Cancer treatment: optimization of CAR T-cell therapy

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 to 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.

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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 cause 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 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.

Janina Dörr, Lisa Gregor et al.: Ablation of prostaglandin E2 signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours. Nature Biomedical Engineering 2026