Before being a disease responsible for the various and numerous clinical alterations of the patient’s organs, cancer is first and foremost uncontrolled abnormal cell growth, leading to the proliferation of a tumour. Pre-clinical studies aim to understand how, at the cellular level, treatment helps to limit progression and destroy tumour cells.
The tumour and its environment
Genetically unstable tumour cells synthesise altered and abnormal proteins that are antigens that are normally recognised by the immune system: Tumour associated antigens (TAAs).
In addition, these same tumour cells find themselves in a situation of metabolic stress and consequently produce large quantities of stress proteins: Heat Shock Proteins (HSP). These HSPs are molecular chaperones that know how to bind and stabilise other proteins (especially tumour proteins) and diffuse into the blood, away from the tumour.
Ciocca DR, Calderwood SK. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. Summer 2005;10(2):86‑103.
The role of hydroxyapatite
We have demonstrated that the characteristics of hydroxyapatite particles (sintering temperature, size, shape) have a major influence, after their phagocytosis, on the inflammatory mechanism and activation of the cells of the innate and adaptive immune system.
Overall, we have proven, from cell lines, that the hydroxyapatite particles were able to activate inflammasomes (objectified by synthesis of IL-1β) and could be, as such, considered an inducer of innate immunity.
Regarding adaptive immunity, we have also demonstrated that dendritic cells express, in the presence of hydroxyapatite particles, various receptors that influence lymphocyte stimulation (in particular CD 40)) As well as an MHC class II cell surface receptor HLA-DR) whose expression inhibition is known to contribute to the escape of cancer cells from the surveillance of the immune system.
The role of the tumour HSP-antigen protein complex
Hydroxyapatite-loaded particles, during the preparation of a vaccine prepared from canine osteosarcoma, with a combination of tumour antigens and identified HSPs (gp 96 and HSP 70) led to the stimulation of monocyte Toll-type receptors (TLR 2 and 4) ).
On the other hand, hydroxyapatite particles alone did not reproduce this stimulation proving the specific role of HSPs generated by tumour stress to activate the innate immune system.
In addition, we demonstrated that gp96 and HSP70, concentrated by adsorption on hydroxyapatite particles, were able to bind to a specific receptor (cell surface molecule: CD91or LRP1) to be the first step in sensitising CD8+ T cells.
Tumourigenesis (tumour formation and progression) evaluated on a gliosarcoma model in rats compared the efficacy of the hydroxyapatite vector alone, isolated HSPs-associated hydroxyapatite and HSPs-loaded hydroxyapatite and cancer cell membranes (tumour-associated antigens).
The study showed a significant reduction in the size of induced tumours of vaccinated rats compared to the control group, with no side effects.
The histology of the sacrificed animals showed necrosis and the presence of apoptotic cells of the tumours of the vaccinated group.
Promising results in veterinary health
The therapeutic effects of our treatment in dogs with B-cell lymphoma have been described in a series of multicentre studies. They compared over five years of follow-up, time to lymphoma progression, and mean survival of two groups of 150 dogs treated with chemotherapy alone versus the same protocol with APAVAC chemotherapy.
The results showed that our autologous vaccine is effective in prolonging the time to disease progression (304 days vs 41 days) and the disease survival rate (505 days vs 159 days) when used in combination with chemotherapy.
Opportunities and challenges of active immunotherapy in dogs with B-cell lymphoma : a 5-year experience in two veterinary oncology centers. Marconato et al. Journal for ImmunoTherapy of Cancer. 2019 7:146
Currently marketed as an extemporaneous veterinary medicinal product, this treatment has also been used in indications of melanoma, osteosarcoma, and various other solid tumours. We have had feedback on its effectiveness for various types of cancers, including advanced stages, without systemic side effects.