Immunotherapy: a new two-in-one weapon against resistant tumors

Electron microscopy image showing cGAMP-VLP (large spheres on the image, indicatElectron microscopy image showing cGAMP-VLP (large spheres on the image, indicated by the arrows), a new anti-cancer immunotherapy drug developed by Dr Nicolas Manel’s team. Institut Curie

Pressing the gas pedal and lifting the brake at the same time is the innovative idea of Dr. Nicolas Manel, Inserm researcher and team leader at the Institut Curie (Immunity and Cancer Unit - Institut Curie, Inserm) to improve the response to immunotherapies. For several years, the researchers have identified a signaling pathway - STING - that is essential for accelerating the response to immunotherapies. Today, the team has taken a new step by identifying a new biological drug capable of activating STING specifically in the key cells of the immune system. This work, published in the journal Science Immunology on January 13, 2023, opens up promising therapeutic perspectives for developing new strategies and increasing the effectiveness of cancer immunotherapies.

Immunotherapy is an anti-cancer strategy that has been in the news for the past 15 years. In receptive patients, it gives spectacular results, but 50 to 80% of patients do not respond to these treatments. At the Institut Curie, the Innate Immunity team led by Dr. Nicolas Manel, director of research at Inserm, has just developed an innovative strategy that could well change the situation for these patients.

The researcher uses the mechanical metaphor to explain how current anti-checkpoint immunotherapies work: "These therapies lift the ’brake’ on the immune system to recognize the patient’s cancer cells as cells to be destroyed (without these inhibitors, the immune system cannot attack the cancer cells). But they only work if there is a "natural gas pedal" for the immune system to attack these cells. This gas pedal is linked to a biochemical pathway called STING and is missing in 50 to 80 percent of patients."

Understand the fundamental mechanisms

It was about five years ago that researchers realized the gas pedal role of STING. Pharmaceutical companies immediately developed small molecules to activate STING. Although their results were convincing in vitro, they proved disappointing in the clinic.

At the Institut Curie, Dr. Nicolas Manel and his team went back to basics to decipher the entire cascade of events involved: "What our study reveals is that STING must be selectively activated in certain cells, the dendritic cells, to have an accelerating effect, whereas activating STING in other cells can destroy the immune response.

The researchers used pseudoviral particles (which resemble viruses but are non-infectious) because they are efficiently captured by dendritic cells. They then placed the natural molecule that activates STING, called cGAMP, inside the particles. The resulting drug, named cGAMP-VLP, preferentially activates STING in dendritic cells, without negatively impacting other immune system cells. These activated dendritic cells thus educated lymphocytes to recognize tumor antigens. The researchers thus identified a much sought-after therapeutic product capable of activating the gas pedal!

"Tested in different systems (in vitro, in animals and on human tumor samples), this strategy showed a strong antitumor effect, even at low doses. Combined with an anti-checkpoint immunotherapy, it is even more effective," says the researcher.

For him, it is therefore time to offer this new therapeutic weapon to patients. This is the objective of Stimunity, the biotech company he co-founded, which, with the current fundraising, could launch the clinical development of this innovative immunotherapy.

If these results were confirmed in humans, it would be possible to attack cancers that have been resistant to all known treatments, without chemotherapy or radiotherapy.

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