Attack of the killer cells
From the very beginning of his career, Andreas Mackensen has focused on how to manipulate the immune system to make it attack cancer cells. He is now also using genetically engineered immune cells to fight autoimmune diseases.
Andreas Mackensen doesn’t really believe in miracles. At least he didn’t until 2021, when together with Georg Schett, Director of Department of Medicine 3, he was the first to use CAR-T cells to treat a patient with the autoimmune disease lupus erythematosus. In mouse models, the treatment had already appeared to be successful in regulating the hyperactive immune system. “At the beginning, I was skeptical, and later overwhelmed: All disease parameters disappeared, the young woman has now been disease-free for three and a half years,” says Mackensen. “It really is a miracle.”
The Director of Department of Medicine 5 – Hematology and Oncology carries out research into chimeric antigen receptors, or CAR-T cells for short. They are already used as a standard treatment option for relapses of certain types of cancer of the blood or lymphatic system. T-cells are taken from the patient’s own body and genetically engineered to recognize features found on the surface of cancer cells known as antigens and eliminate the cancer cells.
Now that this cell treatment has also proven so successful for severe autoimmune diseases, the immunologists Mackensen and Schett and their team are being inundated with requests. A few months ago, a 15 year old girl with lupus was successfully treated with CAR-T cells. Mackensen: “The ultimate goal of my research has always been to develop treatments that benefit patients.” From an early stage, he spoke out in favor of producing CAR-T cells directly at Uniklinikum Erlangen. In 2019, Mackensen and his team had their application approved for the first time by the government of Upper Franconia. Since then, Erlangen is one of the few academic centers in Europe permitted to produce CAR-T cells for clinical applications.
Focus on cancer research
Of course, the researcher is still continuing his research on CAR-T cells for treating cancer, particularly in the area of solid tumors. These are malignant masses of tissue that can originate in any organ and form metastases anywhere in the body. “The challenge here is finding an antigen that is exclusively located on the cancer cells,” explains Mackensen. “In addition, solid tumors can encapsulate themselves and try to avoid detection from the immune system.” A study funded by the Federal Ministry of Research is currently underway in collaboration with working groups in Münster, Regensburg and Hannover focused on CAR-T cells aimed at targeting tumors predominantly occurring in childhood – sarcomas and neuroblastomas – as well as breast cancer.
The CAR-T cells recognize the antigen GD2 on these tumor cells, and can confidently home in on their target. The researchers have also incorporated a booster by ensuring that the CAR-T cells produce the hormone interleukin 18. “When the CAR-T cells attach to the tumor cells, they are already quite exhausted,” Mackensen explains. This is when the hormone is released. It stimulates the CAR-T cells. They get the push they need to attack the tumor cells.”
Rocky path towards CAR-T cell production
Erlangen is one of the few academic centers permitted to produce CAR-T cells in Europe. It took nearly five years until the authorities responsible, the government of Upper Franconia, granted permission in 2019. Andreas Mackensen and his team supporting the head of production PD Dr. Michael Aigner had to meet numerous bureaucratic requirements and set up a laboratory classed as security level S2 with clean rooms before they were permitted to conduct work involving genetic engineering. In addition, qualified staff are required, with approximately a dozen people working in the laboratory. The cells are produced in a closed system (prodigy system), a type of bioreactor, developed by the company Miltenyi Biotec®. All clinical studies with CAR-T cells require the permission of the department at the Paul-Ehrlich-Institut responsible for cellular therapies.
Stem cell transplants for leukemia
As speaker for Erlangen for the collaborative research center (CRC) transregio 221, Andreas Mackensen is also conducting research into making allogeneic stem cell transplantation, the only hope for a cure for certain types of leukemia, safer and more successful. After being treated with chemotherapy or radiation therapy targeting the leukemia but also intended to prepare the patient’s immune system for the transplant, patients receive stem cells from a healthy donor. “This is also a type of cellular immunotherapy in which the donor’s immune cells have a decisive role to play,” explains Mackensen. “In order to cure the disease, the tissue from the donor and the recipient must differ in their characteristics to a certain extent. Scientists discovered that this was the case after realizing that bone marrow transplants between identical twins led to the highest relapse rate for leukemia.”
The immune cells from the donor recognize leukemia cells as being foreign and eliminate them. This is known as the graft-versus-leukemia (GvL) effect. On the other side of the coin, however, the donor’s immune cells may also attack healthy tissue, with this being known as graft-versus-host disease or GvHD for short. The CRC hopes to specifically boost the GvL reaction and at the same time control GvHD better using new therapeutic approaches. This is another area where CAR-T cells come into play. In a bid to improve the GvL effect, donor lymphocytes are fitted with a CAR, a chimeric antigen receptor, that allows them to fight leukemia in a more targeted way.
Author: Simone Harland
This article is part of the FAU magazine
Innovation, diversity and passion: Those are the three guiding principles of our FAU, as stated in our mission statement. At FAU, we live these guiding principles every day in all that we do – in research, in teaching and when it comes to sharing the knowledge created at our university with society.
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