German Cancer Research Center

Tumor vaccines can help the body fight cancer. These vaccines alert the patient's immune system to proteins that are carrying cancer-typical alterations. Physicians and cancer researchers have now treated adult patients with advanced midline gliomas, difficult-to-treat brain tumors, with a peptide vaccine for the first time. The vaccine mimicked a mutational change in a histone protein typical of this type of cancer. The vaccine proved to be safe and induced the desired immune responses directed against the brain tumor. Tumor vaccines can help the body fight cancer. These vaccines alert the patient's immune system to proteins that are carrying cancer-typical alterations. Physicians and cancer researchers from Heidelberg and Mannheim have now treated adult patients with advanced midline gliomas, difficult-to-treat brain tumors, with a peptide vaccine for the first time. The vaccine mimicked a mutational change in a histone protein typical of this type of cancer. The vaccine proved to be safe and induced the desired immune responses directed against the brain tumor. Crucial for the success of cancer vaccinations are protein structures by which the immune cells can recognize the cancer -- and which are not present (or only to a small extent) on healthy cells. Mutations in the tumor genome often lead to protein structures that are altered in a way typical of cancer. Diffuse midline gliomas are among the most aggressive brain tumors. They usually occur in children and young adults near the brain stem and are therefore difficult to access surgically. Chemotherapy or radiation therapy also have limited effectiveness. In this type of cancer, mutations characteristically occur in the gene encoding histone H3 (H3K27M), a packaging protein of DNA. The mutation gives rise to a novel protein structure -- a so-called neoepitope -- that can be recognized as foreign by the patient's immune system. "Such mutations, which occur in identical form in many patients, are rare in cancer. They literally lend themselves to the development of tumor vaccines because they occur in all cancer cells, since the mutated histone is causative for the development of midline gliomas. This means that vaccination against the mutated protein gets to the root of the problem," explains Michael Platten, Director of the Department of Neurology at the University Medical Center Mannheim and Head of Department at the German Cancer Research Center (DKFZ). The researchers led by Katharina Sahm and Michael Platten synthetically reconstructed the section of the histone H3 protein with the characteristic mutation. Using this peptide, they were able to curb the growth of H3K27M-mutated tumors in a mouse model. Encouraged by the results, the team decided to test the mutation-specific vaccine produced at the University of Tübingen in patients in a phase I-trial*, which is still ongoing. In parallel, the physicians, together with colleagues from Munich, Berlin, Bonn and Münster, treated eight adult patients with the peptide vaccine in time-limited individual curative trials. These patients, who could not be enrolled in the trial protocol, suffered from diffuse midline gliomas with H3K27M mutation that progressed after standard therapy. Some of the affected individuals received therapy with immune checkpoint inhibitors in addition to tumor vaccination. No serious side effects were observed in any of the vaccinated patients. Five of the eight treated patients developed specific immune responses against the mutant protein, which were dominated by CD4 T-helper cells. In one of the patients who had shown a strong immune response, the tumor regressed completely and she remained tumor-free for 31 months. The vaccine peptide, which is comparatively long at 27 amino acids, worked in patients with different HLA variants. HLA proteins are responsible for the presentation of the mutant peptide on the cell surface and differ from person to person depending on their genetic background. Supported by the HI-TRON Mainz -- Helmholtz Institute of the DKFZ, the researchers also observed that immune responses decreased over time, so repeated administration of the vaccine could support a sustained effect. "We cannot make any further statements about the efficacy of the vaccination based on these treatments. In any case, the current study has given us valuable information that will help us to further optimize the development of brain tumor vaccines in the future," explains the study's senior author Katharina Sahm, senior physician at the Neurological University Hospital Mannheim and DKFZ researcher. A phase I-trial is currently underway to test the vaccine against the H3K27M mutation in patients with newly diagnosed midline gliomas. Evaluation is expected to begin around 2025. The project was funded by the Translational Oncology funding program of German Cancer Aid (Deutsche Krebshilfe). * INTERCEPT-H3 trial:

