Michael Weller1, Jin Ye Yeo2
1Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland; 2CCO Editorial Office, AME Publishing Company
Correspondence to: Jin Ye Yeo. CCO Editorial Office, AME Publishing Company. Email: editor@thecco.net
Expert introduction
Dr. Michael Weller (Figure 1) has been Chairman of the Department of Neurology at the University Hospital and the University of Zurich, Switzerland, since 2008. He qualified in medicine in Cologne, Germany, after completing his thesis on proliferative disorders of the retina. A postdoctoral fellowship at the Department of Clinical Immunology, University Hospital Zurich, Switzerland, followed where he identified death receptor targeting as a potential treatment strategy for glioblastoma. From 1995-2007, he received his education in Neurology and established a strong experimental and clinical Neuro-Oncology research group at the University Hospital of Tübingen, Germany.
Dr. Weller was involved in major practice-changing clinical trials including the registration trial for temozolomide in glioblastoma and served as principal investigator on the NOA-03, NOA-04, NOA-08, and G-PCNSL-SG-1 trials in Germany and the DIRECTOR and ARTE trials in Switzerland. Dr. Weller has a research focus on the immunology of gliomas and served as the principal investigator of the phase III immunotherapy trial, ACT IV (Rindopepimut). He was a lead investigator in the three immune checkpoint inhibitor trials in glioblastoma, CheckMate 143, 498, and 548, and leads the AGILE platform trial in Europe.
Dr. Weller has co-authored more than 850 original publications in peer-reviewed journals, including The New England Journal of Medicine, Cell, Science, Nature, Nature Medicine, Lancet Oncology, PNAS, The Journal of Clinical Investigation, and The Journal of Clinical Oncology. He has also received several awards in recognition of his contributions to cancer research, including the German Cancer Award in 2007 and the San Salvatore Foundation Award in 2021.
Figure 1 Dr. Michael Weller
Interview
CCO: Your early work on proliferative disorders of the retina and clinical immunology laid the foundation for your focus on glioblastoma. How did these early experiences shape your approach to neuro-oncology research, particularly in glioblastoma?
Dr. Weller: As a young medical student at the time, it was not so easy to find the right subject for a medical thesis which allowed me to gain some insight into translational medicine. Since I always thought of joining the clinical neurosciences, I went to see the Institute of Neuroanatomy in Cologne, Germany, which was in a collaborative research effort with Ophthalmology. Thus, starting experimental research around the retina was a bit of an unplanned sequence of events. Still, the techniques that I learned there, including cell culture, early days of immunohistochemistry, and studies on cellular longevity, were very helpful later on. However, if the neurosurgery department back then had been equipped with a translational laboratory, I would have started to work on glioblastoma much earlier.
CCO: Could you provide a brief overview of the advancements in the diagnostics and therapy for glioblastoma? Are there any examples that hold significant promise?
Dr. Weller: When we state that there is not much progress in the field of glioblastoma, we typically refer to large phase 3 trials, and here, progress is really very modest. However, e.g., in the canton of Zurich, Switzerland, median survival with glioblastoma has increased from 4 months in the 1980s to around a year these days. I believe that safer neurosurgery, safer radiotherapy, and better follow-up with recognition of potential complications of the disease and their treatment have all contributed to progress. Yet, we are waiting for true progress of oncological treatments and I believe that broader immunotherapy approaches targeting the microenvironment and ex vivo drug sensitivity profiling in a disease-agnostic manner hold great promise for Neuro-Oncology.
CCO: You have been a pivotal figure in glioblastoma research, particularly through your involvement in practice-changing clinical trials. What do you consider the most significant breakthrough in glioblastoma treatment during your career?
Dr. Weller: I find it difficult to consider any breakthrough of the last decades as very significant compared with other disease areas across oncology. In neurology, we have learned to be more modest because we also wait for breakthroughs in Alzheimer’s disease or motor neuron disease. Overall, the introduction of temozolomide has provided a relevant advance for patients with tumors with MGMT promoter methylation. Additionally, although still rather debated, tumor-treating fields have emerged as a novel mode of treatment with some activity beyond brain tumors.
CCO: What do you see as the next frontier in immunotherapy for glioblastoma, and how might it address the current limitations of existing treatments?
Dr.Weller: We have to arrive at the conclusion that classical immunotherapy based on immune checkpoint inhibition is unlikely to provide a major advance. More broadly acting approaches, such as immunocytokines that may also target the microenvironment, hold more promise, with a lead compound, L19TNF, in advanced development. We have seen a series of high-ranking publications from the CAR-T cell field in 2024, but here we are still waiting for convincing proof of efficacy.
CCO: Looking ahead, what are the most pressing unanswered questions in glioblastoma research?
Dr. Weller: I believe that the next decade will see a focus on the specific biological features of glioblastoma as a tumor that grows and affects patients exclusively within the brain, but is not able to spread throughout the organism, suggesting that there may be unique interactions between tumor cells and the brain tissue, which support and maintain tumor growth. This field of cancer neuroscience has just emerged and I do see opportunities for addressing such interactions pharmacologically, e.g., by glutamate antagonism or exploring specific vulnerabilities by drug profiling, as has recently been demonstrated for the antidepressant drug, vortioxetine.
CCO: How do you plan to address them through your future studies and clinical trials? Could you provide a glimpse of the projects you are currently working on?
Dr. Weller: Our research group in Zurich is very actively engaged in clinical trials exploring the immunocytokine L19TNF, and we are also working on a CAR-T cell approach that does not depend on the expression of a specific target antigen. Personally, I am convinced that ex vivo drug profiling now termed “pharmacoscopy” holds great promise, and the focus is now on conducting a proof-of-concept study to show that drugs like vortioxetine may have a role in the treatment of glioblastoma.
CCO: How has your experience been as an Editorial Board Member of CCO?
Dr. Weller: It is an honor to serve as a foreign expert on the Editorial Board of CCO. Communication has always been straightforward, and I must admit that I did not have the opportunity to contribute too much. The workload has been very acceptable.
CCO: As an Editorial Board Member, what are your expectations for CCO?
Dr. Weller: I wish CCO, my colleagues in China, and the Editorial Team that the journal will prosper and will assume a more prominent role across oncology journals, given the major role that Chinese oncology, including drug development and clinical trials, will play in the future. I do think that the inclusion of expertise from outside of China is a fruitful way to support the future development of CCO, like we should increasingly involve expertise and input from China in Europe and the US.