ERC Starting Grant funds in vivo CAR-T cell therapy using lipid nanoparticles and genome editing
核心洞察
Dr. Karl Petri of University Hospital Würzburg (搜索) received a nearly €1.5 million ERC Starting Grant to develop CAR-T cells (搜索) generated directly inside the body.
The project combines lipid nanoparticle delivery with novel genome editing tools to integrate the CAR blueprint into a safe-harbor region of the T cell genome.
The approach aims to achieve long-lasting CAR expression while avoiding the uncontrolled genomic integration risks associated with viral vectors.
Dr. Karl Petri from the Chair of Cellular Immunotherapy and the Department of Medicine II at University Hospital Würzburg (搜索) (UKW) has been awarded a prestigious ERC Starting Grant from the European Research Council (搜索) (ERC), endowed with almost 1.5 million euros, to develop a technology for producing CAR-T cells (搜索) directly inside the body. The project addresses a central limitation of current cell therapy manufacturing: personalized CAR-T cell production in the laboratory is associated with considerable time and cost and is not always successful.
Since their first approval in 2017, CAR-T cells (搜索) have fundamentally changed the treatment of selected blood cancers, including certain forms of leukemia (搜索), lymphomas (搜索), and multiple myeloma (搜索), and in some patients they can achieve long-lasting remissions. However, the conventional process requires T cells to be obtained from the patient's blood, genetically modified in the laboratory to express chimeric antigen receptors (搜索) (CARs), and then transferred back into the body.
"Immune cell therapies have enormous potential, not only in cancer medicine. What is still lacking is a truly efficient and safe technology for producing such therapies directly inside the body. We aim to close this gap by combining different technologies," said Karl Petri.
Combining viral and non-viral approaches
To generate CAR-T cells (搜索) in vivo, a vector is required, which can be of viral origin or take the form of nanoparticles. Conventional laboratory production generally uses viral vectors, which introduce DNA containing the CAR gene into T cells. This DNA is permanently integrated into the T cells' genetic material, allowing long-term CAR protein production. However, it is not possible to fully control where in the genome viral vectors integrate. In in vivo CAR-T cell therapy, this risk may be increased, because viral vectors administered throughout the body could reach and genetically modify not only T cells but potentially other body cells as well.
An alternative delivery method is lipid nanoparticles, which can safely introduce mRNA—the blueprint for CARs—into T cells. The disadvantage is that this blueprint is very short-lived, meaning T cells express the CAR protein on their surface for only a few days before the RNA molecule is degraded and CAR production ceases.
"We now want to combine the best of both worlds: long-lasting CAR expression and a safe platform with targeted integration of the blueprint," said Karl Petri. "To achieve this, we are developing a lipid nanoparticle-based in vivo CAR-T cell therapy using novel genome editing tools. This will place the genetic information of the CAR into a so-called safe-harbor region of the T cell genome, where it can safely remain."
Safety and preclinical validation
It is already known that lipid nanoparticles are generally suitable for transfecting T cells in vivo, and Karl Petri has demonstrated that the new genome editing tools work in T cells. "Our preliminary data are very promising. The challenge now is to bring the components together and optimize the gene-editing tools so that the CAR blueprint reaches the T cells as efficiently, durably, and safely as possible," he said.
Safety is a central component of the project. The team will carefully investigate every individual step and assess whether the treatment is safe and well tolerated, using analysis methods they have developed themselves. "For example, we investigate where the nanoparticles are distributed in the body and precisely determine where the genetic information is integrated into the cells' genome," explained Petri.
Over the next five years, Petri and his team aim to collect the necessary basic research and safety data from studies in cell cultures and mice. These data are intended to form the basis for a Pre-IND (Pre-Investigational New Drug) meeting, which is intended to provide the basis for future clinical translation.
A strong research environment
The project draws on the strengths of the Würzburg research location. Prof. Hermann Einsele, Director of the Department of Medicine II, and Prof. Michael Hudecek, Director of the Chair of Cellular Immunotherapy, are two renowned CAR-T cell experts based in Würzburg. Prof. Jörg Vogel, Managing Director of the Helmholtz Institute for RNA-based Infection Research (HIRI), is a recognized specialist in ribonucleic acids (RNA). Structures such as the National Center for Tumor Diseases (NCT) WERA and the Bavarian Center for Cancer Research (BZKF) facilitate clinical translation.
"If our plan succeeds, we will have a very strong platform for the in vivo generation and modification of cell therapies," concluded Karl Petri.
The new project will also expand his research group, with plans to recruit two additional doctoral researchers and/or a postdoctoral researcher at the start of 2027, increasing the current team of six scientists and one physician to a total of nine members. Part of the research group is already supported by funding from the German Research Foundation (DFG) through the Emmy Noether Programme, where the team is developing novel CRISPR 2.0 tools to produce and further improve targeted CAR-T cell products for cancer treatment.