Marcel Van Den Brink
President, City of Hope Los Angeles; City of Hope National Medical Center, Duarte, California, USA
What initially inspired you to specialise in oncology, particularly immuno-oncology?
Two moments. The first one is what I would call my ‘patient zero’, when I was in medical school. There's this moment towards the second half of your medical training where, for the first time, you go on the clinical wards. This was the first time that I wore a white coat, and I was so happy and proud. I had to do a night shift on the oncology ward, and during the night, I saw a wonderful, beautiful young man of my age, 24 or so, die from metastatic melanoma. That made an enormous impression on me. I thought, this is a terrible disease for which, in those days, the 1980s, we really didn’t have much to offer. I decided I would like to dedicate basically my life and my career to that field.
The second thing that happened is when I started working during the last part of medical school, with the future mentor for my PhD, a legendary guy by the name of Jon van Rood. There's an EBMT Award named after him; he is a legend within the field of bone marrow transplantation, and is one of the discoverers of the human leukocyte antigens (HLA) system. A lot of the HLA typing that we need to be able to do for kidney transplants, bone marrow transplants, etc., was all developed by him. Van Rood was one of the most visionary people I've ever met in my life. On a very small scale, through all of my career, I have tried to emulate what I saw him do. In 1987, when the field was almost non-existent, he said I should look at immuno-oncology. The only glimpse of hope in those days were some studies by another legendary scientist, who is still active now at the National Institutes of Health (NIH), called Steven Rosenberg, who had just published a study with a cell therapy with natural killer (NK) cells, called lymphokine-activated killer cells. My mentor told me this was an area that I should pursue. So that's how I got started. I went to Pittsburgh, Pennsylvania, USA, to learn more about NK cells, to use that for my PhD. After that, I was hooked.
You have been elected to the Royal Netherlands Academy of Arts and Sciences as a Foreign Member of Medical, Biomedical and Health Sciences. Has this opened any doors for you in research and clinical practice?
I think what it has mostly helped me with is to have a more global perspective on healthcare, its hassles, and its hurdles. I now read frequently about all of the active issues around science and healthcare in the Netherlands. I can’t say that it has directly impacted on my own clinical practice, but I would still argue that my training in the Netherlands has forever stayed with me when it comes to certain ways of organising healthcare.
Since 2004, I have also been an active member of Deutsche Knochenmarkspenderdatei (DKMS), the largest global organisation to get donors lined up for allogeneic bone marrow transplantation; they sign them up at a rate of 1 million people all over the world. They're in seven countries at the moment. If you're part of an organisation like that, you deal with how to do bone marrow transplantation all over the world. How is it organised within the USA, Europe, Africa, and South America? We are active in all of these continents. So that global perspective has always been very important to me, and where the rubber hits the road is really within DKMS.
Are there any projects currently underway at City of Hope in Los Angeles, California, USA, that you are particularly excited about?
My perspective is now much bigger than immuno-oncology, because I'm the president of City of Hope. I would argue that one of the things that we are known for is our bone marrow transplantation programme, and our current CAR T-cell programme. In cell therapy, we are one of the biggest in both of these areas, and also in terms of outcomes, we are always among the best.
One of the most exciting things about City of Hope is that it's in an accelerated growth phase, and is going national; we are no longer just a Los Angeles cancer network, providing the most outpatient cancer care in the greater Los Angeles area. We now have hospitals and sites in three other states: Phoenix, Arizona; Atlanta, Georgia; and Chicago, Illinois. We also have a research institute in Arizona. So the journey that City of Hope is on to be a national cancer centre, with research spread out nationally is amazing, and it is very exciting for me to be part of that. I’m excited by the national profile that they're trying to achieve.
What do you consider to be the most significant development in immune therapies for cancer patients over the span of your career?
There are several milestones. First of all, you have to put it into context. Immunotherapy of cancer was first mentioned in 1900, by German scientist Paul Ehrlich; it was always in the back of many people's minds. But it has been very difficult to turn it into meaningful therapies. The Cancer Centre that I used to work at, Memorial Sloan Kettering Cancer Center in New York, USA, had a legendary leader in in its early days, who actually was trying to come up with vaccines. He used a little bit of microbiome research, by putting bacteria into a growing cancer, trying to trigger an inflammation; it was a mixture of vaccination and bacteria to increase the inflammation at the cancer site. Decades passed with no progress. When I started to do my research, there was a little bit of work going on in vaccines, but nothing really worked.
A breakthrough moment, as I previously mentioned, is cell therapy with activated NK cells, in the late 1980s. A second project that was started in those days was something called tumour infiltrating lymphocyte cells, also started by Rosenberg. Last year, this became an officially approved therapy for patients with melanoma. It was a long journey, but those two things really paid off in the end. The biggest breakthrough, however, came with checkpoint blockade, certain drugs that can block the pathways and activations of T cells; ‘block the blockers’ is basically the theory. This is now a massive therapy, picked up by big pharmaceutical companies. As it stands now, it's one of the most successful therapies in all of cancer, in terms of use and outcomes. Specifically, looking at pathways like CTLA-4, and PD-1, those are the two big ones.
