What already works against leukemia should soon also help against other tumors
Genetically modified immune cells are a powerful weapon against leukemias and lymphomas. The Cell Therapy Research Cluster at University Hospital Frankfurt is looking for ways to hunt down other tumors with the help of the body’s own immune defenses. To this end, scientists in Frankfurt are examining how malignant cells proliferate in order to create an environment around themselves that neutralizes the immune system and in so doing torpedoes cell therapeutics.
To kill malignant cells, you can bombard them with lethal radiation or torment them with toxins. If the tumor is localized, you can also try to remove it surgically. Or else you can use a weapon that has been optimized over millions of years to avert danger from the organism: the immune system.
The body’s own defense shield is not only there to fight viruses or bacteria. It also constantly weeds out cells that are not working according to plan and could become dangerous for us – for example by starting to divide uncontrollably. However, this protection is not completely foolproof: Every now and then, degenerated cells manage to escape the immune system’s watchful eye.
One reason for this is that immune cells have been trained, figuratively speaking, to be cautious: “They are strictly calibrated not to act against the body’s own structures,” says Professor Thomas Oellerich, Director of the Department of Hematology and Oncology at University Hospital Frankfurt, “because otherwise they could cause enormous damage to the organism, which is why they generally only attack what they have identified as foreign.”
Immune cells are “programmed” against cancer
The problem, however, is that the only difference between cancer and healthy tissue is usually just a few changes in the genome, and it is precisely this which makes it difficult to detect. Nevertheless, experts today consider the immune system to be one of the most promising approaches in the fight against tumor diseases because it is meanwhile possible to program the body’s own defenses specifically against certain characteristics of cancer cells.
Immune cells have special receptors that they use to track down their opponents. They consist of a kind of antenna located on the cell’s surface and something like a signal processor inside it. If the antenna detects certain characteristics on the surface of another cell – for example such as ones indicating a viral infection – it sounds the alarm. It notifies the signal processor inside the cell, which then puts the immune cell into combat mode so that it destroys its opponent.
“It is meanwhile possible to genetically manipulate these receptors,” explains Oellerich. “The antenna is modified in such a way that it responds to the surface molecules of cancer cells and then activates the immune cell via the signal processor.” The medical term for this is chimeric antigen receptors (CAR). With their help, it is possible to cure life-threatening diseases, an example being acute lymphoblastic leukemia (ALL), a form of blood cancer that mostly occurs in childhood. In 2012, Emily Whitehead, a seven-year-old child in the USA, was the first ALL patient to be treated with CAR immunotherapy. In this disease, normal B-cells that belong to our immune system transform into malignant cells.
Cure for life-threatening leukemia
B cells and their precursors carry a protein called CD19 on their surface. The doctors collected immune cells from Emily’s blood that are capable of killing other cells: cytotoxic T cells. They armed these with a receptor whose antennae responded specifically to the CD19 protein. “These CAR T cells then destroyed all B cells and their CD19-positive precursors, including the leukemia cells,” explains Oellerich. “This successfully eradicated the cancer.” Meanwhile, CAR modification of other immune cells, the natural killer cells, is also being clinically tested. This will hopefully lead to further progress in cell therapy.
Today, Emily Whitehead is considered cured. CAR T cells have also significantly improved the chances of a cure for other cancers of the hematopoietic system, the lymphomas. In 2013, the prestigious journal Science even deemed immunotherapy against cancer the “Breakthrough of the Year”. The treatment is, however, not without risk: Initially, some patients experienced life-threatening overactivation of the immune system or severe inflammatory reactions in the brain.
Nevertheless, the Cell Therapy Research Cluster at University Hospital Frankfurt is placing great hopes in the new form of treatment. “For certain types of lymphoid malignancies that do not respond to other therapies, it is now the method of choice,” says Oellerich. “We use it to treat around 60 patients a year at University Hospital Frankfurt. Thanks to close monitoring of patients and advances in the clinical management of CAR technology, we also have better control of side effects today than when this new type of therapy was first introduced.”
Unsuccessful in solid tumors
So far, unfortunately, this approach can only be used against a few types of cancer. It has not yet found application in the treatment of brain, pancreatic or lung cancer. There are several reasons for this: On the one hand, it is very difficult to identify a suitable surface structure that is present on tumor cells but not on healthy ones. This means that for many cancers scientists simply do not know against which characteristics they should program the immune system’s antennae.
