A canine parasite could help fight incurable cancers

A canine parasite could help fight incurable cancers

Currently, cancer remains the second leading cause of death in the world, despite improvements in patient care.

The seriousness of these diseases lies in their great diversity. Although some types of cancer are effectively treated 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 great challenge for our health system.

For several years, the development of immunotherapies, treatments that take advantage of various components of the immune system to fight tumors, has been a promising way to achieve this goal.

Some of these promising immunotherapies use modified viruses, which cause adverse effects in many patients. To overcome 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.

First immunotherapies: 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 more specifically against cancer.

This approach exploits different strategies, be it the use of antibodies that prevent cancer cells from inactivating the immune system (called immune checkpoint inhibitors) or that specifically target cancer cells, or even the use of microorganisms that induce a strong immune response to destroy the tumor. cells.

These immunotherapeutic approaches have been used since 2001 to treat melanoma: the development of the first antibody to inhibit immune checkpoints, ipilimumab (trade name: Yervoy), allowed more than 53.6% of treated patients to survive 2 years. This antibody recognizes a protein (CTLA-4) that intervenes in the inactivation of T lymphocytes, immune cells that have antitumor activity in particular. By binding to this protein, ipilimumab inactivates T cells, which can then proliferate.

In 2015, another breakthrough in melanoma care shrank tumors and increased survival for some patients affected by the disease. This strategy is based on the use of a herpes virus (herpesvirus type 1), modified to multiply in tumor cells and cause their death (commercial name: Imlygic). This virus has also been modified to produce a human protein that stimulates the antitumor immune response.

Immunotherapies could hold the key to treating cancers that are currently incurable, because they are refractory to existing antitumor therapies. This is especially the case for glioblastoma, a serious brain cancer for which the median survival of patients is 15 months after diagnosis, or pancreatic cancer, associated with a median survival of 8 months.

However, the use of viruses as part of immunotherapies may not be trivial. In fact, there is a particular risk that their genetic material will integrate with that of human cells (in the case of certain DNA viruses), causing unwanted mutations that could have harmful consequences.

To overcome this problem, we have developed with our collaborators an immunotherapy based on a microorganism called Neospora caninum (N. caninum).

Neospora caninum, a microorganism as a new therapeutic hope?

Identified in 1984 in dogs, Neospora caninum It is a unicellular parasite. It is also intracellularly obligate, meaning that it infects other cells in which it replicates.

Responsible for serious neurological disorders and abortions in certain animals (cattle and canines), it is otherwise completely harmless to humans and most rodents, probably due to differences in immune responses. Instead N. caninum is able to multiply in vitro in cells of human or mouse origin.

Like the viruses used in immunotherapy, N. caninum it can destroy the cells it infects. Induces a strong cellular immune response, sought to fight cancer. These two characteristics therefore make it a relevant candidate for antitumor immunotherapy.

With this in mind, we decided to test its efficacy in the context of an immunotherapy intended to treat mice for cancer of the thymus (gland located in the upper chest, behind the breastbone, between the lungs) called a thymoma. Benign and slow-growing, this type of cancer is usually asymptomatic and is mainly treated by surgery.

The interest of this model is to provide evidence of the anticancer efficacy of N. caninum before testing it in models of cancers refractory to existing treatments.

Our results, published in the scientific journal Journal of Cancer Immunotherapy show that, in mice, N. caninum it is capable of controlling the development of a tumor until its complete regression, and this, in three different ways. These very positive results were obtained not only after the (unmodified) microorganisms were administered directly into the tumor, but also at a distance from it.

Three mechanisms that control tumor development

First, N. caninum It has been shown that it can directly destroy cancer cells. Four days after treatment, vacuoles (compartments located within a cell) containing the microorganisms were observed in the tumor cells. made up of N. caninum, allow it to multiply in the host cell while being protected 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 it is capable of multiplying in cancer cells and therefore, by extension, of destroying them. N. caninum it was detected in other cells, but did not persist or cause damage.

The second way that N. caninum controls tumor development through stimulation of a cellular immune response. After treatment, a strong mouse immune system response was detected within the tumor. This reaction is characterized not only by high levels of inflammatory molecules, but also by the recruitment of immune cells specialized in the destruction of cancer cells, whether they are infected with N. caninum or not. These cells are the cytotoxic T lymphocytes and the cells natural killer (NK), whose peculiarity is to produce proteins that degrade cell membranes, causing their destruction, and therefore that of the cells.

Finally, N. caninum affects tumor development through reprogramming of the tumor microenvironment. Tumors persist in the body because they are particularly capable of “numbing” the immune system within them, forming the so-called immunosuppressive microenvironment, which promotes their development.

In this particular microenvironment, several poor prognostic factors are expressed. This is the case, for example, of the growth factor VEGF (Vascular endothelial growth factor), a protein involved in the creation of new blood vessels (which 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. caninum, these two molecules are produced at lower levels within the tumor. This decrease in concentration allows the tumor microenvironment to be reprogrammed to participate in the elimination of cancer cells.

Promising preliminary results

Obtained in mice, these results are still preliminary, but very encouraging. They show that N. caninum could be a good candidate to enrich the arsenal of immunotherapies against cancer.

Betting on using a microorganism to treat cancer was risky, due to its ability to multiply in cells. However, in this model of thymic lymphoma (thymoma), N. caninum it was no longer detectable at the end of the experiments. Although humans are not susceptible to infection by N. caninumits clearance by the immune system must be confirmed before considering therapeutic use.

After having demonstrated its efficacy in a benign cancer model, it now remains to study the anticancer properties of N. caninum in a hard-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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