Conversations with giants in medicine A conversation with Marc Feldmann

Sir Marc Feldmann’s research over the JCI: How did you stumble into doing tute went into a financial crisis. Gus had last 30 years has focused on the under- your research with someone [Gustav Nos- to remain to resolve it, and he sent me to a standing of autoimmune disease, specifi- sal] who was famous for antibody forma- number of conferences where he had been cally the treatment of rheumatoid arthritis tion and immune tolerance? invited, and they were wonderful, because as (RA). Feldmann (Figure 1), now at the Ken- Feldmann: I decided, at the end of the first a young student I met many of the immu- nedy Institute of Rheumatology at Oxford year’s hospital work, to do some research. nological stars of the time. I met Av Mitchi- University, championed the importance Visiting the Walter and Eliza Hall Insti- son, a very charismatic scientist to this day. of antigen presentation and cytokines in tute, I realized it was quite different from I decided to work with him, continuing to autoimmunity, a concept that led to TNF-α other university departments. In about work on cell interactions and to try and blockade. This idea was considered hereti- 30 minutes, it became pretty clear that it characterize some of the mediators that cal in the 1980s until he and Sir Ravinder was where I wanted to go. I didn’t know acted as signals from one cell to another. Maini led clinical trials showing that block- until many years later that I had applied far After years of working with mice, my ing TNF-α effectively treated rheumatoid too late and that they had already chosen medical training encouraged me towards a arthritis refractory to previous therapy. their four PhD students. There were five major challenge, tumor immunology, and I TNF-α antibodies Remicade, Humira, research units, but that year only four stu- started to look at immunity in human can- and Enbrel are now the cornerstone of a dents were accepted because Gus Nossal cer patients. It was absolutely impossible to $25 billion industry. Many more stories was going on a sabbatical to Paris. I turned measure any immune responses to cancer. about getting pharma to speed delivery to And so, I made the conclusion that what is patients and the power of persistence can needed for cancer is to develop an autoim- be seen on the JCI website, http://www.jci. mune disease, to get the immune system to org/kiosk/cgm. target the cancer. Thus a reasonable next JCI: Where and how did you grow up? step was to try and understand mechanisms Feldmann: I was born on the Russian- of autoimmunity, a topic of interest discov- Polish border. My father, an accountant, ered by [Frank] Macfarlane Burnet, Gus was lucky enough to be able to take his Nossal’s Nobel Prize winning predecessor. family out of there at the end of the war JCI: So, you started working on autoim- and we went to France where his sister had munity? arranged the necessary formalities, but life Feldmann: In 1982, a couple of papers in France in the immediate postwar era had come out looking at the role of HLA was difficult. He had two cousins — both antigens and their upregulation in sites of doctors — one in New Haven, one in Mel- autoimmune diseases, one from Deborah bourne. They both filled out immigration Doniach and Franco Bottazzo at Middlesex papers for him and the Australian ones Hospital. They came to visit me one day to came first, so off we went to Melbourne. ask what I thought of the upregulated HLA My father’s cousin that had sponsored class II in a diseased tissue, like Graves’ dis- our immigration was quite a charismatic ease thyroid. I started to think and realized Figure 1 and entertaining person and he made that this observation was actually a missing Marc Feldmann on May 20, 2013. Image credit: medicine into a very glamorous career. Alena Soboleva. link — I developed an idea of how autoim- My brother and I decided that was more mune diseases were triggered and were sus- interesting than accountancy, and so we tained through the upregulation of anti- went to study medicine at the University up in February, totally unknowing that gen presenting function. of Melbourne. The teaching was good, the Gus had shown judgment to take an extra I wrote a hypothetical paper about this, students encouraged. I got married while I student, and thus launched me on a poten- which was published in The Lancet in ‘83, was a student; so it was a good time. tial research career. The focus of my PhD and despite its age, it’s not an embarrassing The University hospital I chose in order was to improve the generation of immune read. It outlined a link to understanding to learn clinical medicine more quickly, St. responses in vitro, to grow cells from the autoimmunity and cell interactions with Vincent’s, had far few clinical students and spleen of mice in conditions enabling them some of the key molecules. Once autoim- was in the Irish part of Melbourne. Half the to mimic immune responses in vivo. I stud- munity and upregulated antigen presenta- patients had serious alcoholic problems. I ied cell interactions, immune regulation tion were linked, then many other things make a joke at times that I owe my research and mediators, and learnt from and col- follow. What upregulates antigen present- career to alcohol. I chose, though, to do laborated with many senior scientists. ing molecules? At the time, the only known research to understand medicine in greater JCI: After your PhD, you then decamped signals were cytokines and so I focused on detail and uncover new treatment approach- back to Europe to do postdoctoral research studying cytokines in autoimmunity. es, which seemed to me to be more interest- at the Imperial Cancer Research Fund. JCI: I imagine this must have been part of ing than seeing a lot of alcoholic patients Feldmann: While I was a PhD student, I what drove you to look at the joint after an with insoluble problems, day after day. had another piece of good luck. The Insti- initial focus on autoimmune thyroiditis?

