Researcher for therapy of acute leukaemia and myelodysplastic syndrome
José Carreras Centre
Prof. Ulrich Mahlknecht has over 15 years of experience in oncology in Germany and serves as the current Head of Department for Internal Medicine, Haematology and Oncology at the St. Lukas Klinik. In 2007, he was appointed as a Professor at the University of Saarland to the Chair of Immunotherapy and Gene Therapy. Here, he researches new molecular concepts for the therapy of acute leukaemia and myelodysplastic syndrome at the José Carreras Centre for Immune and Gene Therapy.
Section 1: Status Quo
1.1. What are the key trends in gene therapy right now?
The modulation of immune cells in the context of an advanced immunotherapy is a key issue. There is a lot of research going on in the CAR-T cell-based therapy area, but there are also limitations and although CAR-T cells are a good idea, there are several problems that go along with it.
In Germany, we have the problem that we only have a few certified centers who can conduct this therapy. So actually, in total, just a dozen centers in Germany right now are able to do this and that’s a formal limitation. On the other hand, we also have limitations on the side of the patient. We have the problem that in some patients we are not able to collect a significant number of T-cells. The idea in that context is to use allogeneic T-cells from a donor. I think that this is where the research is moving towards for a number of tumors and hematological malignancies. Of course, it does not change the idea that these immune cells need to be altered or modified genetically.
Here, the modification is being made on the basis of a virus, and the virus needs to be integrated into the genome in order to work properly. However, this idea is not new, and the first experiments were carried out about 30 years ago. The problem that we had back then was that these insertions into the human genome or into the mammalian genome were not longstanding insertions. After a defined number of cell divisions, this integrated virus disappeared again and was not functional anymore. This is still the issue we have today. We have however made quite a few progressions in that area which means that the virus, and the genetic modification that has been introduced by the virus, into the genome is lasting for longer than initially possible.
It’s still a proof of principle and we do not know what happens in the long run. The experiments that have been published with the CRISPR technology, are a breakthrough because for a long time we have been able to observe that we have a long-term expression of these antigens by these T-cells allowing the basis for an antigen-antibody interaction in the immune system. It has not been possible for many years, but now it appears to work, but we do not know for how long it works and the problems that we had in the beginning, when we used retroviruses to integrate these genetic alterations into the mammalian genome, in quite a few cases we had the problem that these viruses changed the cell in a different way than what was anticipated.
This meant that these patients in the end developed leukemia out of it because these viruses had their own catastrophe going along. In a few patients it worked, and in a Science paper that was published, in February this year, it was reported that we had long-term expression of these antigens in the immune system; this was something new.
1.2. Which geographies are currently leading in clinical gene therapy applications?
I believe it’s the European firms that are doing research in the US. The research funds in the US are just as limited as in Europe, but of course, we have a lot of European entities going to the US for research and they do a great job there and frequently don’t come back. For me, the number one research country, is still the United States.
In Germany there is a formal limitation because the centers in Germany need to be approved by the German Society for Hematology and Oncology. It’s a decision that has been made by this society, that for the next few years at least, these treatments, because they are so innovative, should only be carried out at university centers. It’s also the logistics behind that, because usually when you perform cell harvesting only university or large clinics are able to do that; so that’s the reason for this. However, if we have companies who offer this as a service, I think it will go into this direction, whereby they do the harvesting and genetic alteration. In this case, you would send them the patient cells and you receive them back as modified cells. I think that could be an opportunity for other centers, smaller hospitals, and maybe in the outpatient clinic to offer such services for the patient.
1.3. What are the major challenges to the approval of gene therapy solutions?
Well, the problem is that in the European Union, and even more so in Germany, we are so restricted by governmental regulations, that it is extremely difficult to conduct phase three or phase two clinical studies because they are extremely expensive. There is a lot of formalism behind that and that’s certainly the reason why many pharmaceutical companies are conducting their research in China, India or in other countries where they are not limited and where they can do whatever they want.
I would be happy if I could say these restrictions will be eased, but my concern is that the opposite will be the case because we can observe this in every situation in Germany whereby, we are becoming more limited with whatever research we perform. Therefore, I’m really concerned that this will probably not be facilitated in the near future, at least in Germany.
1.4. What are pharmaceutical companies doing in this space?
Many of the big companies, such as AstraZeneca, Roche and Novartis, buy startup companies who have the initial idea of performing a new gene therapy method, such as a genetic approach. Then they conduct their first research in a developing country under another name because that’s also a risk for the company. If the research goes wrong, that would certainly damage the vision of the company and affect their reputation. That’s why they are quite happy to have it running under another name and if it doesn’t work it was not their play. In the end, if it works, of course it is easier for a small company if they have the marketing being done by a big brother.
This of course causes problems if you are conducting clinical trials outside of the EU and you are trying to get approval by the EMA. On one hand we have safety issues, ethical issues and we have also genetic issues because, of course, genetic variations work differently in diverse genetic ethnic groups. This means that if we conduct a clinical trial in India, where 99.99% of the genetic makeup is the same, nonetheless, we will have genetic variations which could alter the genetic response or the response to a specific treatment. Of course, in order to transfer the data that has been gained in India or China, we need additional studies to confirm that the results will be the same in another genetic group.