Scientists identify a new and surprising function of a membrane protein on the surface of cancer cells: It supports and stabilizes an important 'co-stimulatory' factor that enhances the activation of T cells, thus improving the immune response against the tumor. Scientists from the German Cancer Research Center (DKFZ) identify a new and surprising function of a membrane protein on the surface of cancer cells: It supports and stabilizes an important "co-stimulatory" factor that enhances the activation of T cells, thus improving the immune response against the tumor. The study was conducted in collaboration with researchers from the Netherlands Cancer Institute. Many types of cancer can be successfully treated with immune checkpoint inhibitors (ICI). This treatment is often simply referred to as "immunotherapy." The blockade of inhibitory immune checkpoint proteins such as PD-L1 forms the basis of this treatment. But a concomitant lack of stimulatory signaling can render the therapies useless. This is considered one of the reasons why many cancer patients do not benefit from immune checkpoint inhibitors. T cells are the key players in the immune defense against tumors. Their activation is tightly controlled by a variety of inhibitory and also stimulatory immune checkpoints. However, tumor cells often sabotage this system by manipulating the expression of checkpoint proteins to escape destruction by the immune system. Among the activity-promoting co-stimulatory proteins is CD58. When it binds to its receptor on an immune cell, the cell receives a stimulatory signal. If the binding of CD58 to its receptor is blocked, the immune response against many cancers is impaired. "It is intriguing to observe that many cancer cells inherently express CD58, a molecule that essentially contradicts their own survival when they come under immune attack. We therefore wanted to understand what controls the expression of CD58," says Chong Sun, an immunologist at the German Cancer Research Center. With their current study, the researchers found that the membrane protein CMTM6 interacts and positively regulates the expression of CD58. The surprising thing is that CMTM6 simultaneously interacts with PD-L1, the important inhibitory immune checkpoint molecule that most current ICI therapies target. CMTM6 protects PD-L1 from degradation and likewise also stabilizes CD58 via this mechanism. This mechanism potentially fine-tunes immune response. Moreover, using a model of TCR-T cell treatment in the culture dish, the researchers showed that CMTM6 loss from tumor cells impairs T cell activation. They also found that the influence of CMTM6 on CD58 plays an important role in the antigen-specific interaction of T cells with tumor cells and also affects the response to PD-L1 blockade. "It is fascinating that CMTM6 controls two important players in our immune system, CD58 and PD-L1, even though they have opposing functions. And what is more interesting is that when we dive into the analysis of tumor samples from patients who received ICI therapies, it appears that CD58 might just take a leading role in shaping the response, in most cases," explains Beiping Miao, one of the first authors. Using mice to which human leukemia cells had been grafted, the team demonstrated that loss of CMTM6 protects cancer cells from CAR-T cell therapy. Additionally, in human cancer cells from tumor biopsies, widespread expression of CMTM6 and CD58 was observed, with higher expression of CMTM6 or CD58 significantly correlated with better response to immunotherapies. "Our findings highlight the importance of CMTM6 and CD58 expression in cancer cells during an immune response against tumors. Our next step is to explore the possibility of adjusting their expression in laboratory experiments. Our goal is thereby finding a way to improve cancer immunotherapies," said Sun.

Martinsried / Munich, Germany, September 5, 2023 - iOmx Therapeutics AG (iOmx), a clinical stage biopharmaceutical company developing cancer therapeutics based on next generation immune checkpoint targets, today announced the appointment of Dr. Nils Peter Debus as Chief Business Officer (CBO) to drive the company’s new stage of growth. Dr. Debus is an accomplished life science leader with 27 years of industry experience and an outstanding track record in Business Development & Licensing. Dr. Apollon Papadimitriou, CEO of iOmx, said: “Nils brings us significant strategic business expertise with a proven success in building partnerships and executing transformative collaborations and acquisitions. His broad industry experience, will be invaluable as we further grow our global business development activities.” Dr. Nils Debus, CBO of iOmx, added: “iOmx has made impressive progress in a brief time, leveraging its iOTarg platform to address novel immune checkpoints on myeloid cells and advancing its first novel immune checkpoint inhibitor into the clinic. By identifying novel tumor evasion biology, we will further unlock the immune system's potential to combat cancer and tackle tumors, which currently show resistance to existing immunotherapies. I look forward to working with Apollon and the entire iOmx team to build strong partnerships with pharma to maximize our strategic options. We invite the biopharma community to explore our exciting platform and advanced programs for collaboration opportunities.” Before joining iOmx Dr. Debus held the CBO position at OSE Immunotherapeutics (Paris, France), a company focusing on innovative treatments for immuno-oncology and autoimmune disorders. At Boehringer Ingelheim (Ingelheim, Germany), he spent nine years in senior BD&L roles with a focus on biosimilars, strategic transactions and alliance management, handling R&D pipeline and commercialization deals, as well as patent negotiations. At Merz Pharmaceuticals (Frankfurt, Germany) he served as VP of BD. He started his BD&L career at Schering AG (now Bayer) in Berlin, Germany. Dr. Debus is a microbiologist by training and holds a PhD in embryonic stem cell research from Humboldt University (Berlin, Germany). In addition, he received training in corporate finance from Duke University (Durham, USA). About iOmx Therapeutics iOmx Therapeutics ( ) is a biopharmaceutical company focused on developing first-in-class cancer immuno-therapeutics addressing novel immune checkpoints hijacked by cancer cells. Utilizing its iOTarg™ high-throughput screening platform, iOmx has identified a number of proprietary tumor-associated next-generation immune checkpoints and is advancing a clinical stage pipeline of promising drug candidates that have the potential to address cancers, which are resistant to current immunotherapies. The company’s lead candidate OMX-0407 targets SIK, an immune protective kinase family in multiple solid tumors, and is currently being investigated in Phase I clinical trials. Founded in 2016, based on the work of its scientific founders Philipp Beckhove MD, and Nisit Khandelwal Ph.D., conducted at the German Cancer Research Center, iOmx is today backed by international venture capital investors, such as Wellington Partners, Sofinnova Partners, M Ventures, MIG Capital and Athos Biopharma. iOmx is based in Martinsried/Munich, Germany. Media contact MC Services AG Katja Arnold, Julia von Hummel, Shaun Brown T: +49(0)89 2102280 iomx@mc-services.eu