The Journal of Clinical Investigation http://www.jci.org Volume 124 Number 1 January 2014 1 conversations with giants in medicine

Feldmann: The reason we had original- well accepted. The popular concept was liams, we used anti-CD4, CTLA4-Ig, and ly been interested in thyroid disease was that autoimmune diseases were driven by cyclosporine, and all of them gave a very because it was possible to get abundant CD4 T cells, and thus many companies marked prolongation of the benefit of anti- human diseased cells for research. Howev- were starting to work trying to cure RA TNF in mouse models. The approach for er, critical for scientific research is funding. with anti-CD4 monoclonal antibodies. As clinical use where we could not use 2 unap- Because current therapy of thyroid disease we tried to get support to test our idea, we proved drugs was to use small molecules is actually pretty good, there’s no incen- quickly found that they weren’t interested that were approved and, after a number of tive to improve it. I considered what other in anti-TNF for treating rheumatoid arthri- iterations, we finally decided on methotrex- disease had many of the local features and tis, even if they had already made anti-TNF ate. It was the second phase of our success- had reasonable amounts of disease tissue monoclonals for treating sepsis following ful translational research and has made for available for study in detail. Rheumatoid Tony Cerami’s interesting work. much more durable therapy. To this day we arthritis seemed to be a logical disease that JCI: But in this case, your former student, don’t understand exactly how methotrex- could be studied with the same technology. Jim Woody, was at Centocor? ate works, nor do we understand exactly JCI: Not to mention that it occurs in Feldmann: That was very, very fortunate how this combination works, but we had approximately 1% of the worldwide popula- because, although Centocor was also pre- clues from the very beginning, when a tion, and therefore, would be a bigger market. occupied with antibodies to CD4, Jim was patient that was doing very badly on anti- Feldmann: Exactly. It was much easier to senior enough that he was able to help us TNF was subsequently given methotrexate get grants, and when I expressed an interest do an anti-TNF clinical trial. We were very and had a very good response. in rheumatoid arthritis, I met my long-term fortunate because we had tried to get anti- JCI: You’ve said you did these clinical tri- colleague, Ravinder, better known as “Tiny TNF antibodies from companies in the UK als because you were interested in science, Maini.” He is a scientifically educated rheu- and we talked and we talked and we talked, and wanted to treat patients but you’ve matologist and had been also interested in and they all thought it was too dangerous, also been lauded with several honors and mediators from lymphoid cells during his and too unlikely to work. awards, and including the 2003 Lasker lab phase at the Kennedy Institute. JCI: You had stunning success once you Prize, and in 2010, you were knighted by We started by trying to obtain as much started your clinical trials. Queen Elizabeth II. human diseased joint tissue as possible, to Feldmann: We wanted to do a formal Feldmann: Yes, that was very gratifying. try to establish the important rate limiting clinical trial right from the beginning, with Before the knighting ceremony, they write cytokines. We started to “fish” in the cytokine placebo controls, but it turned out that the to you and ask some interesting questions pond before others suspected that it might perception that blocking a host defense and one is, “Can you kneel?” And then, be very important. At the time people were molecule like TNF was dangerous was too “Can you get up?” These are relevant ques- very interested in cytokines as cancer thera- ingrained to enable us to go straight to a pla- tions considering the average age of people peutics, not as potential drivers of autoim- cebo controlled trial. We could not convince getting a knighthood. It was a very nice cer- mune diseases, which was why my ideas were anybody that since anti-TNF had been used emony at Buckingham Palace. considered heretical, and some companies in several thousand patients that already had Awards in science are useful as a motiva- refused to help us by giving us reagents. severe infection with bacterial sepsis, it could tional, aspirational tool, and I can tell you JCI: And yet, you persisted and hit upon be given safely to people without infection. it is wonderful to know that you haven’t using TNF-α blockade. It only took about three hours for us to wasted all your allocated time on this plan- Feldmann: We persisted because we just realize that something was happening after et doing research — to know that it has been couldn’t believe that these very potent mol- infusion of infliximab. It was given slowly, useful to society. And you can convince your ecules, present in such abnormal quantities over 3 hours to avoid infusion reactions, parents, relatives, and spouse that the effort with prolonged production kinetics, could but as the first patients were getting it, and time away from family was worthwhile. just be a byproduct of disease. Helped by they told us they were starting to feel bet- JCI: If you weren’t wasting your time skills from my PhD days, we developed ter, less tired, and so we had a clue within a doing all this work, what vocation do you methods to culture synovium, and then few hours of starting. think you would have chosen otherwise? my postdoc, Fionula Brennan, was able to What we had accomplished in round one Feldmann: I grew up in Australia, a sports- do a pivotal experiment, which was to put was to show that TNF was a good therapeu- mad culture. I did play a lot of tennis and TNF-α antibodies into a mixed synovial tic target. There was a good clinical effect I enjoyed it. Tennis was a very low-ranking culture and show that production of IL-1 but it wasn’t durable with a single course of sport in the social hierarchy in Australia; in and lots of other inflammatory cytokines treatment. The question was whether any Melbourne the top is Australian rules foot- were down regulated by the neutralization complicated multigenic disease involving ball, which makes American football appear of TNF. That was the first clue that TNF many different cells could be eradicated tame. But I’m about one foot too small for was the long sought therapeutic target. with a single targeted therapeutic, and I being good at Australian rules. So instead, JCI: This quickly took off such that in 1992 think all physicians know the answer: seri- I played tennis. But that had an advantage, you and Maini started your first open label, ous diseases like HIV and cancer are treated as I’m 100% certain that none of my school non-blinded trial in 20 RA patients that were by polypharmacy. friends are still playing Australian rules now, otherwise refractory to other treatments. For immunologists, the simplest thing but I can still play tennis. But that’s not seri- Feldmann: The excitement was pal- was just to go back to first principles — ous. If had I not become a scientist, I would pable, but there were hurdles, one of “What drives immune responses? T cells.” have tried to be an artist. which was that our idea of TNF blockade And to start asking, “What might happen downregulating other cytokines was not if T cells were blocked?” With Richard Wil- Ushma S. Neill

2 The Journal of Clinical Investigation http://www.jci.org Volume 124 Number 1 January 2014