Combination therapy for the treatment of metastatic melanoma using magnetic nanoparticles
Horizon Europe Marie Skłodowska-Curie Actions Doctoral Network
The research axis of our project
Objective: New treatment for metastatic melanoma
This project has received funding from the European Union’s Horizon Europe research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101073025.
Metastatic melanoma, a hard-to-treat cancer
If not detected early, melanoma spreads (metastasizes) to other parts of the body (16% of patients are first diagnosed at an advanced stage). In this case, the prognosis is poor with a median survival of 6 to 9 months, and the 5-year survival rate as of 2018 for distant metastatic melanoma is 22.5%. Metastatic melanoma is the fastest growing malignancy in men and second in women. The incidence of melanoma has increased by 3 to 7% in Europe, where melanoma accounts for 20,000 deaths annually (60,712 deaths worldwide and mortality estimated to reach 105,904 in 2040).
The limits of current therapies
There is an urgent need to improve the current therapies (chemotherapy, radiotherapy) that have a limited efficacy. A single therapy is not efficient to tackle metastatic melanoma and a combination of therapies is thus emerging as a necessity to efficiently eradicate all cancer cells. Recently, the development of immunotherapies has shown promises, in particular chimeric antigen receptor (CAR)-T cells. Nevertheless, the physical barriers represented by cellular and non-cellular components of the tumor microenvironment combined to the abnormal tumor vasculature and high interstitial fluid pressure, hamper an efficient tumor infiltration of CAR-T cells.
The objectives of Melomanes
In this context, thanks to a network of 18 partners (including 10 non-academic partners), MELOMANES aims to train 12 doctoral researchers for the development of a combined therapy exploiting the properties of magnetic nanoparticles to induce damage on the tumor microenvironment by magnetic and optic hyperthermia in order to facilitate the infiltration of CAR-T cells.
Nanoparticle synthesis and functionalisation
A key innovation of the proposed therapeutic strategy for the treatment of metastatic melanoma is the use of nanoparticles to improve the effect of the immunotherapy.
This research axis focuses on advanced chemistry of nanomaterials, and is closely related to the assessment of the heating capacity of the nanoparticles and to safety and biocompatibility considerations, in order to contribute to a responsible and sustainable nanomedicine.
Synthesis of nanoparticles
Altering the tumor microenvironment using photothermia and magnetic hyperthermia is the essential role of the nanoparticles. The synthesis thus focuses on metallic nanoparticles. Our researchers finely tune their composition, size and shape, to control their magnetic hyperthermia and photothermal properties.
Functionalisation of nanoparticles
Once the particles are synthesised, it is essential to functionalise them. Functionalisation is used for several purposes:
- improving the stability in the blood medium
- targeting specifically the tumor microenvironment and cancer cells
- labelling to make bioimaging possible
- acting on biological mechanisms of the metastasis
Multiple strategies for functionalisation are explored, and selected according to the stability and the efficiency of the nanoparticles, assessed in the Heating capacity on animal-free models axis. The functionalisation of the metallic nanoparticles functionalised for better dispersibility and biocompatibility.
Heating capacity on animal-free models
The therapeutic strategy of Melomanes is to use nanoheaters localised in the tumor microenvironment to allow a better infiltration of the modified cells of the immunotherapy. In this research axis, the heat-generating nanoparticles are screened for their hyperthermia properties, and their ability to alter the tumor microenvironment is evaluated on new animal-free models. It connects the work on the nanoparticles synthesis and functionalisation and on the combined hyperthermia and immunotherapy.
Heating capacity of nanoparticles under infrared light and magnetic stimuli
The metallic nanoparticles prepared by the researchers of the axis Synthesis and functionalisation of the nanoparticles display heating properties under two different stimuli:
- when they are illuminated by a laser of near-infrared light (photothermal properties)
- when they are exposed to a high-frequency magnetic field (magnetic hyperthermia)
In this research axis, the ability of the tailored nanoparticles to generate heat is measured and optimised for each stimulus separately. The effect of the combined stimuli of light and magnetic field is evaluated on a device specifically design for this therapeutical strategy. These two physical stimuli are expected to have complementary effect, and potentially synergistic effect, on the alteration of the tumor microenvironment.
This early assessment of the nanoparticles helps guiding their synthesis and functionalisation towards optimised efficiency, while keeping the Safety and biocompatibility matter under close scrutiny.
Animal-free models to assess the alteration of the tumor microenvironment
The effect of the nanoparticles on the tumor, and especially on the nearby biological environement, called tumor microenvironment, needs to be evaluated. Models are useful for this evaluation. Indeed, while the tumor microenvironment is a complex biological medium, models help testing separately different mechanisms and different biological components, at different scales (intracellular, cellular and tissue levels). They also significantly reduce the need for animal testing.
Tumor spheroid
For the assessment of the different components of the tumor microenvironment separately, a 3D model of a tumor is developed. This multicellular tumor spheroid is a good alternative to traditional 2D cultures, that are too simplified to mimick key cell-cell and cell-matrix interactions, and in vivo studies, that are complex to operate and analyse.
For this study on melanoma, the spheroid model includes not only cancer cells, but also structural cells (fibroblasts) and intercellular matrix components.
Tumor-on-chip
Taking profit of the properties of liquids circulating in small channels, also called microfluidics, the emerging field of organ-on-chips is promising for the development of new therapies. Indeed, it enables to increase the complexity of spheroid models by mimicking cell migration, while keeping control of the biological environment. This is especially useful for immune cells, as they kill their targets, such as cancer cells, when they are in contact.
A melanoma-on-chip model is thus developed to study the interactions between the immune cells and the melanoma microenvironment. Following this study, the ability of the nanoparticles to alter the tumor microenvironment model will be evaluated, and will help tailoring the therapeutic protocol, including the amount of nanoparticles and immune cells to be used.
When coupled to a lung-on-chip or liver-on-chip model, this tumor-on-chip model can also be used to assess the toxicity and safety aspects of the combined therapy.
Combined hyperthermia and immunotherapy
In the strategy of the combined therapy of Melomanes, the melanoma cancer cells, from primary tumors and metastases, are eliminated using chimeric antigen receptors modified T cells, also called CAR-T cells.
In this research axis, advanced cell biology is harnessed to design specific and efficient cells that can be used after the alteration of the tumour microenvironment by the magnetic nanoparticles. The combined therapy is evaluated using the animal-free models, as well as in vivo.
Targeted and efficient immunotherapy
Cancer immunotherapy boosts the immune system to help it fight the disease. It exploits the fact that cancer cells often have molecules on their surface that can bind to antibodies or T-cell receptors, which can cause an immune system response.
Improving antitumor T cell activities
In this project,
T cell receptors for better recognition
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Our results in this research axis
Safety and biocompatibility
Evaluating the toxicity of particles and cells
Our results in this research axis
Responsible and sustainable nanomedicine
Frameworks for sustainability and responsibility
