Some basic concepts about the immune system
The immune response is the process by which the body protects itself against infections caused by viruses, bacteria, and parasites, as well as against the development of cancerous cells, through a series of well-coordinated events. The innate immune response serves as the first line of defense by acting immediately and non-specifically against threats, while the adaptive immune response takes over by deploying targeted defense mechanisms against each specific invader. Once activated by the innate system, the adaptive system must learn to recognize the enemy, which explains the delay of about a week before becoming fully effective. In parallel, a memory of the invader is created, allowing the immune system to respond rapidly and specifically in case of a future attack.
Immunotherapy: A powerful and promising weapon against cancer
For several decades, a new therapeutic approach to cancer has been emerging: immunotherapy, which includes all treatments designed to activate or reactivate the immune system. These interventions can target different stages of the immune response, influencing both the innate and adaptive mechanisms. In recent years, the management of certain cancers, such as melanoma and lung cancer, has significantly improved thanks to “Immune Checkpoint Inhibitors.” This type of immunotherapy prevents the exhaustion of CD8 T lymphocytes, often considered the soldiers of the immune system due to their ability to eliminate infected or defective cells.
Lipopolysaccharides (LPS): Bacterial compounds able to trigger an anticancer immune response
Since the 19th century, it has been known that components of the membrane of certain bacteria, called lipopolysaccharides (LPS), activate an innate immune response, thereby triggering immune mechanisms to fight cancer. However, the clinical use of LPS has so far been limited due to its side effects, which resemble severe flu-like symptoms. Currently, only bladder cancers, which can be treated through local injections, are managed using bacterial extracts.
The collaboration between chemists at HEPHAISTOS-Pharma, experts in LPS, and biologists specializing in the innate immune response from Professor Dumontet’s Oncopharmacology team has led to the development of a more effective and significantly less toxic LPS derivative: HEPHA-440. This compound is obtained by extracting LPS from the Bordetella pertussis bacterium, followed by chemical detoxification and formulation into liposomes, small lipid particles around which LPS aggregates. Administered intravenously, HEPHA-440 has demonstrated its ability to block tumor growth in mice, both as a monotherapy in a bone cancer model and in combination with “Immune Checkpoint Inhibitors” in other solid tumor models, without causing severe side effects.
NB: A solid cancer is a type of cancer that forms a mass in tissues, as opposed to blood cancers. Solid cancers account for 90% of cancers in humans.
Learn more
Keys results obtained with detoxified LPS in liposomal formulation:
Richert et al. Cancers. 2023
Chettab et al. Front Immunol. 2023
Bone Cancer: A need for new treatment!
Each year in France, approximately 150 people, the vast majority of whom are children and adolescents, are diagnosed with a type of bone cancer called osteosarcoma. With current treatments, relapses occur in 20 to 40% of patients. Moreover, the management of this cancer has seen no significant improvement in the past 30 years. This new immunotherapy could therefore represent a major clinical breakthrough and has been granted orphan drug designation for the treatment of osteosarcoma by the European Medicines Agency (EMA).
Objectives of the project
With the financial support of the ANR and the collaboration of all the partners in the RHU SyStInn, the aim of the project is to evaluate the efficacy of HEPHA-440 alone in patients with bone cancers and in combination with “Immune Checkpoint Inhibitors” in various other solid cancers (phase II clinical trials), after determining the maximum tolerated dose in humans through a dose escalation (phase I clinical trial).
Alongside this clinical evaluation, fundamental research continues to deepen the understanding of the mechanisms of action of HEPHA-440. This knowledge will help accurately identify the patients and types of cancers most likely to respond positively to this treatment, thereby optimizing the benefit/risk balance.
What is going to happen next?
If HEPHA-440 proves to be safe in humans and effective against certain solid cancers, a phase III clinical trial will be launched. This final step before commercialization aims to assess the drug’s efficacy in large patient cohorts by comparing it to the standard treatment or a placebo, as well as identifying any rare side effects that may not have been observed in previous phases. Due to the significant health benefits that HEPHA-440 could offer, early market approval may be considered in consultation with regulatory agencies.
Medical, Societal & Economic impact of the RHU SyStInn project
- Improvement in the management of osteosarcomas, a pediatric cancer that has not seen any major medical advancements in the past three decades.
- Potentially effective therapy for a wide range of cancers.
- Introduction of a new generation of innate immune system stimulants, overcoming the limitations of those currently on the market with an optimized drug profile: safe, soluble, and effective.
- Treatment that could benefit a large number of patients due to its potential for large-scale production.
- Intravenous administration for greater efficacy, with significant potential for therapeutic applications and combinations.