Section 2: Emerging Trends in Gene Therapy
2.1. What are some of the key recent innovations in gene transfer delivery systems?
The adenovirus transfer of genetic material is the oldest method integrating genetic material into the mammalian genome. But of course, CAR-T cell-based gene therapy is innovative, and the vision in this field is that we are trying to get away from retroviral and adenoviral constructs. That would be great because of the problems that I mentioned previously.
Other gene transfer delivery systems include liposomes but the issue with liposomes is that the entry is facilitated into the cell. It’s a new transport vehicle, but we do not have long-term data on it. The idea is good and innovative, and we also have another problem that we might circumvent by using liposomes; this is because when we offer genetic material to the T-cells, this genetic material is being recognized internally by the immune cells as foreign material. Therefore, it is being degraded quite easily. With liposomes my hope is that this intracellular degradation of genetic material is not as easy.
2.2. Which therapeutic areas could benefit most from gene therapy solutions?
Oncology will be a main benefactor of gene therapy technology. Other areas that I would anticipate could be successful are in the fields of neurology such as multiple sclerosis or ALS, which are also triggered by the immune system. I would hope that there is also a therapeutic window in that area. On the other hand, I think the main targets are certainly hematological malignancies where we do not have too many genetic alterations in the neoplasia itself.
It might be a little different in solid tumors, but my hope is that maybe the combination of a CAR-T cell approach or genetic therapeutic approach, in the treatment of solid tumors, means we’re rendering the immune system more aggressive against the tumor. If we combine that, for example, with targeted therapeutic approaches or with chemo, I think that combination could make a change.
2.3. What is the role of advanced analytics such as ML and AI in gene therapy?
It’s a good question and unfortunately, I don’t have a specific answer to it. I’m sure we won’t be able to fight against this trend. We are being transferred into these situations, but it is very difficult to to calculate behavior with genetic material but I’m sure at some point in the future it will be done. However I do not know what will await us with that and what will pop up in the end.
2.4. How will payer reimbursement models for gene therapies evolve in the near future?
That’s still a topic that needs to get on the table. We have in Germany, a governmental institution, the GBA, which does these price regulations. If you think about the principle of CAR-T cell therapy, and if you think of it as a pattern tree method, it is actually not that expensive. Just to do the methodology itself is not so expensive and if you compare it to other drug-based treatments, in the end, it could even be that CAR-T cell therapy turns out to be the cheapest version.
Furthermore, the advantage is that you only need to do one or two sessions, but of course we need a reimbursement system which makes it possible to offer such a novel treatment to everybody, without a destruction of our healthcare system going along with it. If you help only one person with an innovative treatment such as CAR-T cell therapy, but you are running out of money and there are 100,000 people that you cannot treat anymore, you most definitely will run into a problem. Of course, this is also a political issue that needs to be resolved and physicians are usually not part of that.
Section 3: Gene Therapy Applications in Oncology
3.1. What are the promising gene therapy applications for specific cancer types?
I would say that the main application will be for leukemias. We have an incredible unmet need in the field of ALL and AML, which are frequently based on only very few genetic alterations. These could be great targets and my hope would be that gene therapeutic approaches make a change in that field because there has not been too much innovation in that area lately.
3.2. What are the main biological altering mechanisms of oncologic gene therapy?
Gene silencing has been an investigative topic over the last decade, but the problem is that targeted gene silencing is difficult. Gene silencing through epigenetic mechanisms is an opportunity and a possibility to do that, but frequently it’s not targeted. That makes it quite difficult because you do not really know which genes you are actually silencing. We have conducted a study ourselves in this area about a decade ago, and we thought we were silencing genes. We did actually silence genes, and the tumor regressed and almost disappeared. However, when we checked which genes were silenced, actually the genes that we silenced were completely different genes and not the ones that we were targeting.
Therefore, it’s an effect which might work but the mechanism is not so clear at the moment because it depends on the balance of genes that you silence. If you silence more genes that promote tumor progression and you silence less of the genes which block tumor progression, then in the end, you have a shrinking tumor. However, you do not really know which of the genes you are really silencing and which you are actually activating.
Suicide genes was another mechanism which was a hype about 10 years ago, but to my knowledge, it was not a real breakthrough.
3.3. What are the emerging trends around chimeric antigen receptor (CAR) T-cell gene therapy?
This therapy will absolutely cause a large change because the greatest advantage of the method is that you can also offer it to patients suffering from multiple comorbidities; so that’s an incredible advantage. You can also offer it to the elderly population but at the moment, we are extremely limited with treatment opportunities, at least in Germany. The logistics behind this is tedious at the moment, sometimes it’s difficult to collect enough cells and in Germany, this CAR-T cell treatment is only being offered by university centers now.
Maybe in five years, it will be different, and it will also be offered in the outpatient clinic. I do not see a limitation for that, it will certainly expand, and it will definitely change the field in the treatment of solid tumors and hematological malignancies; this I’m sure of.