AI-assisted analysis helps discover new targets for CAR-T cell therapy for acute myeloid leukemia

14 Mar 2023

Some forms of blood cancer can be treated with an innovative immunotherapy. Now Munich-based researchers may have found specific targets for the treatment of AML.

Specialists for novel immunotherapies: Professor Sebastian Kobold (Mitte), Dr. Adrian Gottschlich und Ruth Grünmeier | © LMU Klinikum / S. Hartmann

One of several forms of leukemia (cancer of the blood), AML is a deadly disease. Five years after the initial diagnosis, only one-third of patients are still alive. Up to 85 percent of patients appear to be cured after intensive chemotherapy. In more than half of such cases, however, the disease returns within one to two years because the chemotherapy has not destroyed all leukemia cells. In the event of a relapse, a stem cell transplant is the only hope for curing the patient. But even then, the long-term probability of survival is less than 20 percent. New treatment options are therefore urgently needed.

Unlike other forms of blood cancer, acute myeloid leukemia (AML) cannot currently be treated with CAR-T cell immunotherapy. This is due to the lack of specific molecular targets by which certain immune cells could specifically target AML cells. Two research teams led by Professor Sebastian Kobold together with Dr. Adrian Gottschlich from the Division of Clinical Pharmacology at LMU’s University of Munich Hospital and Dr. Carsten Marr together with Moritz Thomas from the Institute of AI for Health at Helmholtz Munich have now succeeded in discovering such targets. Their results have been published in the journal Nature Biotechnology.

CAR-T cell therapy is an innovative approach. CAR-T stands for “chimeric antigen receptor in T cells.” T cells are a type of immune system cell. Using various molecular tricks, cancer cells evade the conventional attempts of T cells to attack them, such that T cells no longer recognize their enemies. During CAR-T cell therapy, T cells are removed from the patients and then genetically engineered to produce a specific protein (CAR) on their surface. When these CAR-T cells are injected back into the patient’s body, they engage only their target – CD19 – which ensures that they recognize the patient’s cancer cells and bind to them in a targeted manner, resulting in the death of the cancer cells.

Two candidates out of 25,000

However, the approved CAR-T cells against CD19 are not suitable for AML, because CD19 is not usually present on the surface of AML cells. Clinical results with CAR-T cells directed against other surface molecules of AML cells have been sobering so far, according to scientists. This is because CAR-T cells were unable to distinguish between healthy and degenerated cells – with significant side effects induced accordingly.

Physician Sebastian Kobold and physicist Carsten Marr, together with colleagues from LMU’s University of Munich Hospital and the Institute of AI for Health at Helmholtz Munich, set out to find alternative molecules that would ideally be found exclusively on the surface of AML cells. With the help of extensive bioinformatic analyses and the integration of expression data from more than half a million individual cells, two candidates finally crystallized out of 25,000 potential cell surface molecules. These molecules go by the name of CSF1R and CD86. “Such an analysis would not have been possible a few years ago, since the required single-cell data has been generated only very recently,” says Marr, who led the AI-assisted analysis part of the study at Helmholtz Munich.

The researchers produced CAR-T cells in the laboratory at University of Munich Hospital that precisely target these molecules. The cells were then tested on different AML models, including AML cells from patients. The results, according to Kobold, are promising: “Not only are these CAR-T cells effective against AML, they also destroy hardly any healthy cells.”

The study impressively demonstrates how synergy between interdisciplinary research groups can lead to breakthroughs in health research, which can pave the way for cutting-edge therapies. The researchers’ next goal is to develop GMP (good manufacturing practice) capable processes to produce CAR-T cells that can be used in clinical trials with AML patients. This is to take place within the framework of the Bavarian Cell Therapy Accelerator research alliance, which is supported by the Bavarian Research Foundation. Kobold expects the first tests with patients to take place in the next two to three years.

Gottschlich, A., Thomas, M., Grünmeier, R. et al. Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia. Nature Biotechnology, 2023

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