Dr. Jacques Banchereau (Figure 1) is director of the Baylor Institute for Immunology Research (BIIR) and holds the Caruth Chair for Transplantation Immunology Research. He received his PhD in biochemistry from the University of Paris in 1980 and later served as director of the Schering-Plough Laboratory for Immunological Research in Dardilly, near Lyon, France. While there, he discovered, with his colleagues at DNAX in California, a large panel of novel interleukins, molecules that assist in regulating T-cell functions. He was among the first to discover how to grow human dendritic cells (Figure 2). Dr. Banchereau came to Baylor in 1996 to develop BIIR. He has served on the National Institutes of Health's (NIH's) Experimental Immunology Study Section, Center for Scientific Review. He has authored or coauthored more than 260 papers in major international journals and 160 book chapters and reviews; many of his publications are highly cited. Dr. Banchereau is a frequent speaker at national and international scientific conferences. His research interests focus on human immunology, particularly dendritic cell biology, genomic approaches to the diagnosis of human diseases, the pathophysiology of autoimmune diseases and cancer, and the design of novel vaccines.
Figure 1.
Jacques Banchereau, PhD, director of BIIR and the W.W. Caruth, Jr., Chair in Organ Transplantion Immunology.
Figure 2.
Interstitial dendritic cell: (a) immature and (b) mature.
Michael A. E. Ramsay, MD (hereafter, Ramsay) (Figure 3): When did you first realize that you were interested in science?
Figure 3.
Michael Ramsay, MD, president of Baylor Research Institute.
Jacques Banchereau, PhD (hereafter, Banchereau): From early on I was encouraged to collect butterflies, stones, minerals, fossils, and all kinds of things related to nature and science.
Ramsay: Who encouraged you?
Banchereau: My parents.
Ramsay: Were they scientists?
Banchereau: No, not at all; they were elementary school teachers. I don't know why, but this interest in science appeared in my early childhood. But what I recall is that my heroes at the time weren't athletes or movie stars but scientists, like Madame Curie, Louis Pasteur, Albert Einstein, and Alexander Fleming. Having role models like that was really important, and kids today are not exposed to stars in the field of science. For today's kids the stars are mostly from sports.
Ramsay: Who would be the stars in medicine today? If they got the limelight, who would they be?
Banchereau: That's a tough question, and I am not sure that I have an answer for you. In 1967 Christiaan Barnard transplanted the first heart. Since then, many outstanding scientists have contributed to improved health, but no one publicly stands out. Feldman and Maini developed tumor necrosis factor (TNF) antagonists for arthritis and psoriasis, but they did not reach “stardom.” Yet, what they have accomplished is helping so many hundreds of thousands of people. Hopefully, a scientist will find a cure for cancer. Maybe that person will be a star.
Ramsay: So we need role model scientists?
Banchereau: Yes, absolutely. And we need to have a system to get there. We need to develop an effective public relations strategy. Perhaps the scientists themselves are not working to demonstrate the beauty and the importance of their job. All of the scientists elected to the National Academy of Sciences should do something to glamorize or valorize science. We hear in the news about those scientists who are frauds, like the stem cell researcher from Korea. That's what the kids hear about. And these unscrupulous individuals represent probably 0.00001% of all scientists.
Scientists are necessary parts of everyday lives, even though the average person usually doesn't appreciate that fact. NIH-driven discoveries are critical to subsequent industrial development. So a crisis in research means a loss of innovation. And we are facing the situation where other countries will invest and become prominent. So to keep innovation, we need to make the jobs of scientists attractive to kids.
Ramsay: One factor in public relations may be the number of discoveries being made now. If you look back 50 years, there weren't so many major discoveries, and those that were made really hit the news.
Banchereau: That is absolutely correct. You know, you cannot be a Renaissance man like Leonardo Da Vinci anymore. But yet, I think there is a big lack of communication with the public. That is sad because science is a tremendous job, and I am very proud to have chosen this career.
Ramsay: When did you become interested in immunology?
Banchereau: About 30 years ago. I first studied immunology in 1973 and 1974 and basically hated it. That was probably one of the rare units that I did not do well in during my studies. I remember my father telling me when I was a teen that immunology was a science that seemed to have a lot of future, based on the need for vaccines and all of the problems linked to the immune system.
Ramsay: It is interesting. I was in medical school in the mid-1960s, and immunology was one chapter at the end of a biology textbook. That was immunology.
Banchereau: Yes. Now how did I really get into immunology? I was very fascinated by the nervous system, which I was studying during my undergraduate years. In 1975, after 5 years of undergraduate studies, which made me a pharmacist, I had to choose a field of focus. What fascinated me in neurology then was that many molecules were identified as mediators. I was particularly fascinated by the hypothalamus pituitary axis. We had follicle-stimulating hormone, luteinizing hormone, adrenocorticotropic hormone, and the protein sequences. It was really satisfying to see that the biological response could be made by a protein of known structure. However, the problem with studying the nervous system rather than the endocrine system was finding a model system. How can you study vision or, even harder, memory and feelings in a quantitative fashion? It seemed to me like the immune system would function based on similar molecules and would be more amenable to study.
So in 1975 I moved from Angers, my hometown in the Loire Valley, to Paris and joined a biochemistry lab that was doing some immunology. In 1981, one of the most important decisions in my life was to take a job at Schering-Plough. In 1979, Nagata had cloned a gene coding for alpha interferon; that was the first gene cloned for one of those immune molecules that were called lymphokines. Schering-Plough had bought the rights from Biogen and decided to build a research center in France dedicated to the study of immune molecules. As this was the major topic of my PhD dissertation, it represented a great opportunity that I jumped into.
Ramsay: That was a change in science too: even today a lot of science is done in academic centers, but more and more major discoveries are coming through commercial entities.
