Researchers at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité – Universitätsmedizin Berlin, Campus Berlin-Buch, have succeeded in generating cells of the immune system to specifically target and destroy cancer cells.
The research findings of Matthias Obenaus, Professor Thomas Blankenstein (MDC and Charité), Dr. Matthias Leisegang (MDC) and Professor Wolfgang Uckert (Humboldt-Universität zu Berlin and MDC) as well as Professor Dolores Schendel (Medigene AG, Planegg/Martinsried) have now been published in Nature Biotechnology online (doi:10.1038/nbt.3147)*.
This mouse possesses “high-affinity” components of the human immune system to fight cancer. (Photo and Copyright: SFB-TR 36)
The immune system of the body is trained to distinguish between “foreign” and “self” and to recognize and destroy exogenous structures. In cancer, however, the immune system appears to be quite docile in its response.
While it is capable of detecting cancer cells because they often bear characteristics (antigens) on their surfaces that identify them as pathologically altered cells, usually the immune system does not mount an attack but rather tolerates them. The reason: The cancer cells are endogenous to the body, and immune cells do not recognize them as foreign, as they would pathogens. The researchers want to break this tolerance in order to develop therapies against cancer.
T cells are the linchpin in the attack of the immune system. On their surface they have anchor molecules (receptors) with which they recognize foreign structures, the antigens of bacteria or viruses, and thus can target and destroy invaders. Cancer researchers and immunologists are attempting to mobilize this property of the T cells in the fight against cancer. The objective is to develop T cells that specifically recognize and attack only cancer cells but spare other body cells.
Now Matthias Obenaus, Professor Blankenstein, Dr. Leisegang, Professor Uckert and Professor Schendel have developed human T cell receptors (TCRs) that have no tolerance toward human cancer antigens and specifically recognize the antigen MAGE-A1, which is present on various human tumor cells. Instead of directly using human-derived TCRs, which do not mediate substantial anti-tumor effects, the scientists took a “detour” over a mouse model.
First, the researchers transferred the genetic information for human TCRs into the mice, thus creating an entire arsenal of human TCRs (Nature Medicine, doi: 10.1038/nm.2197). When the humanized mouse T cells come into contact with human cancer cells, they perceive the tumor antigens as foreign – like viral or bacterial antigens. Thus, the T cells can specifically target, attack and destroy the tumor cells.
The researchers subsequently isolated the human T-cell receptors of these mice, which are specifically targeted toward the tumor antigen MAGE-A1. Then they transferred the T-cell receptors into human T cells, thereby training them to recognize the cancer cells as foreign.
Some people possess T cells which naturally recognize MAGE-A1 on tumor cells, but only in the Petri dish. In studies using an animal model, only the human TCRs derived from mice were shown to be effective against the tumor. The TCRs from human T cells ignored the tumor completely.
The comparison with the tweaked human TCRs from the mouse model shows that the TCRs of patients cannot recognize the tumor antigens sufficiently; they are too weak. “The fact that our TCRs from the mouse are better is a strong indication that the T cells of a human are tolerant toward MAGE-A1,” said Matthias Obenaus and Professor Blankenstein.
Using the T-cell receptors they developed, the researchers are planning an initial clinical trial with patients with MAGE-A1 positive multiple myeloma, a malignant disease of the bone marrow.
*Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice
Matthias Obenaus1, Catarina Leitão1,7, Matthias Leisegang1, Xiaojing Chen1, Ioannis Gavvovidis1 Pierre van der Bruggen2,3, Wolfgang Uckert1,4, Dolores J Schendel5 & Thomas Blankenstein1,6
1Max Delbrück Center for Molecular Medicine, Berlin, Germany. 2Ludwig Institute for Cancer Research, Brussels, Belgium. 3De Duve Institute, Université Catholique de Louvain, Brussels, Belgium. 4Institute of Biology, Humboldt University, Berlin, Germany. 5Medigene AG, Planegg/Martinsried, Germany. 6Institute of Immunology, Charité Campus Buch, Berlin, Germany. 7Present address: Institute for Molecular and Cell Biology, Porto, Portugal.
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
13125 Berlin, Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
Barbara Bachtler | Max-Delbrück-Centrum für Molekulare Medizin (MDC) Berlin-Buch
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
CWRU researchers find a chemical solution to shrink digital data storage
22.06.2017 | Case Western Reserve University
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
Germany counts high-precision manufacturing processes among its advantages as a location. It’s not just the aerospace and automotive industries that require almost waste-free, high-precision manufacturing to provide an efficient way of testing the shape and orientation tolerances of products. Since current inline measurement technology not yet provides the required accuracy, the Fraunhofer Institute for Laser Technology ILT is collaborating with four renowned industry partners in the INSPIRE project to develop inline sensors with a new accuracy class. Funded by the German Federal Ministry of Education and Research (BMBF), the project is scheduled to run until the end of 2019.
New Manufacturing Technologies for New Products
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
22.06.2017 | Life Sciences
22.06.2017 | Materials Sciences
22.06.2017 | Materials Sciences