EG: You mention that you’ve already introduced these cells into patients and successfully treated cancer that is resistant to other therapies – what are some of the results you’ve seen so far? 

SR: We are treating patients who have blood cancers – leukemias and lymphomas – and we engineer the cells with a receptor that redirects them to recognize and kill those tumors. And as Dirk has said, this is a living therapy, so you may need to put in just a very small number of cells. And these cells will multiply in the patient until the tumor is eliminated. Using this approach, we’ve already treated more than 150 patients – patients who have failed all other treatments, and have no further treatment options. The remission rates – meaning complete elimination of measurable cancer cells – are as high as 90 percent for acute lymphoblastic leukemia. So this is really revolutionizing how we think about using the immune system to treat cancer. It comes back to the idea that by understanding the behavior and capabilities of the cells that you’re using in this therapy and their ability to LAST in the patient, we are entering a period in which we can examine expanding this cell therapy to many types of cancers. Dirk is already doing this in the clinic with infectious diseases, which doesn’t require engineering. He can select virus-specific T cells out of peripheral blood of stem cell donors, and use them to treat patients with certain viral infections after bone marrow transplants.

DWH: Ultimately, what really joins these two Focus Groups is that we are both using cells in our therapy concepts. And that’s how Dirk, Stan and I actually got together. In our discussions, we were developing ideas about how to synergize our expertise from the fields of immune therapy and regenerative medicine to develop ground-breaking concepts – to really magnify both fields. The RM Focus Group approaches the topic from the perspective that you have a tissue defect – for example, a large bone defect based on a trauma or tumor removal. Or, from a soft tissue perspective, you have breast cancer that necessitates the removal of the breast – but then after the cancer is treated, you want to regenerate the tissue. In regenerative medicine, we try to rebuild tissue by also using cells – yet with a different approach than the one which is currently being used in immune therapy. We combine cells with what is defined as a scaffold, because we really need the structural support to rebuild tissue, whereas with immune therapy based on the concept developed by Stan and Dirk, we inject T cells into the blood stream that subsequently proliferate and migrate to the site of infection or into the tumor tissue to destroy it. We start with something which is empty, and then we want to build up volume. Our group specializes in using 3-D printing to fabricate patient-specific scaffolds. This technology allows us to run computer simulations to shape the volume as well as the form of the tissue we want to build. We use so-called additive biomanufacturing technologies to design and fabricate the scaffolds, and then add the patient’s own cells with the goal of generating a lot of extracellular matrix. And then – similar to immune cell therapy – the cells and scaffold are implanted and interact with the patient’s own body cells to regenerate the tissue. It is very important to have the surgical expertise to implant the tissue-engineered constructs (TEC) in the right way, as well as to provide optimal, post-operative treatment and to develop large preclinical models which mimic the human patient as closely as possible. That’s why my Focus Group is actually hosted by the TUM Clinic for Plastic Surgery and Hand Surgery, and co-directed by my host department chair, Prof. Hans-Günther Machens.

EG: Let’s delve into the Focal Period and talk about what you’ve accomplished – and what your scope of cooperation will entail moving forward.

DB: The Focal Period concept is a great idea developed by the TUM-IAS. The Institute has given us the unique opportunity to generate international collaborations with researchers at TUM. I believe the next step now is to further tap the synergies between experts working in very different areas – and develop something unique in the international research and clinical landscape. We may be using cells for therapy differently, but in the end, we all work with living drugs as the basis of our research. I think the other similarity we share is that we often have to start our work with mixtures of cells – and with cell mixtures that are often not very well defined, or that differ substantially from donor to donor. We believe that if we have better-defined cells, we can translate this into better therapy. And this is a need we recognized to be of major importance in different fields of cell therapy and regenerative medicine. 

EG: Maybe we could talk about this interdisciplinary approach – what were some of the insights gained during the workshops? 

SR: The real key was, maybe, gaining deeper insight into the research, and an introduction into the various issues that we’re studying. I’m an immunologist – I study lymphocytes, and I’m trying to understand the behavior of those lymphocytes. Yet we also had participants who were experts in biomaterial sciences who gave us insight into the scaffolds they’re using to grow specific types of cells, and how those scaffolds can influence cell behavior. Others were experts in new technologies for editing the genome. So I think a key takeaway from the Focal Period is this: As top experts in our respective fields, we had the chance to get to know each other better – and better understand how the work being done by others might fit into our own.

DB: I think we are already very excited to see that, yes, we have been able to take some of the principles that we’ve learned from basic research to try to translate them into clinical applications. For example, to treat an infection. Stan was already pioneering this area of research quite a few years back, but when he started, there was perhaps the general belief – for many reasons – that it would require us to generate large amounts of these cells in order to do effective therapy. And what we’re now seeing is that there is a strong regenerative capacity within defined subtypes of T cells. What we have learned – and this might be of relevance for many other cell therapy approaches as well – is that if you start out with the right cells, you might only need to generate a very low number of cells for therapy. Furthermore, using a low number of cells for therapy could even have advantages over using more, especially with respect to side effects and acute toxicities. So, unexpected aspects from different fields – including regenerative medicine – came together, which is now helping us to facilitate the generation of the most effective therapeutic cell products.

SR: The reason I believe the field is still in its infancy – even though we’re already having some success in the clinic – is that cancer is a big problem. And we’re treating a very small number of types of cancers, and what we’ve got, really, is the first evidence that says you can engineer immune cells to recognize and destroy a tumor in a patient. But that doesn’t mean you can engineer immune cells to destroy EVERY tumor in every patient. There are different types of cancer: you have to identify targets and understand the microenvironment of those cancers. So there’s still a lot of work to be done. A cancer is often referred to as a wound that won’t heal. Because, in fact, some of the ways in which a wound evolves – those same processes are initiated by cancer. And some of that is actually to shut down the body’s immune response. We need to learn from our colleagues who are doing tissue regeneration and trying to repair wounds that won’t heal – to understand how best to do that. We’re early on, but I think we do have what I say is really first proof of principle for clinical applications, of the concepts and principles that we’ve worked on through the Focus Groups. 

DB/SR/DWH: In closing we would like to thank TUM and especially the Institute for Advanced Study for providing us the opportunity to work together on the quest to develop 21st century therapy concepts