Banchereau: Absolutely. I was very fortunate to be at Schering-Plough at that time. Industry basically discovered all of the interleukins. It's in industry that my close friends at DNAX, Bob Coffman and Tim Mosmann, discovered the TH1 and TH2 cells, subsets of CD4+ T cells, which represent a fundamental concept in immunology. With my friends at DNAX in California, we discovered many cytokines, including interleukin (IL)-4, IL-5, IL-10, IL-13, and IL-17—all those things that are now in immunology textbooks. We discovered them, sequenced them, studied their biological functions, and definitely had a great time. It is thus true that many major discoveries now in the field of medicine were made in industry, although the pendulum has swung back a little bit now. There were 15 or 20 absolutely extraordinary years of discovery, and now industry has moved its focus into the medical application of these discoveries, which makes a lot of sense to me. This was the revolution of biotechnology, and much of its medical application is now coming for patients' relief.
Ramsay: So you were at Schering-Plough until 1996. What brought you to Baylor?
Banchereau: Several factors. One was the fact that I thought that I had peaked in my career at Schering-Plough. I had been the director of the institute in France for 12 years, and I knew they were very comfortable with me there. The options for me would be very minimal. Furthermore, I was disappointed by the decision of Schering-Plough not to go forward with a discovery we had made in Dardilly, which is the high-throughput generation of human monoclonal antibodies. And above anything else, I wanted to create an institute dedicated to human immunology. Now this is called translational research, as opposed to basic research and clinical research. To tell you the truth, I do not like these artificial categories at all. There are only two areas of research: good science, which we need to strongly encourage, and bad science, which we need to eradicate.
My vision of a human immunology research institute dates back to the late 1980s and early 1990s, when I was realizing that, even with all the Schering-Plough researchers, there was no way that we could ever study the pathophysiology of these new cytokines that we were discovering. The need for an integrated network of physicians, physician-scientists, and scientists was clear to me. I was seeing development of disease-specific centers, which were using all of the modern tools that we were developing. Along this path, biology would become like physics, where very large teams of scientists collaborate on a defined question that requires huge equipment. As I realized that it was difficult to bring a hospital into a research institute, I was starting to think that it might be easier to bring a research institute into a hospital.
Early in December 1995, Jim Forman, a professor at the University of Texas (UT) Southwestern Medical School, was leaving messages for me every day. He told me that Baylor wanted to build up a human immunology program, and he told me about Dr. John Fordtran (Figure 4) and the importance of Baylor in Dallas. We concluded that I would stop by Dallas on my next trip to California, which was in early February 1996. At that time, I was particularly interested in developing novel vaccines based on the targeting of dendritic cells. These improved vaccines would be used for cancer, HIV/AIDS, tuberculosis, malaria, and many of the other scourges that the world suffers from.
Figure 4.
John Fordtran, MD, president of Baylor Research Institute when BIIR was established.
Critical for my move was my desire to work in the USA. I wanted to learn how to perform clinical trials and learn about the Food and Drug Administration. I was familiar with Texas since in 1993 to 1994 I was a visiting professor in the Department of Microbiology at UT Southwestern, invited by Don Capra, who was one of my advisors in the human monoclonal antibody program. Don thought that the potential to develop a translational research institute was great at Baylor. Then, Dr. Fordtran, the president of Baylor Research Institute (BRI) at that time, and all of the top physicians and executives at Baylor put together a tremendous package that included a brand-new research building.
I recall during this time speaking with Marvin Stone (Figure 5), director of the Sammons Cancer Center. He was a very strong supporter of developing a human immunology institute. In fact, one of Dr. Stone's aims for the Sammons Cancer Center is to coordinate cancer research with patient care and treatment. Marvin remains a great friend and supporter of BIIR.
Figure 5.
Marvin Stone MD, director of the Baylor Charles A. Sammons Cancer Center. Photo: Gittings.
My vision is that we need to apply all of what we have learned in immunology to patients, to curing people or improving their lives if we cannot cure them. My dream would be to cure cancer or HIV. I am convinced that a proper use of immunology will be very valuable for patients suffering from autoimmunity (rheumatoid arthritis, diabetes, and lupus), cancer, infectious disease, transplant rejection, and allergies.
Ramsay: What happened to this human monoclonal antibody technology that you were talking about? I understand that monoclonal antibodies are currently the new fashion in drug design.
Banchereau: You are absolutely right there, Mike. Well, the technology that we had established basically permitted us to immortalize every human B cell. And it has not been used. In 1991, our paper in Science got front-page coverage in the Wall Street Journal, which attracted Schering-Plough's interest. The company funded an integrated program on human monoclonal antibodies. Then there was a human monoclonal antibody called Centoxin, made by Centocor, which was supposed to treat septic shock. In 1993, it appeared that the trials on Centoxin had not been very solid, which brought a lot of skepticism about human monoclonal antibodies. A lot of people pulled out of that field. We know that today monoclonal antibodies represent a formidable therapeutic revolution. The market for human monoclonals is now $15 billion a year and growing. It is estimated that by the year 2010 this market will be in the neighborhood of $25 billion to $30 billion a year.
Actually, we are reviving this technology at BIIR. We have made monoclonal antibodies against interferon and are making many more as we are celebrating the institute's 10th anniversary.
Ramsay: Do you want to talk about the vision for BIIR?
Banchereau: The vision is simple: we need to be the best for the goals that we have established. We are working for that, working very hard indeed. It's not just a slogan. We are trying very hard, and it definitely takes a lot of resources from Baylor and its philanthropists; it takes a lot of resources from the NIH, but it takes a lot of resources from the BIIR scientists as well. The members of the institute are highly dedicated. They work late into the evening and often come into work on the weekends. However, given the broad scope of our vision, we are going to need more strong leaders. We need to increase our faculty number so as to expand our multidisciplinary effort, which will permit us to generate new drugs or develop diagnostic assays for diseases that involve the immune system. This will allow us to respond to large requests for applications published by the NIH.
Ramsay: What are the areas of BIIR's focus?
