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Today, we consider the brain an immune-privileged organ.German version/Deutsche Version
It is a tiny mutation in its gene that makes IDH1, which comprises about 400 amino acids, a cancer trigger. It causes the strongly basic arginine at position 132 to be replaced by a more weakly charged histidine. This change in polarity takes place in the small pocket, of all places, to which the substrate isocitrate is inserted in order to be converted into 2-oxoglutarate by oxidation and subsequent cleavage of carbon dioxide. As a result, mutant IDH1 enzymes produce 2-hydroxyglutarate (2-HG) instead. Even this seems to be only a small difference of one hydrogen atom more or less. But it has huge consequences: 2-HG disturbs the balance and speed at which genes of DNA are unwound and read by causing the attachment of excessive methyl groups to their chromatin packaging. This, in turn, mistakenly activates oncogenes and inactivates tumor suppressor genes. Thus, 2-HG is an oncometabolite that causes healthy glial cells to become cancer cells.
The mystery of the missing T cells
Characteristic fragments of proteins that are foreign to the body or altered are presented by cancer cells as a neoepitope on their surface. This enables the immune system to recognize and eliminate them. Often, however, it is only effectively directed to them by a vaccination. Based on this consideration, Michael Platten’s group synthesized a number of such peptide fragments of IDH1 that contained the mutated arginine position and selected a suitable candidate from these as a vaccine. By injecting this peptide in mice, the group succeeded in mobilizing the immune defense against it and thus stopping the progression of IDH1-mutated gliomas. Lukas Bunse co-developed this vaccine.[1] Since its preclinical success, he has been instrumental in the clinical trials of this vaccine as head of the translational companion program. At the same time, a problem that he had encountered during vaccine development as part of his medical doctoral thesis was not letting him go. He had investigated how strongly the immune system of unvaccinated glioma patients reacts with spontaneous T-cell attacks to the discovery of the IDH neoepitope. He noticed that there were far fewer T cells in the tumor tissues of most of these patients than had been expected. “The neoepitopes on the cancer cells should have led to a local proliferation of T cells in the vicinity of the tumor,” Bunse says. “However, this was by no means the case. There was obviously something about the mutant tumor cells that was not good for the T cells.” This hypothesis led Bunse to immediately follow up his medical doctoral thesis with a scientific one in the MD/PhD program at Heidelberg University. In it, he discovered a previously unknown role for the oncometabolite 2-HG in cancer.[2]
How gliomas paralyze immune cells
In tumor extracts from patients with IDH1-mutated gliomas, Lukas Bunse found traces of 2-HG. Apparently, the tumor cells had exported a certain amount of the metabolite they produce, because an excessively high intracellular concentration of it would potentially harm them themselves and reduce their fitness. These exported molecules encounter T cells in the immediate vicinity of the cancer cells, i.e., in the middle of the tumor tissue, which have swarmed in to curb tumor growth. Some of these molecules are taken up by the T cells and interfere with their metabolism. This is because 2-HG is able to trigger a signaling cascade that inhibits the T-cell-specific transcription factor NFAT. As a result, the affected T cells can no longer read genes that they need for their function and proliferation. They are paralyzed. So, with the help of the 2-HG that gives rise to them, the glioma cells simultaneously create an environment that accelerates their growth, because this largely removes them from the control of the immune system. This reads so easily: But methodologically, Bunse had to overcome numerous challenges to prove this tumor cell-extrinsic role of the oncometabolite 2-HG, which cost him a total of six years. For good reason was his PhD dissertation with the title Phenotype and modulation of T cell responses in isocitrate dehydrogenase 1 mutant gliomas awarded summa cum laude.
Phase I study with encouraging result
While the larger part of this work was dedicated to elucidating the extracellular effect of 2-HG, Bunse analyzed in the other part the immune response of glioma patients who had participated in the first phase I trial of the IDH1 vaccine. Overall, this review of the vaccine turned out very well in terms of its tolerability and immunogenicity. Serious adverse events were not observed in any of the 20 men and 12 women who were administered the vaccine, typically eight times, after most had had all or part of their tumor surgically resected and standard therapy of radiation and/or chemotherapy. Specific immune responses to the peptide vaccine were detected in 93 percent of the patients. Three years after receiving the eighth vaccine shot, 82 percent of patients who had shown such an immune response were still alive, without their tumor having progressed during this period.[3] Evidence is now strengthening that progression-free survival in many vaccinated patients lasts much longer. “The data are so encouraging that we, as a team led by Michael Platten, have designed and started another Phase I study,” says Lukas Bunse. This will test the combined administration of the IDH1 vaccine with a checkpoint inhibitor, which stimulates the immune system by releasing its brakes, in patients throughout Germany whose glioma has recurred after resection and standard treatment.
