LMU physician Sebastian Kobold
Photo Credit: © LMU / Stephan Höck
Scientific Frontline: Extended "At a Glance" Summary
The Core Concept: An advanced form of immunotherapy in which Chimeric Antigen Receptor (CAR) T cells are genetically engineered to resist immunosuppressive signals found within solid tumors, enabling the immune system to effectively destroy cancer cells that were previously resistant to treatment.
Key Distinction/Mechanism: While standard CAR T-cell therapy is highly effective against blood cancers, it often fails against solid tumors because a metabolite called prostaglandin E2 (PGE2) suppresses the T cells' function. This new approach involves removing the specific receptors on the T cells that PGE2 binds to; by eliminating these binding sites, the T cells become "deaf" to the tumor's suppression signal and remain active to attack the malignancy.
Origin/History:
- 2024: Professor Sebastian Kobold’s research group at LMU University Hospital identifies that PGE2 blocks T cells in the tumor vicinity.
- 2026: The team, in cooperation with the University of Tübingen, publishes their success in engineering PGE2-resistant cells in Nature Biomedical Engineering.
Major Frameworks/Components:
- Chimeric Antigen Receptor (CAR) T Cells: Patient-derived immune cells modified to recognize specific cancer proteins (like CD19).
- Prostaglandin E2 (PGE2): An immunosuppressive metabolite in the tumor microenvironment that normally inhibits immune response.
- Receptor Knockout: The genetic removal of PGE2 receptors from T cells to prevent immunosuppression.
Branch of Science: Immunopharmacology, Oncology, Biomedical Engineering, Clinical Pharmacology.
Future Application: Immediate application involves clinical studies for lymphoma patients who do not respond to standard therapy, followed by potential trials for solid tumors such as pancreatic, bowel, and breast cancer.
Why It Matters: This development addresses the primary limitation of current CAR T-cell therapies—their ineffectiveness against solid tumors. By overcoming the tumor's defensive immunosuppression, this optimization could significantly expand the range of treatable cancers, offering new hope for patients with aggressive solid tumors like pancreatic and lung cancer.
In 2024, Professor Sebastian Kobold’s research group at LMU University Hospital had already shown that the metabolite prostaglandin E2 can block T cells – the killer cells of the immune system – in the vicinity of a tumor, such that they do not attack cancer cells. This is one of the reasons why therapeutic CAR T cells have lacked success against solid tumors such as bowel or pancreatic cancer.
Now, Kobold’s immunopharmacology team at the Institute of Clinical Pharmacology has turned this discovery into potential practical use, in close cooperation with Professor Jan Böttcher at the University of Tübingen. The researchers modified CAR T cells such that the prostaglandin E2 can no longer bind to them. This allows CAR T cells to destroy solid tumor sites. The new study was recently published in the journal Nature Biomedical Engineering.
Using CAR T cells to direct the immune system of a cancer patient against tumor cells, and thus combat the life-threatening disease, often works very well in patients with certain leukemias (blood cancer) and lymphomas (lymph node cancer). That is to say, the cancer disappears or at least does not further progress and causes the patient to die.
CAR-T stands for chimeric antigen receptor modified T cell. Cancer cells employ various molecular tricks to elude the ‘normal’ lines of attack of these immune system cells. As a result, the immune cells do not recognize their enemies, the cancer cells, anymore. In modern therapies, T cells can be taken from patients and genetically engineered to produce a certain protein (CD19) on their surface. When these modified CAR T cells are reintroduced into the body, CD19 ensures that the CAR T cells recognize the cancer cells and bind to them with precision. This causes the cancer cells to die.
Unfortunately, solid tumors like bowel, pancreatic, prostate, and lung cancer have developed mechanisms for rendering CAR T cells ineffective. “However, we are gaining a better understanding of the underlying molecular mechanisms all the time,” says Kobold. His team has demonstrated, for example, that prostaglandin E2 (PGE2) in the microenvironment suppresses the function of T cells by binding to special receptors on the surface of T cells.
Now the Munich-based researchers and their colleagues have genetically engineered therapeutic CAR T cells that are no longer able to produce these special receptors. As a consequence, PGE2 can no longer bind to the CAR T cells and have its immunosuppressive effect. This was demonstrated with models of breast or pancreatic cancer, where the CAR T cells kept the tumors in check. Moreover, these CAR T cells proved to be highly effective in tumor samples from human patients with pancreatic or bowel cancer or neuroendocrine tumors.
“Soon it will be possible to test our approach in clinical studies,” says Janina Dörr, lead author of the study. Initially, this will not involve people with solid tumors, but with lymphomas. Barely half of lymphoma patients have been able to benefit from CAR T therapy to date. “According to our findings, there is a good chance that therapy with silenced PGE2 will be considerably more successful,” explains Kobold. Should this prove to be the case, a study on patients with solid tumors could follow if suitable funding is found.
Published in journal: Nature Biomedical Engineering
Authors: Janina Dörr, Lisa Gregor, Sebastian B. Lacher, Arman Oner, Yi Sun, Ignazio Piseddu, Luisa Fertig, Sebastijan Spajic, Stefanie Lesch, Stefanos Michaelides, Matthias Seifert, Adrian Gottschlich, Natasha Samson, Lina Majed, Daria Briukhovetska, Donjetë Simnica, Viktoria Hartmann, Kathrin Gabriel, Sonia Cohen, Genevieve M. Boland, David Andreu-Sanz, Emanuele Carlini, Sophia Stock, Anne Holtermann, Philipp Jie Müller, Thaddäus Strzalkowski, Marcel P. Trefny, Stefan Endres, Russell W. Jenkins, Jan P. Böttcher, and Sebastian Kobold
Source/Credit: Ludwig-Maximilians-Universität München
Reference Number: ongy021426_01
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