested on a hundred adult volunteers with metastatic or advanced solid tumours. A first American patient has already received a dose of this treatment.
Viruses that kill cancer cells, known as oncolytic viruses, have been known for decades. In recent years, they appear to be a very promising way to treat cancers that are inoperable and resistant to other therapies. CF33-hNIS is derived from a poxvirus — a type of virus responsible for certain skin infections. It was developed by the Los Angeles-based City of Hope cancer care and research center in collaboration with Imugene, an Australian biotechnology company.
The initial virus was modified in such a way that it penetrates cancer cells to duplicate itself there. The infected cell eventually bursts and then releases thousands of virus particles into the host organism. These act as antigens, and thus stimulate the immune system to attack nearby tumor cells. But that’s not all: the host’s immune defenses are also stimulated so that they are more responsive to other immunotherapies, the researchers point out.
Oncolytic virus and immunotherapy: an effective alliance
The chimeric virus behind the treatment, CF33, was developed by Professor Yuman Fong of the City of Hope center. It has already proven itself on millions of humans as a therapeutic agent, as it happened to be the active component of the smallpox vaccine. CF33 results from a combination of genomic sequences from several strains of “cowpox” (or vaccinia) virus, a virus similar to that of human smallpox. The gene Human Sodium-Iodide Symporter (hNIS) to which it has been combined here, allows the virus to be tracked live by imaging and to mediate targeted radiotherapy.
A phase 1 clinical trial was started in April. It aims to recruit around 100 candidates from approximately 10 sites in the United States and Australia; patients eligible for treatment include those with any metastatic or advanced solid tumor, for whom radiological progression has been observed after at least two prior lines of treatment, including treatment with immune checkpoint inhibitors — these checkpoints (checkpoints) are used by tumors to protect themselves from immune attack.
Immune checkpoint inhibitors are effective in some cancers; they are monoclonal antibodies which specifically target the receptors and ligands involved in the inhibition of tumor immunity. However, the relapse rate of patients is high and they eventually stop responding (or develop some resistance) to this treatment. However, research shows that oncolytic viruses can prime a person’s immune system and increase the effectiveness of immunotherapy, by increasing the level of PD-L1 (Programmed Death-Ligand 1) in tumors.
The PD-L1 ligand is expressed on the surface of several cancer cells; it prevents apoptosis (self-destruction) of carrier cells. It acts as a sort of marker that will prevent T lymphocytes from destroying cells. If these markers are more numerous, they will be more visible anti-PD-L1 antibodies. ” Interestingly, the same characteristics that make cancer cells resistant to chemotherapy or radiation therapy actually enhance the success of oncolytic viruses, such as CF33-hNIS Fong said.
First results expected for 2025
It is intended to initially administer Vaxinia as monotherapy. Participants will receive low doses of the treatment by direct (intratumoral) injection or intravenously. Once acceptable safety has been demonstrated in this small group of patients, some other participants will receive Vaxinia in combination with pembrolizumab — a monoclonal antibody specifically directed against the PD-L1 checkpoint.
Like any phase 1 trial, the objective is to test the safety of the product, its tolerance and to identify any adverse effects. It will also be used to determine the dose and frequency of administration of the treatment. The trial is expected to last two years in total (the end of data collection is set for December 2024). CF33 had been successfully tested in mouse models of colon cancer; the researchers observed at the time “an increased influx of lymphocytes and macrophages into the tumors”, as well as durable tumor regression and long-term survival. However, it is impossible to say for the moment that the treatment will show the same effectiveness in humans.
If CF33-hNIS proves safe, well tolerated and effective, it could help improve the quality of life of patients with cancers that are difficult to treat with current therapeutic approaches. It should be noted that another oncolytic virus, approved by the Food and Drug Administration, is already used as a treatment for advanced melanoma: it is talimogene laherparepvec (T-VEC), a modified version of the virus ‘herpes. Its direct intratumoral injection triggers local and systemic immunological responses leading to the death of tumor cells.