Banchereau: We are working in four areas: cancer, with a focus on metastatic melanoma and breast cancer; autoimmune diseases, with an emphasis on systemic lupus erythematosus and systemic arthritis; infectious diseases, with a focus on the pathophysiology of respiratory syncytial virus (RSV) and the design of an avian influenza vaccine; and, last but not least, transplantation, with a focus on preventing rejection of engrafted organs by the recipient's immune system.
We have started our program with cancer, and I really would like us to be stronger in cancer by recruiting additional faculty. I think we are very strong in the autoimmunity area. We need to develop that group and have more investigators as well. The infectious disease and vaccines program, which we started 3 years ago, is doing very well, but we need to strengthen it also. For transplantation, we have some very interesting findings. We are not yet at a critical mass, but with the recruitment of Dr. Shinichi Matsumoto, that is going to be better.
Everyone usually understands what it takes to build a cancer center or an autoimmunity center. I wanted to create a human immunology center where all those disciplines would talk to each other, because the common trouble with the diseases is an alteration of the immune system. Today we have a dendritic cell–based cancer vaccine. The dendritic cells we are using were discovered by studying patients with lupus. I think that what we are going to get for inducing tolerance to grafts in our transplant patients will derive from what we have found in studying viruses. This interdisciplinary approach is very important and is the beauty of the system. Many traditional scientific institutions have started to realize that, and other institutions talk to me about wanting to do that. Actually, such interdisciplinary programs represent the objective of the NIH Roadmap for Medical Research. So that's my vision.
Ramsay: One of the things that differentiates your institute from many other immunology institutes is that you truly are a translational research institute.
Banchereau: No other institute I know of is dedicated only to human immunology and the translation of the discoveries into phase I clinical trials. When you look at the way the institute is built, with its outstanding core facilities, you would think that the institute is more similar to a biotechnology company than a traditional academic institution. Each time we add a faculty member or a new core facility, we extend our multidisciplinary outlook. Thus, every new faculty member brings a new strength that addresses a hole in our repertoire of expertise. As we can raise funds, we hope to attract up to 10 additional faculty members in the next 3 years. These scientists, in turn, will then raise a lot of funds through their synergistic interactions.
Ramsay: Raising funds is important, and you've done extremely well with federal grants. Baylor has supported you strongly, but the community has also, and you've had some significant philanthropy from different foundations, entities, and individuals.
Banchereau: Absolutely, and I am very thankful for the strong support that I've received to pursue my vision for a translational research institute. There have been no surprises in this regard. I had felt the level of commitment in my early interview with Boone Powell. He said that he would strongly support this new endeavor for Baylor, and Joel Allison has pursued that goal even further. Everyone's support played an important role in my decision to move from a very comfortable position in France at Schering-Plough. The support that we get from Baylor University Medical Center (BUMC) and Baylor Health Care System (BHCS) is very important for us, and I believe that the institute also helps BUMC and BHCS in several ways.
But BIIR is also supported by philanthropy. Individuals like Louis Beecherl, Erle Nye, Milton Levy, Mike Graham, and all of the donors to the BHCS Foundation have been fundamental to our success. The Communities Foundation of Texas and the Alliance for Lupus Research have also been extremely good to us. We have received $3 million in grants from the Alliance for Lupus Research in New York City. We are now working with the Crohn's and Colitis Foundation of America. We haven't yet approached the Gates Foundation, but we are getting ready to do so within the next year.
We recently recruited an eminent transplant specialist, Dr. Matsumoto. He will be heading up an islet transplant center in Fort Worth that will be a part of BIIR. Already, Fort Worth–area philanthropists have shown great interest in this exciting Baylor program. It will show that Baylor research extends throughout the metroplex and can benefit the entire North Texas area.
All of this support is tremendous, but we must still submit applications for federal funding, quite a few applications as a matter of fact. BIIR averages over one grant application submitted per month, and every investigator is expected to get federal funding sooner or later. We have been very pleased that our overall success rate is well above the current federal average, which is only around 10% of the applications submitted. We have been fortunate considering the tight budgets of the NIH.
Some of our larger grants have been instrumental in the development of our programs. In 2000, together with our collaborators at Rockefeller University, we received a multimillion dollar program project grant in melanoma vaccine research (Figure 6).We have recently heard that our renewal application for this project has been approved, which will allow us to conduct a new clinical trial with our melanoma vaccine. In 2001, we were awarded a contract from the Defense Advanced Research Projects Agency (DARPA) to develop what we call “the intelligent-missile vaccine,” a vaccine that targets dendritic cells. This allowed us to successfully compete in 2004 for a new $15 million U19 grant from the National Institute of Allergy and Infectious Diseases (NIAID). The goals of this grant are to develop an in vivo model of the human immune system, which we now have, and to understand how biothreat agents affect the immune system so that we can develop vaccines against them. We are currently working hard on a new multimillion dollar DARPA contract as well as several NIH R01 applications.
Figure 6.
Hideki Ueno, Jacques Banchereau, Karolina Palucka,and John Connolly celebrate the completion of the supplementalmaterial required for the melanoma vaccine program project application submitted to the National Insatitute of Health.
Our autoimmunity program has also been extremely successful at obtaining federal and private foundation funding. Already this year, we have received over $9 million in new funding for lupus research, including a recently announced award of over $6 million from the NIH. This new funding will allow us to create a Center for Lupus Research, which will be directed by Virginia Pascual. These recent successes in obtaining lupus funding are in addition to current funding that supports our systemic arthritis program.
Ramsay: Doesn't your U19 grant also support your annual symposium?
Banchereau: Yes, it does, and that brings up another important topic, the education component of the institute. Throughout the year, we bring in top scientists to present their research and share their expertise. The highlight of the year in this regard is our annual symposium. The symposium focuses on human immunology and biodefense and will be held on November 4th and 5th this year in conjunction with the celebration of BIIR's 10th anniversary. Our symposium series has been very successful, and we are currently planning another symposium on autoimmunity. It is part of Virginia Pascual's Center for Lupus Research and will probably be held each spring.
