The European Research Council (ERC) awards the project DART with an ERC Proof of Concept

The Pereira Lab secures its third ERC grant with the project DART – “Driving Tumor Antigen Presentation by RNA-mediated Transdifferentiation.” The awarded project aims to develop an effective approach to perform RNA-based reprogramming of tumor cells into dendritic cells. DART is built on clinical and industry collaborations: Cristiana Pires and Fábio Rosa from Asgard Therapeutics, Anders Wittrup from Lund University, and Inge Marie Svane from Herlev Hospital in Denmark.

Cancer immunotherapy has changed the framework of cancer treatment through strategies like immune checkpoint blockade (ICB) or adoptive cell therapies. However, effectively tackling refractory tumors remains a challenge, which hampers the broad use of immunotherapies. Tumor cells often develop mechanisms of immune evasion. Tumor immunogenicity depends on the presence of a particular type of dendritic cells – antigen-presenting type 1 conventional dendritic cells (cDC1s). Increasing the presence of these cells within tumors strongly correlates with better patient survival and response to treatment. We had previously identified a combination of three transcription factors (collectively called PIB) involved in the fate determination of cDC1s. Our group has successfully delivered the PIB factors to tumor tissue in viral vectors, hence directly reprogramming cancer cells into antigen-presenting cDC1-like cells. Reprogrammed tumor cells counteract immune evasion, thereby restoring tumor immunogenicity.

DART was inspired by the RNA technologies used to develop the novel COVID-19 vaccines and aims to develop RNA vectors for PIB delivery. Using RNA instead of viral vectors poses substantial advantages such as price and scalability. The strategy behind DART is to deliver PIB with different RNA moieties (linear modified RNA, circular RNA, or self-amplifying RNA) to induce PIB expression at various levels and persistence within the tumor cells. This project paves the way to a safe, cost-effective, and fully personalized cancer immunotherapy. By establishing RNA-mediated reprogramming as a stand-alone therapy, or a combination with ICB, this research can change the outcome of cancer immunotherapy.