Congratulations! What does this ERC Proof of concept grant mean to you?
– Thank you so much. I am extremely proud to have received this ERC Proof of Concept grant. This is the third ERC grant awarded to my team – three is a special number to me and for the cellular reprogramming field – it is the number of factors required to reprogram tumour cells to dendritic cells. This ERC grant is a very special recognition for me and the team. It provides us the tools required to develop RNA-mediated reprogramming of tumour cells to dendritic cells, and to move forward a very scalable potential cancer immunotherapy.
What are the goals behind the project DART?
– The project DART stands for “Driving Tumour Antigen Presentation by RNA-mediated Transdifferentiation”. The story behind this line of research begins with a particular type of cells. Antigen-presenting type 1 conventional dendritic cells (cDC1s) are a set of dendritic cells, considered critical for kick-starting and promoting anti-tumour immunity. The presence of these cells correlates with improved patient survival. Still, cDC1s are very rare in the peripheral blood and in tumours. To reinstate them meant we could counteract tumour evasion mechanisms.
Aiming to merge direct cellular reprogramming with immunotherapy, Filipe Pereira and his research group have identified three factors (transcription factors that bind DNA and modulate gene expression: collectively called PIB) that can reprogram fibroblasts or cancer cells into antigen-presenting cDC1s. Reprogrammed cells become immunogenic and help the body mounting an antigen-specific immune response to eliminate disease.
– In the past, our group has found a way to carry these proteins to the tumour in viral vectors. However, the use of viral vectors has significant downsides for translation medicine: price, safety, and complex manufacturing.
The goal of DART’s is to develop RNA vectors encoding PIB to reprogram cancer cells in vivo, meaning that the process of reprogramming occurs within tumour to dendritic cells. The researchers will test delivering PIB with linear modified RNA, circular RNA and self-amplifying RNA moieties. These are three different ways to express the factors that translate in different levels and persistence of the reprogramming factors in the cell.
– We envision that RNA-mediated reprogramming can be efficacious as mono therapy* or in combination with already used therapies. Low immunogenic tumors, in which anti-tumor immune responses are poorly established, such as breast tumors or glioblastomas, respond poorly to approved immunotherapies. The RNA-based direct reprogramming of cancer cells administered intra-tumourally would allow to restore immunogenicity of tumour cells setting in motion anti-tumour immunity towards tumor antigens in a tumor agnostic way and in a very scalable fashion.
– Additionally, we will work towards the development of systemic delivery with cancer-specific action that may allow to treat tumors at unreachable locations. I would like to emphasise that our collaborations with clinicians and industry partners, including Asgard Therapeutics, are pivotal to DART.
* to treat a disease with a single drug
How did you initially come up with the idea for this research?
– In the past years, I have been motivated to bring together the fields of cellular reprogramming and immunology. Initially, I became interested in dendritic cells for their powerful capacity for antigen presentation and initiation of immune responses.
In the ERC Consolidator grant project TrojanDC, Filipe Pereira and his team aimed to develop a new modality for cancer immunotherapy, by efficiently reprogramming cells into antigen-presenting cDC1s. They successfully reprogrammed mouse and human tumor cells to elicit an organised immune response, using the PIB factors.
The reprogrammed cDC1-like cells in vivo induced tumour regression and long-lasting systemic immunity. The idea for DART evolved contemporarily with the development of new RNA modification technologies recently distinguished with the Nobel prize and their application to develop the RNA-based COVID-19 vaccines, explains Filipe Pereira.
– As we aim for an off-the-shelf therapy, with long-range patient fitting that maintain its personalised, cancer-specific nature the idea to test RNA as a delivery vector to reprogram tumour cells in vivo became clear. As the treatment of immunological “cold” tumours remain a challenge in immunotherapy, the DART project presents an RNA-based direct reprogramming as a strategy for treating currently unresponsive, refractory tumours.
What impact do you anticipate this research will have on society at large?
– I think the societal impact may be very significant. This project seeks to develop a scalable immunotherapy approach, that is inexpensive, easy to produce and that could be applicable to every cancer patient. The COVID-19 vaccines have shown us what RNA-based therapies could achieve. The direct reprogramming of cancer cells with RNA vectors, can become a reality for personalised medicine in cancer treatment. For this we need to show during the DART project that the cellular reprogramming of cancer cells mediated by RNA is sufficient to turn tumour cells into immunogenic cells and this leads to tumor remissions in vivo. The concept behind DART has very broad application.