Ramsay: So, Jacques, you mentioned that Baylor receives benefits from the successes of BIIR. Why is the Baylor support of research good for Baylor?
Banchereau: The progress of our research benefits Baylor in a number of tangible ways. One is the significant image that we have in the international scientific community. Our work is well known around the world. Other faculty members and I are constantly being asked to present the results of our research across the USA as well as throughout Europe and Asia. Baylor is globally recognized as a place of high-quality research. This impacts many areas of Baylor beyond just BIIR. Patients come from all over the country to get our dendritic cell vaccine; some have even come from Mexico, Canada, and France.
BIIR has initiated a program to recruit exceptional physician-scientists who will see patients and conduct clinically relevant research. We are committed to offering Baylor patients the most recent therapies by conducting clinical trials with the latest drugs. This will bring more patients to the hospital. BIIR currently has four physician-scientist faculty members (Figure 7): Virginia Pascual, a pediatric rheumatologist who sees patients at Scottish Rite Hospital; Wenru Song, a member of Texas Oncology; Michelle Gill, a pediatrician from UT Southwestern specializing in infectious diseases; and Lei Li, a geneticist who is involved in the development of our diagnostics program. By the end of the year, we expect to have more physician-scientists, including Shinichi Matsumoto, who will be starting soon. We are in the process of identifying others.
Figure 7.
Virginia Pascual, MD, Wenru Song, MD, PhD, Michelle Gill, MD, PhD, and Lei Li, MD, PhD.
Our research has led to clinical trials in a number of areas. We are starting our seventh clinical trial to test dendritic cell–based vaccines for metastatic melanoma. The successes that we have seen from these trials obviously benefit the patients involved but, ultimately, Baylor becomes even more recognized as an innovative medical center that is pursuing cutting-edge clinical research. We see Baylor as the Mayo Clinic or the Cleveland Clinic of the future.
The research into dendritic cell–based cancer vaccines led us to create a spin-off company, ODC Therapy, which will carry these vaccines through the clinical trials process to the marketing stage. We are currently in talks to create a second spin-off company specialized in diagnostics. We have licensed the rights on the treatment of lupus to Argos Therapeutics, which sublicensed it to Novo Nordisk. Some day significant royalties may come back to the institute if the product is efficient and sells well.
Ramsay: The institute building, the Zelig H. Lieberman Building, is really unique. Tell me a little bit about your thought process in helping to design it.
Banchereau: To be an architect on the building, so to speak, was a very important element of the equation and represented one of the attractions for me to come. We needed to create a building whose structure would entice scientists to interact, as this is a critical step in the progress of research (Figure 8). We created a lot of meeting spaces. We also made sure that the scientists would also be directly connected to their labs. There was the option of putting all of the faculty together in the corner of the institute, but then they would have been separated from their labs. I don't think that is good. So we have the right balance in terms of the scientists being in connection with their labs and the scientists being able to talk to each other. However, we are a little short of space now, particularly since we are trying to increase the number of faculty. The core facilities are in the center of the building, and the laboratories are on the periphery. The Marvin Stone Library overlooks a shaded lawn and houses our journals and books. Marvin kindly provided antique microscopes from his private collection, which are on display in the library (Figure 9).
Figure 8.
The Zelig H. Lieberman Building.
Figure 9.
A panel from the Marvin Stone Library on the second floor of the Lieberman Building, showing books and some of the microscopes that were donated by Dr. Stone from his private collection.
The institute had to be beautiful; I made a big point of it. In 1996, the Baylor campus had very little research, as many small programs were discontinued to focus resources on an integrated human immunology program. This decision had been made in 1993 by a group of physicians and Baylor executives. They had to identify a leader, which took a few years. We had to recruit a new team, and moving scientists is difficult. They like to go into established institutions where they are all communicating. That's why you have 18,000 people in Bethesda doing science at NIH. Therefore, there was a need to do something special for us to be able to attract people. At the beginning, we had a very difficult time convincing people that something special would come out of the institute. But today, 10 years later, when we have demonstrated that we can do good science, people aren't so anxious about coming because they like the building and see in it Baylor's commitment to the operation and because they like the people working in it.
Ramsay: So now the building is full, and we need a second building. What's your plan for the second building? Would you like to have a look-alike or something very different?
Banchereau: Well, that's a good question. I love art and have a lot of different kinds of paintings and sculptures at my home. I love architecture as well, and the metroplex is blessed with gorgeous buildings made by fabulous architects. Well, if I had to make the choice, I would like the second building to be a glass building—glass and stainless steel, like the Institutes of Medicine at Harvard. They are very nice buildings. I think that the glass building would allow the reflection of the Lieberman Building.
Ramsay: You've been termed the “father of dendritic cells.”
Banchereau: Some have called me that, but my friend, Ralph Steinman, deserves that title more than I do. My group was certainly fortunate to find a method to grow large numbers of dendritic cells in vitro in 1989. This method has made the study of dendritic cells considerably easier.
Ramsay: Can you talk a little bit about the initial discovery of dendritic cells?
Banchereau: This is a great question. I always like to ask people how they discovered something. This discovery was in some ways serendipitous, unlike our discovery of an efficient method to make human monoclonal antibodies. With my DNAX colleagues, we had discovered granulocyte-macrophage colony-stimulating factor (GM-CSF) in 1984, and in the subsequent years we were trying to find clinical applications for this molecule. So we were testing GM-CSF on human bone marrow hematopoietic stem cells. We were thinking that GM-CSF in combination with another cytokine could create a better drug. My bright undergraduate student, Christophe Caux, put hematopoietic stem cells in culture with GM-CSF and TNF. At that time, in 1989, everybody said that TNF blocked hematopoiesis. What a surprise! In those cultures there was an extraordinary amplification of cell numbers. We said, “Oh, that's interesting. You know, we could think about this combination for facilitating bone marrow grafting.” However, in 1990, we noticed that the addition of TNF to cultures resulted in a change of the phenotype and morphology of the expanding cells. We realized that we had found a way to make large amounts of dendritic cells and felt it was an important discovery, as people were studying them essentially by purifying them from tissues with great effort.
