Overcoming the Limits of Immunotherapies
Optimizing CAR-T Cells with CRISPR 2.0
As part of the German Research Foundation (DFG) Emmy Noether Program, Dr. Karl Petri is establishing a research group at the University Hospital Würzburg (UKW) to develop and enhance novel CRISPR 2.0 tools for generating and improving cancer-targeted CAR-T cell products.
Würzburg. CAR-T cells are highly effective in treating selected blood cancers. However, challenges remain with this new therapy, which was first approved in 2017 in the USA and a year later in Europe for treating acute lymphoblastic leukemia (ALL). For instance, no effective CAR-T cell therapies for solid tumors exist. Furthermore, CAR-T-induced remissions are not always durable, and the production of CAR-T cells is slow and laborious. Dr. Karl Petri of the University Hospital Würzburg (UKW) aims to address these issues using an advanced CRISPR method to increase the efficiency of cancer-directed immunotherapies. The German Research Foundation (DFG) supports his research project with nearly two million euros over the next six years under the Emmy Noether Program.
Prime-CAR Inspection Project in the Emmy Noether Program of the DFG
His project is called Prime-CAR Inspection. "Prime" stands for the CRISPR 2.0 method CRISPR Prime Editing, which allows for targeted and programmable incorporation of DNA changes into therapeutic T cells; "CAR" stands for chimeric antigen receptor, which equips the patient's own T cells to recognize and target specific surface molecules of cancer cells; "Inspection" refers to the safety validation of new gene-editing methods using advanced molecular diagnostics.
"While the conventional CRISPR-Cas9 method introduces a double-strand break into the DNA molecule, the CRISPR Prime Editing method requires only a single-strand break, allowing for more precise genome modifications," explains Karl Petri. All twelve possible base pair substitutions, as well as small insertions and deletions, can be precisely incorporated into the T cell genome using CRISPR Prime Editing.
Karl Petri states: "If CRISPR-Cas9 is described as DNA scissors that can selectively knock out gene functions, then Prime Editing is comparable to an eraser and pencil that can be used to rewrite DNA precisely."
In addition to optimizing gene-editing techniques, the Prime-CAR Inspection project also aims to standardize the safety validation of new gene-editing techniques to facilitate clinical translation and ultimately provide more effective CAR-T cell products for patients with multiple myeloma and other cancers.
Improving Cancer-Targeted CAR-T Cells with Safety-Validated CRISPR Prime Editors
"Currently, CAR-T cell therapy is approved for selected blood cancers. Our goal is to expand the application of CAR-T cell therapies and improve their effectiveness so that solid tumors can also be effectively treated with CAR-T cells. We also want to modify CAR-T cells to achieve longer and more durable remissions," says Karl Petri.
His research also focuses on allogeneic CAR-T cells, modified T cells from healthy donors. "With CRISPR 2.0 editing, certain molecules on CAR-T cells could be modified so that the immune system does not reject the foreign cells. This way, larger quantities of CAR-T cells can be produced more cost-effectively."
For CAR-T cell therapy, white blood cells are separated from the rest of the blood components through leukapheresis from the patients' blood. The cells are genetically modified in the laboratory and reintroduced to the patients as a living drug via a ten-minute infusion. A single "activated" T cell can destroy 1000 tumor cells. Ideally, the T cells remain in the body for life, eliminating hidden or newly emerged tumor cells.
University Medicine Würzburg Offers a Unique Research Environment
Karl Petri came to Würzburg in the summer of 2023 after a six-year research stay at Massachusetts General Hospital and Harvard Medical School in Boston. Under the mentorship of Prof. J. Keith Joung and Dr. Vikram Pattanayak, he focused intensively on new technologies like CRISPR 2.0 gene editing in the USA. Dr. Petri explains that Würzburg offers a unique research environment for realizing the Prime-CAR Inspection Program. Prof. Dr. Hermann Einsele, Director of the Medical Clinic and Polyclinic II at UKW pioneered CAR-T cell therapy for multiple myeloma, the second most common blood cancer after leukemia. Prof. Dr. Michael Hudecek, head of the Chair for Cellular Immunotherapy, established his own translational research program for CAR-T cells in Würzburg in 2012 and has been repeatedly recognized for his innovative methods. The campus also hosts the Helmholtz Institute for RNA-based Infection Research (HIRI), led by Prof. Jörg Vogel, offering synergy with its expertise in molecular biology methods. HIRI is also home to Prof. Chase Beisel, a pioneer of CRISPR research, enabling further synergies and collaborations. Further interactions, particularly in the editing of immune cells, arise with the neighboring Max Planck Research Group for System Immunology (WÜSI), an initiative of the Julius Maximilian University of Würzburg (JMU) and the Max Planck Society (MPG).
About the Emmy Noether Program:
The German Research Foundation's Emmy Noether Program is aimed at exceptionally qualified postdocs and junior professors in the early stages of their scientific careers. The program allows them to qualify for a university professorship by independently leading an Emmy Noether group over a period of six years.
Wissenschaftlicher Ansprechpartner:
Karl Petri, Petri_K@ukw.de
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