Also to be mentioned is allogeneic bone marrow transplantation, which in my view, and the view of many others, is an immunotherapy of cancer. I've given lectures where I called allogeneic bone marrow transplantation “the original immunotherapy of cancer”; that's always how I have thought about it. The therapy has its earliest roots in the 1950s. In the 1960s, it really got started with the Nobel Prize winner, E. Donall Thomas.
The final big breakthrough is CAR T-cells, which are an amazing feat of engineering of cells; we can compose molecules that are not found in nature by taking different elements of other molecules and putting them together, so that you get optimal activation of T cells that can kill cancer.
I think those would be the big breakthroughs. It's a super exciting field at the moment, that just continues to grow and grow, and has amazing outcomes. One of the fascinating things about immunotherapy of cancer is that, in certain areas, it actually offers you a chance of curing even late-stage cancer. That was one of the things that I always found interesting about allogeneic bone marrow transplantation; we're going for cure, we're not trying to prolong life by some months or maybe a year or so. We want to cure people. That's the amazing opportunity that you have when you work in immunotherapy of cancer, because you basically mobilise the immune system; once you get it activated to kill cancer, it can form memory cells, long-lasting antibody production, etc., so that you keep the cancer in check, hopefully permanently.
You will have the great honour of giving the keynote lecture at the 50th Annual Meeting of the EBMT, where you plan to talk about the role of the intestinal microbiome in cancer immunotherapy. Can you give our readers a brief summary of the developments in this field that you will cover?
The keynote lecture is going to be about the role of the intestinal microbiome in specifically cancer immunotherapy. What I will cover is the impact that changes in the gut microbiome can have on the efficacy and toxicity of allogeneic bone marrow transplantation and CAR-T cell therapy. Think about the microbiome, which is a very popular topic at the moment, covered so widely in the lay press; everybody loves talking about poop, and diet, and things like that. First of all, you have about as many bugs in your body, inside and outside, as you have cells. If you believe in Darwin, and I think many of us do, there must have been a reason why we evolved into super organisms that are basically a symbiosis between all these bugs and our own cells. If you accept that concept, that there must be a reason for all these bugs living inside and outside of you, you can then start to explore what they actually do. The first thing that you have to accept that it is that bacteria are not there just to make you sick, and to lead to infections. A lot of them are doing very useful things. You stand to benefit of keeping your gut microbiome intact, and specifically protecting those commensal bacteria. What we do in the course of many therapies is damage them with our drugs, and with our antibiotics, when people get, for instance, fever and neutropenia. Or we cause, with our therapies, nausea and diarrhoea, which interfere with one’s regular diet. So we see dramatic changes in the gut microbiome. In most cases, those changes are not of any benefit. If you summarise about 15 years of work by us, and by others, you can see that changes in the gut microbe microbiome, specifically loss of commensal bacteria, has led to less efficacy of allogeneic bone marrow transplantation checkpoint blockades, a topic that I won't cover, and a CAR-T cell therapy. In many cases, there are also increased risks and toxicity. That is the topic I will cover, and I will show some of the mechanisms by which that happens.
What do you think is the biggest challenge facing clinicians and patients alike in the field of bone marrow transplantation?
I think there are multiple threats in the areas of bone marrow transplantation and cell therapy. The first is our field of, specifically, allogeneic bone marrow transplantation, which has been more and more focused on incremental changes and modifications, mostly by focusing on clinical research. Clinical research, by nature, will rarely lead to true breakthrough findings, or a new way of doing bone marrow transplantation. For that, you need basic science, translational science, and lab science. People doing that within the area of allogeneic bone marrow transplantation are becoming an endangered species, for multiple reasons. First of all, global healthcare research in general has become more and more focused on clinical research vs. these more basic, translational areas of science and our professional organizations have flexed to this focus. Therefore I’ve seen less and less representation of these folks at professional meetings. So it's a little bit of a catch-22; you get into a downward spiral. It's more and more difficult for people to do research within those fields. A lot of it would benefit from physician scientists, and pure science, and PhD scientists to be able to get funding and to be able to work in the right labs. It’s more and more difficult finding funding sources, and there are fewer senior scientists working in that field, who can really mentor and coach younger scientists. That's a real threat. We're losing our next generation of real scientists within this field. We need them now more than ever, because they need to work on a new breakthrough, a completely new way of doing bone marrow transplantation. For instance, trying to come up with conditioning regimens that are really safe, and don't cause so much damage; or coming up with ways to make graft-versus-host disease something of the past; or coming up with novel ways to prevent relapse. Relapse is the biggest hurdle for bone marrow transplantation; that the cancer does come back afterwards. We need people who are doing innovative research. The area of the disease for which we still do allogeneic bone marrow transplantation is mostly acute myeloid leukaemia and myelodysplastic syndromes. In that field, there is a lot of exciting research going on in other areas; people are coming up with small molecules, are making CAR T-cells, are making antibodies coupled to toxic conjugates to make these antibodies work better as mini-chemotherapy factories. We will go the way of dinosaurs if we don't truly focus on innovation; that's incredibly important. If we don't nurture basic research, and translational research within our field, that's what I would say is the biggest threat for the fields.
Editorial Team: 