Now, I had barely heard of dendritic cells in 1990. Ralph Steinman had discovered dendritic cells 17 years earlier. My real merit at that point was to recognize that we were making dendritic cells, thanks to my reading Ralph Steinman's article. We managed to convince Schering-Plough that this was worth exploring a little further.
Ramsay: What would you say is your initial seminal paper on dendritic cells?
Banchereau: It was published in Nature in 1992 and has been cited more than 1000 times. It's our hallmark paper.
Ramsay: And that makes you the most quoted French author, is that correct?
Banchereau: Actually, I'm currently the fourth most cited scientist in the world in immunology. I don't think that this will last long. I have been much less productive since I've been here, for a hundred reasons. Not that I work less—I think that I work more than I have ever worked in my life—but we had to build a whole program from the building design and construction to the recruitment of each scientist working in it. Furthermore, by nature, translational research does not allow a very high publication rate. And that means that I don't write as many papers as I used to. It could be a little frustrating, but for me being the most cited isn't really a goal in life but rather an important tool to demonstrate the validity of our approaches. We currently have a lot of good papers in the pipeline. Yet it is also important to push publications for our students, postdoctoral fellows, and young faculty. As scientists like to say, “Publish or perish.”
Ramsay: What are some of the most successful discoveries or technologies you've managed to develop based on your study of dendritic cells?
Banchereau: The study of dendritic cells at Baylor (Figure 10) brought us to make major unexpected discoveries, which I'm very proud of. One is the understanding of lupus. This autoimmune disease affects mostly women and is characterized by periods of severe symptom flares that affect many different systems and organs throughout the body. We demonstrated that an excess of interferon circulating in the blood of lupus patients is critical in generating an excessive number of dendritic cells. This induces what we call, in our immunologist jargon, a break in peripheral tolerance. In other words, normally our dendritic cells function to eliminate the lymphocytes that might be reacting with our own molecules. In lupus, the dendritic cells become activated by interferon and activate rather than inhibit these pathogenic lymphocytes. We have now made a monoclonal antibody that can neutralize this excess of interferon. This monoclonal antibody is now licensed to a large company, Novo Nordisk, and hopefully will be a success.
Figure 10.
Dendritic cells are composed of multiple subsets, each with different functions in immune response.
I am afraid that we have not done very well in business development to ensure a smoother transition of our research discoveries into industry. This is important because the end product of translational research is drugs or diagnostic tools to help cure humans. Together with Bill Duncan (Figure 11), BRI's chief operating officer and chief scientific officer, we are working on several strategies to improve the development side of our inventions.
Figure 11.
William Duncan, PhD, Baylor Research Institute's chief operating officer and chief scientific officer.
What might be one of my most important contributions to human immunology is the work with Virginia Pascual on systemic arthritis. This terrible disease in children is characterized by high fever, rashes, and arthritis that can last for years. The cause was unknown and the treatment very difficult, based on the administration of steroids and anticancer agents. We started studying children with systemic arthritis 3 or 4 years ago, and within 2 years we understood the basis for the disease: an excess of IL-1. In addition, we found a treatment, a drug that was available but barely used, Anakinra, an IL-1 receptor antagonist. It's not the definitive treatment because the drug doesn't have good pharmacokinetic properties, but it's now the standard of care. We expect better IL-1 antagonists to reach the market in the future. So for me it's one of the most important things that I have done. Hopefully, this work will also help us obtain funds in the future.
Another unexpected discovery relates to the role of IL-13 in breast cancer. Karolina Palucka (Figure 12) discovered in a humanized mouse model of cancer that T cells infiltrating breast cancer produce IL-13, a cytokine that was actually discovered in 1989 by one of our faculty, Gerard Zurawski (Figure 13), when he was at DNAX. Interestingly, this cytokine is critical in the production of immunoglobulin (Ig)E, the mediator of allergies. We have shown in animals that blocking IL-13 prevents tumor growth, and we are now developing a program to prove this in humans. Phase I trials might be launched in less than 3 years.
Figure 12.
Karolina Palucka, MD, PhD, the Michael A. E. Ramsay Chair in Cancer Immunology.
Figure 13.
Gerand Zurawski, PhD.
Ramsay: Since you've developed a platform to discover the abnormality in an autoimmune disease and to be able to block it or treat it, you can apply that knowledge to a lot of different autoimmune diseases.
Banchereau: Yes. In some way the discovery in systemic arthritis is not directly related to our dendritic cell studies. The dendritic cell studies carried out in lupus permitted us to develop a global strategy to study human diseases. The strategy includes cellular immunology and genomics. Actually, our genomics program is moving swiftly, and many of the genomics tools that we have developed in the past 5 years for the study of lupus are being applied to the study of other diseases.
Ramsay: So you could apply this to other diseases?
Banchereau: Absolutely. This is what we are doing. We have a third disease, which I cannot discuss yet other than to say that we think that we have something quite interesting. We are just overwhelmed with the novel findings that we are making by studying patients. BIIR just doesn't have enough scientists to pursue all of the findings and, I have to admit, it is often a tough call to prioritize what should be done first.
Ramsay: It is really a very exciting time at BIIR.
Banchereau: Yes, it is very exciting. We are like kids in a candy store. I wish that I could bring in some more senior scientists to share the excitement with.
Ramsay: But you are now attracting very senior people to come and join you.
Banchereau: That is correct, and that is a good sign of our success. But we need to work hard to keep our scientists happy, as many other institutions now look into our program and make offers to them!
Ramsay: Talk a little about the cancer vaccines, because most people see vaccines as preventing a disease. You are actually using a vaccine to control or cure a disease.
