FRANKFURT. It is likely that cells in our bodies undergo malignant transformation somewhere in the body every day. In most cases, our immune system recognizes these cells and eliminates them. T cells play a central role in this process. They monitor the surface of all cells by scanning the protein fragments (peptides) displayed there. Unusual peptides indicate that something may be wrong with a cell, enabling the immune system to identify and destroy the malignant cell.

Cancer cells can evade this surveillance in various ways. Some send signals to T cells via so-called immune checkpoints that suppress their activity. This makes an effective immune response more difficult – even when the immune system would, in principle, be capable of recognizing the tumor.

For this reason, checkpoint inhibitors can be used in cancer treatment, including in liver cancer. These drugs block the inhibitory signals and thereby enhance immune responses. However, the immune system must first be able to recognize tumor cells effectively.

This is where ADVANCE comes in. The Spanish-Dutch-German consortium, which also includes Dr Andreas Schlosser from the Department of Dermatology, Venereology and Allergology at Universitätsmedizin Frankfurt, is searching for peptides that are specific to hepatocellular carcinoma (HCC), the most common form of liver cancer. As a potential application, the consortium is investigating the development of an mRNA-based cancer vaccine.

Cancer vaccines have been the subject of intensive research for many years. Unlike preventive vaccines against infectious diseases, cancer vaccines are designed to mobilize the immune system against tumor cells in patients who already have cancer. Within this context, ADVANCE is searching for tumor peptides that have so far received relatively little research attention and could be used in this type of therapeutic strategy.

The key question is: Which peptides identify a cancer cell without also being widely present in healthy tissue? This is where Schlosser and his team come in. The Frankfurt-based researcher explains: “In hepatocellular carcinoma, tumors differ considerably from one another. At the same time, only a limited number of peptides altered by mutations are available as suitable targets. That is why we are searching for additional peptides that are as tumor-specific as possible.”

The researchers are particularly interested in so-called ‘dark’ peptides, which become more prevalent in tumor cells under conditions of cellular stress. “We want to determine which of these dark peptides are presented on liver cancer cells and are largely absent from healthy tissue,” says Schlosser. To achieve this, his team combines mass spectrometry, RNA sequencing and computational methods, including artificial intelligence.

The discovery of previously unknown target structures for cancer immunotherapy is a new research focus at the Department of Dermatology in Frankfurt, headed by Prof. Bastian Schilling. His research group, “Tumor Antigen Discovery and Translational Immunotherapy,” is pursuing this approach not only in liver cancer but also in melanoma and other types of cancer.

If certain dark peptides prove sufficiently tumor-specific and suitable for triggering an immune response, ADVANCE aims to develop candidates for mRNA-based cancer vaccines from them. The mRNA contains the instructions for producing the dark peptides and is encapsulated in tiny lipid droplets (lipid nanoparticles) to protect it.

These lipid nanoparticles are then intended to be taken up by immune cells or other cells. Using the instructions encoded in the mRNA, these cells produce the peptides and subsequently display them on their surface. According to the project plan, the aim is to trigger a targeted T-cell response capable of recognizing and attacking liver cancer cells.

Project coordinator Dr. Puri Fortes from Cima Universidad de Navarra in Spain emphasizes: “Our goal is to demonstrate proof of concept for the efficacy of a first-in-class therapeutic RNA vaccine.” In the longer term, this approach could also prove relevant to other types of cancer. However, many further development and testing stages will be necessary before clinical application becomes a possibility.

ADVANCE was selected under the EIC Pathfinder Open scheme, a funding instrument of the European Union’s Horizon Europe Framework Programme. Through this scheme, the European Innovation Council (EIC) supports early-stage research approaches involving significant scientific and technological risks.

The ADVANCE Partners

Cima Universidad de Navarra, Spain (project management)
Certest Biotec, Spain
Princess Máxima Center for Pediatric Oncology, The Netherlands
Netherlands Cancer Institute, The Netherlands
Goethe University Frankfurt, Germany