There is another factor: Solid tumors are often so compact that this alone makes it difficult for immune cells to penetrate them. They additionally have sophisticated defensive strategies: “Tumors implement a variety of measures to literally neutralize the body’s own defenses,” says Oellerich. “They create a microenvironment for themselves that suppresses the immune system.” This includes, among other things, oxygen depletion in the tumor tissue – which is fatal for the immune system’s troops. They also produce substances that systematically cripple the immune cells. These characteristics make it difficult to use CAR immune cells as a therapy against solid tumors.
Hessian consortium aims to advance CAR cell research
Professor Oellerich is nevertheless optimistic that these difficulties can be overcome. Together with colleagues from the universities of Frankfurt and Marburg, Georg Speyer Haus, the German Red Cross Blood Donor Service Baden-Württemberg-Hessen and the Paul Ehrlich Institute, he has recently been able to raise funds for a major project within Hesse’s LOEWE program, which supports outstanding research. CARISMa, the LOEWE research cluster funded by the program, aims to network cell therapy research in oncology at the partner sites. The main goal is to improve treatment options for various oncological diseases with CAR immune cells.
As the spokesperson for the CARISMa consortium, Oellerich believes there is a good chance of achieving this goal in the coming years – not least because the proposed consortium bundles a broad range of expertise. For example, the scientists at Georg Speyer Haus led by Professor Florian Greten have been working on the tumor microenvironment for years. “Their work has made a substantial contribution to our understanding of how cancer suppresses the immune system,” says Oellerich (see page 29: “Bad neighbors”). Moreover, the Institute of Neurooncology, University Hospital Frankfurt, in close collaboration with the German Red Cross Blood Donor Service Baden-Württemberg-Hessen and Georg Speyer Haus, is currently conducting the first study with CAR-modified natural killer cells for the treatment of brain tumors.
Oncological research at the University of Marburg centers, among other things, on tumor diseases that are difficult to treat, such as pancreatic cancer. The two Hessian universities also complement each other in terms of their scientific methods and the aspects of tumor development they are investigating. “We expect this complementarity to boost innovation,” says Oellerich. “At the same time, we hope that our collaboration will lead to important synergies. In addition to complementary technologies and expertise, we will be able to include larger numbers of patients in cross-site clinical trials and in this way arrive faster at more conclusive results.”
CAR cells made in Hessen
The CARISMa consortium is also in a good position to at least partially mitigate another pressing problem: Immunotherapies with CAR-T cells or CAR-NK cells (NK = Natural Killer) are currently extremely expensive. Although a single infusion is often sufficient to treat a patient, manufacturers currently demand between €200,000 and €400,000 for it. “We hope to be able to program immune cells ourselves in the future and use them for clinical purposes, which would lead to considerable cost savings,” explains Oellerich.
That is why one of the partners in the CARISMa consortium is the German Red Cross Blood Donor Service Baden-Württemberg-Hessen. Under the leadership of Professor Torsten Tonn and Professor Halvard Bönig, it has both the technology and the know-how to produce blood products (including CAR immune cells) for therapeutic purposes. Rather than donor plasma or whole blood, perhaps some of the infusion bags in the future will contain CAR cells made in Hessen.
Zur Person / Thomas Oellerich, born in 1983, has been working as a physician and researcher at Goethe University Frankfurt since 2011. He has been Director of the Department of Hematology and Oncology at University Hospital Frankfurt since 2023. He is also the founding spokesperson for the Profile Area “Molecular and Translational Medicine” at Goethe University Frankfurt. Oellerich studied medicine at the University of Göttingen and the Royal Infirmary of Edinburgh (Scotland) and earned his doctoral degree in Göttingen in 2012. He then worked at the University of Cambridge (England) and the National Cancer Institute (NCI, an NIH institute in the USA). He has received various prizes for his research achievements, including the Langen Science Award and the Artur Pappenheim Prize.
oellerich@em.uni-frankfurt.de
Der Autor / Frank Luerweg,, born in 1969, graduated in biology. He was Deputy Press Spokesperson at the University of Bonn and has been working as a freelance science journalist for 13 years.
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