Banchereau: Yes. This is called a therapeutic vaccine, in opposition to the classic preventive vaccine. Here, together with Karolina Palucka and Joe Fay (Figure 14), we are trying to initiate in the patients an immune response that will destroy the cancer cells. This is difficult, because as everyone knows, cancer is a tough disease, particularly in the advanced stages. Most of the progress made in the field of cancer in the past 50 years applies to the early stages of the disease, when it can be managed. The late-stage patients are the ones that we are studying, for obvious ethical reasons. So we are putting our fate and faith in a very complex situation where we are trying to induce a strong immune response in a patient who is very immunosuppressed by his or her tumor. It is definitely very complex. We approach it by taking the white blood cells from the patient and isolating the precursors of dendritic cells. We then culture them in a bag for 3 to 9 days in the presence of defined growth factors to differentiate them into dendritic cells. We load the dendritic cells with the patient's cancer—not exactly the patient's own cells but a cell line of the same cancer that the patient is suffering from (Figure 15). We inject the loaded dendritic cells under the skin of the patient's arms and legs. We have seen spectacular clinical responses (Figure 16)—but not in all patients, only in about 1 in 10. The effects, however, are really long-lasting and very dramatic. We need to reach 15% on the large scale, which means more than 20 clinical responders out of 150 treated patients.
Figure 14.
Joseph Fay, MD.
Figure 15.
Vaccine generation. (a) A patient's monocytes are isolated, cultured, and activated against cancer cells. Aliquots of vaccine are cryo-stored in nitrogen vapor. (b) The vaccine “filling station,” where aliquots of each vaccine are transferred to individual vials. The vials are labeled, capped, and sealed.
Figure 16.
Dendritic cell–based vaccines loaded with killed allogeneic melanoma cells can induce durable clinical responses. (a) Baseline status of the patient, who was diagnosed with malignant melanoma in December 2000 and experienced progression in June 2002, despite multiple resections, intra-arterial perfusion chemotherapy, and cytokine therapy. (b) Status in November 2003, after the patient had received 7 vaccines. (c) Status in September 2004, 10 months later. The patient had a complete response by January 2004. Reprinted from Palucka AK, Ueno H, Connolly J, Kerneis-Norvell F, Blanck JP, Johnston DA, Fay J, Banchereau J. Dendritic cells loaded with killed allogeneic melanoma cells can induce objective clinical responses and MART-1 specific CD8+ T-cell immunity. J Immunother 2006;29(5):545–557 with permission from Lippincott Williams & Wilkins.
Ramsay: When you say that responses are long-lasting, give me an example.
Banchereau: Our first patient, Brian Monaghan, had metastatic melanoma in the brain. That tumor was removed, but he had another lesion in his belly. That lesion disappeared during the vaccination process and he is alive 7 years later (see sidebar). This is not the most impressive case. We have about four spectacular cases where massive lesions have disappeared. We are now setting up clinical trials that will permit us to rigorously assess the true response rates. In the past 2 years, we've made considerable efforts to design a vaccine that can be used for large-scale multicenter clinical trials. We believe that we have a vaccine that is nearly in its final version. We are still putting the final touches on it, but we are close to being done with the vaccine composition. What we now need to do in these patients is to counteract the overall immunosuppression that they suffer from. A team led by Joe Fay and Karolina Palucka has accrued five patients in a novel trial where we inject cyclophosphamide to remove the cells that suppress immune responses before the dendritic cell vaccine is administered. We are interested in testing new drugs that are not yet on the market. We think that in the long term a combination of a dendritic cell vaccine with certain chemotherapeutic agents will be the standard therapy for cancer. I remain convinced that one day soon we will see 50% dramatic clinical responses in metastatic melanoma.
Ramsay: Do you see this as curing or just controlling cancer?
Banchereau: We see patients whose tumors shrink considerably and others who show no shrinking of their tumor but seem to live long without expansion of their tumors, which is surprising since we accrue patients whose tumors are actively growing. So I think that it will be both. Now our current studies include patients with a very heavy tumor burden. On the long range, after we have been able to demonstrate some efficacy in these very sick patients, we will go to patients with less tumor burden, and everyone expects that they will probably respond better. These trials are going to last a long time, at least several years, because these are going to be stage III patients. So we need to be able to support these trials through the revenues generated by commercialization of a product for patients with metastatic disease. I don't think that it will take us long. We may be very close to reaching success. So we will pursue our efforts for several more years.
Ramsay: You have actually developed a company to help do this.
Banchereau: Yes, absolutely. With Baylor's strong support, we have developed ODC Therapy. When I first visited Baylor in February 1996, I asked Boone Powell whether it would be possible to build start-up companies. He quickly responded yes, and I came on board that day! It was not in the tradition of Baylor to establish such biotechs, so it took a lot of effort and searching. ODC Therapy is permitting us to go to the next level. We now have a dendritic cell vaccine that is of industrial quality and can eventually be commercialized as such. We need to raise more funds to do large-scale trials. Basically, to reach commercialization of a metastatic melanoma vaccine, we need to raise about $150 million. That is the number that business people have come up with. So our chief executive officer, Karen Hargreaves, is working hard to raise the necessary money.
EXCERPT FROM CANCER AND LAUGHTER BY BRIAN AND GERALDINE MONAGHAN
Brian was the first recipient of the dendritic cell–based cancer vaccine in our first clinical trial. (Roman text is by Brian; italicized text is by his wife, Geraldine. Reproduced courtesy of the authors.)
Dendritic cell vaccine
Brian was really excited about getting into the program at Baylor. Me—not so much. However, I was kind of boxed in. I was the one who—since the day we received the diagnosis—had been selling him on the idea of pushing the envelope. I had told him that we would be like the guys on Star Trek and “go where no man had gone before.” Now, it was time for me to put up or shut up. I don't think I was really ready for him to be the first patient for this program, but he believed in it so much and I recognized how important that belief was. And the more I learned about the dendritic cell vaccine, the more I became a believer, too.
