The virus in question has been genetically modified to selectively infect and kill cancer cells. It does not attack healthy cells. The treatment, called CF33-hNIS (or Vaxinia), has already shown its potential in animal models of colon cancer, and preclinical models of lung, breast, ovarian and pancreatic cancer. It will soon be tested on approximately 100 adult volunteers with metastatic or advanced solid tumors. The first American patient has already received a dose of this treatment.
Cancer cell-killing viruses, known as oncolytic viruses, have been known for decades. In recent years, they have emerged as a very promising way to treat non-operable cancers that are resistant to other therapies. CF33-hNIS is derived from a poxvirus – a type of virus that causes 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 original virus has been modified so that it enters cancer cells and duplicates itself. The infected cell eventually bursts and releases thousands of virus particles into the host body. These particles act as antigens, stimulating 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 on which the treatment is based, CF33, was developed by Professor Yuman Fong of the City of Hope Center. It has already proven itself in millions of humans as a therapeutic agent, as it happened to be the active component of the smallpox vaccine. CF33 is derived from a combination of genomic sequences from several strains of the “cowpox” virus, a virus similar to human smallpox. The Human Sodium-Iodide Symporter (hNIS) gene, with which it has been combined here, allows the virus to be followed in vivo by imaging and to mediatetargeted radiotherapy.
A Phase 1 clinical trial was initiated in April. The trial aims to enroll approximately 100 candidates at about 10 sites in the U.S. and Australia; eligible patients include those with any metastatic or advanced solid tumor who have experienced radiological progression after at least two prior lines of therapy, including treatment with an immune checkpoint inhibitor – checkpoints used by tumors to protect themselves from immune attack.
Immune checkpoint inhibitors are effective in some cancers; they are monoclonal antibodies that specifically target receptors and ligands involved in inhibiting tumor immunity. However, the relapse rate of patients is high and they eventually stop responding (or develop some resistance) to this treatment. 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 many cancer cells; it prevents apoptosis (self-destruction) of carrier cells. It acts as a sort of marker that will prevent T cells from destroying the cells. If there are more of these markers, they will be more visible to anti-PD-L1 antibodies. “Interestingly, the same characteristics that make cancer cells resistant to chemotherapy or radiation therapy enhance the success of oncolytic viruses, such as CF33-hNIS,” Fong said.
The plan is to initially administer Vaxinia as a single agent. Participants will receive low doses of the treatment by direct injection (intratumoral) or intravenously. Once acceptable safety has been demonstrated in this small group of patients, some of the other participants will receive Vaxinia in combination with pembrolizumab – a monoclonal antibody specifically directed against the PD-L1 checkpoint.
As with any Phase 1 trial, the goal is to test the safety of the product, and its tolerability and to identify potential adverse events. It will also be used to determine the dose and frequency of treatment. The trial is expected to last a total of two years (the end of data collection is December 2024). CF33 was previously successfully tested in mouse models of colon cancer, where researchers observed “increased lymphocyte and macrophage influx into tumors” and sustained tumor regression and long-term survival. However, it is not yet clear whether the treatment will show the same efficacy in humans.
If CF33-hNIS proves to be 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. Another oncolytic virus, approved by the Food and Drug Administration, is already being used to treat advanced melanoma: talimogene laherparepvec (T-VEC), a modified version of the herpes virus. Its direct intratumoral injection triggers local and systemic immunological responses leading to tumor cell death.