Cancer immunotherapy is a strategy that turns the patient’s own immune cells into a “search-and-destroy” force that attacks the tumour’s cells.
The “search” immune cells are the dendritic cells, which collect and present identifying parts of the cancer cells (antigens) to the “destroy” part (T cells), the immune system’s killer cells.
The problem is that many tumours “learn” how to evade detection by the patient’s dendritic cells. Clinicians address this by collecting dendritic cells from the patient’s blood, loading them in the laboratory with tumour material – antigens that train dendritic cells to better identify the tumour – and then injecting them back into the patient.
However, tumours contain many more antigens than those supplied to the dendritic cells in the lab. Also, lab‑grown dendritic cells often lack some key activation molecules that are needed to fully engage T cells.
A solution can be found in extracellular vesicles (EVs): tiny packets released by cancer cells that carry proteins and other molecules that can help dendritic cells identify the tumour. If dendritic cells could pick up tumour EVs inside the patient’s body, they could trigger more precise and effective immune responses against the tumour.
Scientists led by Michele De Palma at Ecole Polytechnique Federale de Lausanne (EPFL) have developed two bioengineering approaches that exploit cancer EVs and better train dendritic cells to identify cancer cells without the need to load them with tumour material outside the patient’s body.
The first approach, published in Nature Communications, uses a receptor called EVIR (EV-internalizing receptor) to help dendritic‑cell progenitors (immature dendritic cells) take up tumour-derived EVs and more effectively present their antigens to T cells.
De Palma’s lab first developed EVIR in 2018, but this new paper brings the research into a preclinical study. The EVIR-engineered dendritic cells elicited robust immune responses and inhibited the growth of experimental melanomas that are otherwise resistant to mainstream immunotherapy.
The second approach, published in Science Translational Medicine, improves the performance of EVIR so that dendritic cells not only internalize the tumour’s EVs and present its identifying antigens to T cells, but also spontaneously produce additional molecules that can further stimulate them into action. The result is iCAR, (instructive chimeric antigen receptor), which enables dendritic cells to better activate T cells against the tumour.
The studies were conducted by two doctoral students, Ali Ghasemi and Yahya Mohammadzadeh. Together, they outline a path toward engineered dendritic cells that are programmed to acquire and present relevant tumour antigens directly in the body, instead of relying on limited tumour material provided in the lab.
“Our goal is to relaunch the clinical potential of dendritic-cell-based therapies through engineering them for improved performance in vivo – enhanced antigen uptake coupled to cell activation, without the need for antigen exposure ex vivo,” De Palma said.
“To sustain and expand these efforts, I encouraged the founding of EVIR Therapeutics, a biotechnology start-up created to recruit investment and strategic partnerships for bridging the gap between innovation and clinical testing.”
Other contributors were the Agora Cancer Research Center, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Geneva University Hospital (HUG), University of Geneva (UNIGE), Swiss Institute of Bioinformatics (SIB), Ludwig Institute for Cancer Research, and the Netherlands Cancer Institute (NKI).
Cut: Engineered dendritic cells (right) acquire tumour-derived extracellular vesicles that contain cancer antigens (left), stimulating anti-tumour immunity. Image: EPFL/M. De Palma/Ella Maru Studio CC-BY-SA 4.0
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