It wasn't easy to boil this all down into a concept that we could understand, relate to, and want to rally around! I spent quite a bit of time trying to get a handle on this. … My layman's explanation as I presented it to Brian was certainly far from scientific … probably far from correct … but it's certainly more graphic! Here goes: the problem with cancer is that even though we each have cancer-fighting cells within us (called “killer” or “T” cells), for some reason those cancer-fighting cells lose their ability to recognize the bad cancer cells floating around in the bloodstream. They still have the ability to fight; they just don't know what the target is! So—into the bloodstream come an army of dendritic cells, and they are sent to all the crossroads of the body's bloodstream (to the armpits, groin area … the lymph nodes). I even gave the dendritic cells a face and personality… . I decided that they looked like yellow, smiley-faced “pac men” (if you're old enough to remember the first video games). In my scenario, these pac-men came equipped holding signposts. On the signposts were descriptions of the evil, horrible cancer cells, with the dendritic cells telling the other cancer-fighting cells, When you see these evil cancer antigens, you are to recognize them for the evil things that they are, and you are to destroy them! In essence, the program is one of “search and destroy.”
On 9/22/98 we went to Dallas to begin the preparations for the dendritic cell program. The people involved in the program were all great to us, and everyone went out of their way to make us feel special. We spent time with Dr. Jacques Banchereau, a dedicated scientist who was passionate about the work he and his group were doing. We would come to know him better in the coming years and consider him a friend, but for now we were both focused on moving forward with the program.
March 1999: the dendritic cell program resumes
Finally, in March of 1999, we began the dendritic cell vaccine program at Baylor University Medical Center in Dallas, Texas.
Without going into all the details, from early March until the first vaccine injection was administered on April 8th, we traveled to Dallas several times in preparation for the vaccine itself. First, Brian was put through the usual battery of tests, including more MRIs and CT scans.
Then they began a series of injections of Neupogen, a drug designed to build up my blood stem cells, the cells that the dendritic cells are made from. This was followed by a procedure called “leukapheresis,” where blood was taken out of one arm, put through a machine which collected the blood stem cells and separated those from other blood cells, and then returned to the blood via another IV line in the other arm.
Once they had collected enough stem cells, we went back home. At that point, Dr. Banchereau, his close collaborator, Dr. Karolina Palucka, and their team of scientists went to work. I know that there are many people who really get into understanding the exact science of what they're going through, but … we decided to leave the technicalities to the scientists. Once we had both reached a level of trust in them, we decided that we could do no more. I do know that they spent many long hours working on Brian's individualized vaccine, and those hours were really just the accumulation of 10 years of research and work they had already done. We can't begin to understand or truly appreciate the work that these dedicated scientists do to help save lives.
April 8, 1999: the initial dendritic cell injections
All of their research and years of hard work came to fruition on April 8th, the date I received my first injection of the melanoma vaccine. They hand-carried the vaccine over to the hospital from their lab, and it's not an exaggeration to say that they carried it with an air of reverence. I thought that I had been waiting for 10 months, none too patiently, for this vaccine to arrive. But at that moment, Gerri and I looked at each other with the realization that these dedicated scientists had been working on, and waiting for, this particular moment for more than 10 years, not just months. Our wait had been absolutely nothing in comparison. Gerri and I both recognized that for many of these people, this could well be a moment of great significance in their long and often frustrating battle against cancer. We have come to learn that in many ways, these two scientists and the wonderful team with whom they work have put their personal lives on hold and dedicated themselves to working on this vaccine. I have to tell you that I really felt privileged to be the first person to receive it. It was an honor to be the recipient of their hard work.
The room became totally silent as the three subcutaneous injections were given by Dr. Joe Fay—one in my arm and one in each of my thighs—and as the last injection was given, everyone in the room broke into applause. Then, we all waited. And waited. I remember no sense of fear or even concern. I really had complete faith and trust in Dr. Banchereau, and so I was very calm. Not so Dr. Banchereau. He was wired! He looked like “a cat on a hot tin roof.” Every few minutes Jacques would say in his deep French accent, “Brian, do you feel anything? Anything at all?” Jacques has come to be a good friend, and in the past few years, we have shared many stories, some great wine and food, and much laughter.
A home run
Throughout the summer of 1999, Brian continued to receive “all clears” from the MRIs and CT scans, and in early August, Dr. Banchereau called with “very exciting” news. Those are his exact words. Brian of course, being the eternal optimist, translated that into the phrase “a home run.” The blood testing had demonstrated a strong response from his immune system with an increase in both his “killer” cells and their “helper” cells. To say that we feel lucky, blessed, or privileged to have been part of this program is simply a vast understatement. We stay in touch with the people at Baylor, and whenever Brian or I can go anywhere to speak on their behalf, we do so with the feeling that we can never repay them.
More than 5 years after the experimental part began there is hope for cancer patients through dendritic cells. Since that time there has been absolutely no indication of cancer in either my brain or my lymph nodes. As a demonstration, Baylor invited me and another cancer survivor to come to Dallas and discuss the effects of the dendritic program. The other patient's circumstance was even more dramatic in that the melanoma was visible as black spots on her legs. She had tried the most radical chemo imaginable at M. D. Anderson in Houston, but it had been completely unsuccessful. The photos of her condition after treatments at M. D. Anderson and then later at Baylor were startling! She and I agreed with a sense of joy that we might be able, in our own small way, to help so many other cancer patients.
I guess that the one thing I can do is to emphasize the importance of looking at, and taking part in, clinical trials. Maybe it was easier for me to do this than for some, because my odds were so bleak and the course of medical treatment for stage IV melanoma held such little hope. Maybe it's just always been my nature to take risks.
Ramsay: Do you see this as a wonderful opportunity for a forward-looking group of investors?
Banchereau: I definitely think that it is a great opportunity. It is a field where investors are currently rather cautious, as they were 10 to 12 years ago in human monoclonal antibodies. Today everyone wants to invest in human monoclonals. Soon many people will want to invest in cancer vaccines, as success is inevitable and will lead to a gigantic market.
Ramsay: BIIR is also working in an area that has a strong history at Baylor, organ transplantation. You hold the Caruth Chair in Organ Transplantation Immunology. What is being done to improve tolerance for transplant patients?
