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Cancer currently remains the second leading cause of death in the world, despite improvements in patient care.
The seriousness of these diseases(cancer) lies in their great diversity. While some cancers are treated effectively with surgery, chemotherapy, and radiation therapy, others respond little or not at all to these treatments. Improving the management of these diseases is therefore a major challenge for our health system.
For several years now, the development of immunotherapies, and treatments that use different components of the immune system to fight tumors, has been a promising way to achieve this goal.
Some of these promising immune therapies use modified viruses, which cause adverse effects in many patients. To solve this problem, our team studied the possibility of using a non-pathogenic microorganism for humans instead, Neospora caninum. The first results obtained in mice are very encouraging.
Excrescence: First immune therapies have a positive impact
Unlike chemotherapy and radiotherapy, which prevent tumor cells from multiplying but cause serious side effects (because these treatments also attack non-cancerous cells in the body), immunotherapy stimulates the patient’s immune system to fight cancer more effectively.
This approach uses different strategies, whether it be using antibodies that prevent cancer cells from inactivating the immune system (so-called immune checkpoint inhibitors) or targeting cancer cells specifically, or even using microorganisms, which are living organisms that have a strong immune system. induce an immune response to destroy tumor cells. cells.
These immunotherapeutic approaches have been used to treat melanoma since 2001: with the development of the first antibody to inhibit immune checkpoints, ipilimumab (trade name: Yervoy), more than 53.6% of treated patients were able to survive for 2 years. This antibody recognizes a protein (CTLA-4) that plays a role in the inactivation of T lymphocytes, immune cells that have particularly anti-tumor activity. By binding to this protein, ipilimumab inactivates T lymphocytes, which can then proliferate.
In 2015, another advance in melanoma care reduced the number of tumors and increased the survival of some patients affected by the disease. This strategy is based on the use of a herpes virus (herpes virus type 1), modified to multiply in tumor cells and cause their death (trade name: Imlygic). This virus has also been modified to produce a human protein that stimulates the anti-tumor immune response.
Immunotherapies may be key to treating cancers that are currently incurable because they are refractory to existing antitumor therapies. This is particularly the case with glioblastoma, a serious brain cancer for which the mean survival of patients is 15 months after diagnosis, or pancreatic cancer, associated with a mean survival of 8 months.
Using viruses as part of immunotherapies may not be trivial. Indeed, there is a particular risk that their genetic material will integrate into that of human cells (in the case of certain DNA viruses), creating unwanted mutations that can have harmful consequences.
To get around this problem, we have developed immunotherapy with our employees based on a microorganism called Neospora caninum (N.caninum).
Cancer: Neospora caninum, a microorganism as a new therapeutic hope?
Identified in 1984 in dogs, Neospora caninum is a unicellular parasite. It is also obligatory intracellularly, meaning it infects other cells in which it replicates.
It is responsible for serious neurological disorders and abortions in certain animals (cattle and dogs), but on the other hand is completely harmless to humans and most rodents, probably because of differences in immune responses. Unlike N.caninum can multiply in vitro in cells of human or mouse origin.
Like the viruses used in immunotherapy, N.caninum can destroy the cells it infects. It induces a strong cellular immune response, aimed at fighting cancer. These two features, therefore, make it a relevant candidate for antitumor immunotherapy.
With this in mind, we decided to test its effectiveness in the context of immunotherapy aimed at treating mice for cancer of the thymus (a gland located in the upper part of the thorax, behind the sternum, between the lungs), called a thymoma. Benign and slow-growing, this type of cancer is generally asymptomatic and is primarily treated surgically.
The importance of this model is to provide evidence of the anticancer efficacy of N.caninum before testing it on cancer models that are refractory to existing treatments.
Our results, published in the scientific journal Journal of Cancer Immunotherapy show that in mice N.caninum can control the progression of a tumor to complete regression in three different ways. These very positive results were not only obtained after the (unmodified) microorganisms were administered directly into the tumor but also at a distance from it.
Three mechanisms that regulate tumor development
In the first place
, N.caninum has been shown to directly destroy cancer cells. Four days after the treatment, vacuoles (compartments contained within a cell) containing the microorganisms were observed in the tumor cells. Formed by N.caninum, they allow it to multiply in the host cell while protecting it from any degradation. After such a multiplication step, the parasitized cell is destroyed.
The observation of such vacuoles in the tumor means that: N.caninum is capable of multiplying in cancer cells and thereby destroying them by extension. N.caninum was detected in other cells but did not persist or cause damage.
The second way N.caninum regulates tumor development is by stimulating a cellular immune response. After the treatment, a strong immune system response in the mouse was detected in the tumor. This response is characterized not only by high levels of inflammatory molecules but also by the recruitment of immune cells specialized in destroying cancer cells, whether or not they are infected with N.caninum or not. These cells are the cytotoxic T lymphocytes and the cell’s Natural killer (NK), the peculiarity of which is to produce proteins that break down cell membranes, leading to their destruction, and thus that of the cells.
Finally, N.caninum influences tumor development via reprogramming of the tumor microenvironment. Tumors remain in the body because in particular, they are able to “sleep” the immune system in them, by forming a so-called immunosuppressive microenvironment, which promotes their development.
Several poor prognostic factors are manifested in this particular microenvironment. This is the case, for example, for the growth factor VEGF (Vascular Endothelial Growth Factor), a protein involved in the creation of new blood vessels (that bring nutrients to the tumor), or PD-L1 (Programmed Death-Ligand 1), a protein that prevents the death of cells that strongly express it.
However, after treatment with N.caninumthese two molecules are produced at lower levels in the tumor. This decrease in concentration makes it possible to reprogram the tumor microenvironment to participate in the elimination of cancer cells.
Promising preliminary results
These results, obtained in mice, are still preliminary, but very encouraging. They show that N.caninum could be a good candidate to enrich the arsenal of cancer immunotherapies.
Betting on using a microorganism to treat cancer was risky, because of its ability to multiply in cells. In this model of thymic lymphoma (thymoma), N.caninum was no longer detectable at the end of the experiments. Although humans are not susceptible to infection with N.caninumits elimination by the immune system must be confirmed before a therapeutic use is considered.
After demonstrating its effectiveness in a benign cancer model, we now need to study its cancer-fighting properties N.caninum in a difficult-to-treat cancer model, with the goal of one day using it to cure patients suffering from incurable cancers such as glioblastoma.
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