Translation as a two-way street
After earning his second doctorate, Bunse took over as head of the Cell Therapy Research Group at DKFZ’s Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology in 2019, but at the same time started his training as a neurology specialist at Mannheim University Hospital. There, he not only treats tumor patients. In addition to general neurology, his areas of operation also include the emergency outpatient clinic, the shock room, the stroke unit and the intensive care unit. “Of course, when you’re bound by the constraints of everyday clinical practice, it’s not easy to have a research team.” But he welcomes the challenge because he sees himself as a clinician scientist to whom translation is important in both directions, from bench to bedside and back again. With this self-conception, he and his team set out to develop what may become the world’s first T-cell receptor therapy for the treatment of glioblastomas. These are brain tumors in which IDH1 is not mutated but is present in the wild type. Unlike IDH-mutated gliomas, they usually only appear in middle age and have a significantly poorer prognosis.
T cell receptors as therapeutic keys
Glioblastoma cells produce excessive amounts of some proteins, which they present as tumor-associated antigens in fragments on their surface. If glioblastoma patients are now inoculated with these antigens, this provokes the production of T cells as an immune response, which are directed against glioblastoma cells. They do this by forming T cell receptors with which they clasp the presented antigens on the tumor cell surface in order to destroy them directly or indirectly. Once the genes of these T cell receptors have been decoded, they can be produced artificially. These genes, in turn, are used to modify and multiply T cells that have previously been taken from the patient. All extracorporeally modified T cells now carry genes for receptors that can recognize and switch off glioblastoma cells on the basis of their characteristic antigen. Using a suitable gene shuttle, these T cells are administered to the patient. Bunse uses episomal vectors for this, which were also developed at DKFZ and may be safer than the viral vectors used in CAR-T cell therapies because they do not integrate into the genome of the target cell. CAR-T cell therapies fuse T cells with chimeric receptors, in which two different components are fused together to enable them to recognize antigens such as CD19 in particular, which are predominantly found on B cells. Accordingly, they have so far been approved primarily for the treatment of some blood cancers involving B cells. T-cell receptor therapies have the advantage that antigens from inside the tumor cell can also be bound. None has been approved yet. His project was also still a few months away from fruition, says Lukas Bunse. “However, we have already made relatively good progress in preclinical development. The construct is working.” He says it was now first a matter of producing the T cells for glioblastoma-directed receptor therapy in accordance with the requirements of Good Manufacturing Practice so that they can be tested in a Phase I trial.
Research career and family happiness
Lukas Bunse is fortunate to be able to consult with his wife on matters concerning his research. The oldest of their three children will start school this fall. Still using her maiden name, Theresa Bunse was the co-author of the Nature publication in which Michael Platten’s team presented the preclinical results of the development of the IDH1 vaccine in 2014. As head of the Immunotherapy Brain Tumor Models Research Group at DKFZ, she is now trying to understand just as her husband the conditions that determine whether brain tumors respond to immunotherapies. While treatment with checkpoint inhibitors, for example, is now showing amazing success even with solid tumors such as lung cancer, it has hardly worked at all with brain tumors. “Just a few decades ago, it was thought that there were no immune defenses in the brain because inflammatory processes there could have catastrophic effects,” says Lukas Bunse. “Today, we consider the brain an immune-privileged organ whose immune responses are tightly controlled across the blood-brain barrier.” Yet this control fails in autoimmune diseases such as multiple sclerosis or the suppression of immune responses by tumor cells. Regaining control of this is one of his big goals. To help him achieve it, the Aventis Foundation is supporting him on his way to a permanent professorship with its Life Sciences Bridge Award.
Author: Joachim Pietzsch, Wissenswort
Photos: © Uwe Dettmar
[1] Schumacher T, Bunse L et al. A vaccine targeting mutant IDH1 induces antitumor immunity.
Nature 512(7514):324-7. (2014).
[2] Bunse L, Pusch S, Bunse T et al. Suppression of antitumor T cell immunity by the oncometabolite R-2- hydroxyglutarate. Nature Medicine 24, 1192-1203. (2018)
[3] Platten M, Bunse L et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma.
Nature 592(7854):463-468. (2021)