Banchereau: Thanks for asking about that. We have a lot going on in the area of transplantation research. I have held the Caruth Chair for 2 years now and am extremely grateful to the Caruth Foundation and the Communities Foundation for establishing the chair. We have been working toward what we call “the Holy Grail of transplantation,” which is complete acceptance of the engrafted organ without the need for immunosuppressive drugs.
Our program has two main components. First, we seek to identify predictors of tolerance and rejection in the blood of transplant recipients. We have launched a program to identify the biosignatures of graft acceptance in blood from liver transplant recipients. We generated gene expression profiles for 110 blood cell samples from healthy volunteers and study groups comprising liver transplant recipients. We obtain biosignatures for these patients through a combination of microarray analysis of RNA transcripts, flow cytometry, and cytokine profiling. We are now mining these findings with great depth. We also hope to be able to predict early on whether an organ will be rejected. This will permit us to adapt the medication to avoid the rejection.
The second component of our research in organ transplantation is to induce graft-specific tolerance through the manipulation of the dendritic cell system. We have demonstrated that RSV renders dendritic cells tolerogenic by altering their maturation, which inhibits their ability to promote T-cell proliferation. We are learning from this model how to manipulate dendritic cells to induce tolerance. This is another great example of the importance of having an institute that focuses on diverse aspects of the immune system. By studying how respiratory viruses circumvent the immune response, we have made a significant finding that may be important in establishing transplant tolerance.
The organ transplant program is about to receive a huge boost with the arrival of Dr. Matsumoto in the coming months. His research lab will initially be set up in the Lieberman Building, where the islet cell isolation lab is currently. In a year or so, both laboratories will move to Baylor All Saints Medical Center in Fort Worth, where Dr. Marlon Levy operates. This move will also establish a presence for BIIR in Fort Worth. It will essentially be a “BIIR West” campus.
Ramsay: Please talk a little bit about your team.
Banchereau: Of course. The team is the source of BIIR's successes (Figure 17). Everyone in the institute, at all levels, makes up our team, and the interactions across all of the levels are exciting. The strong support from John Fordtran first and then you, Mike, as president of BRI and the addition of Bill Duncan as chief operating officer have all been very fundamental to our current success. Those are the leading “angels” and, of course, all of the upper management team at Baylor. Joel Allison, Gary Brock, Lydia Jumonville, and John McWhorter all support our endeavor with great enthusiasm and Baylor funding. As for the team at the institute, we are now 12 investigators and a total of around 80 scientists altogether, with a very small but highly efficient support staff.
Figure 17.
Staff of the Baylor Institute of Immunology Research in 2005.
Ramsay: Why don't you say a few words about the investigators at the Institute?
Banchereau: I could talk for several hours about them. Each one is unique; each one brings a specific expertise to the institute. I would like to start with Karolina Palucka. She came as a young investigator in early 1998, and she now holds the Michael A. E. Ramsay Chair for Cancer Immunology. She has been essential in many aspects of the institute. She has courageously developed and tackled many projects. She is now more focused on the development of the cancer program and, most particularly, the dendritic cell cancer vaccine as we are carrying out several clinical trials.
Joe Fay was essential in my recruitment. As director of the bone marrow transplant program, he was pushing very hard in 1996 to recruit me here because he knew that bone marrow transplant, which has great successes, is still a risky therapeutic intervention. He believed that, in the long term, dendritic cell therapy might supplant some of the indications of bone marrow transplants. We are not yet there but hopefully we will make it happen, and Joe has been taking care of all of the melanoma patients and all of the healthy volunteers. This is a very important job and we are grateful that, thanks to him, we are now expanding our vaccine centers around the country, where we are starting new multicenter trials.
Virginia Pascual, a pediatric rheumatologist and a collaborator for nearly 15 years, has also been essential to our success. Virginia and I collaborated on B-cell subsets while I was still working on them in France. We became good friends when I went to UT Southwestern as a visiting professor. Actually, Virginia was the one who added the touch that made me leave France for Dallas by saying that Dallas had the best airport in the world, meaning that I could easily go back to France for a visit if I got homesick. Through her daily access to patients suffering from autoimmune diseases and her commitment to them, we have been able to perform complex and lengthy studies. Indeed, she was for many years the director of the pediatric rheumatology division at UT Southwestern. She was then doing her research at BIIR. She has been a full-time Baylor investigator for 2 years now.
A more recent recruit, a senior investigator, is Gerard Zurawski, who brings a lot of expertise in molecular biology. Gerard and I go back 25 years. Gerard was recruited in 1981 by DNAX in Palo Alto, California, the same year that I was recruited at Schering- Plough France. At that time we did not know each other, but Schering-Plough bought DNAX 6 months later. That is how we became colleagues. One of the great BIIR recruitment successes was to bring Gerard and his wife, Sandy, two Californians, from California to Texas. I think that this was really extraordinary, as they are tremendous molecular biologists and protein chemists, an area where we lacked expertise. For many years, Gerard had been the director of the Department of Molecular Biology and Biochemistry at DNAX. Their main area of research is the development of novel vaccines composed of fusion proteins between antibodies specific for dendritic cells and antigens of choice. We have just recruited two more Californians as faculty members, Wenru Song and his wife, Lei Li.
Ramsay: Wenru was at Stanford, wasn't he?
Banchereau: Yes, he was at Stanford working with Ron Levy, the world leader in lymphoma research. Wenru is a medical oncologist whose recruitment is another landmark for BIIR. He is the first physician-scientist recruited for a joint appointment between BIIR and Texas Oncology. Wenru will accelerate the development of highly innovative clinical trials in the field of lymphoma.
We have also recruited a number of young investigators (Figure 18). John Connolly comes from Dartmouth and is an expert in cell biology. He is dedicating most of his resources to the study of RSV, a virus that makes infants severely ill. John is also in charge of a lot of equipment, from fancy microscopes to new tools that permit a detailed analysis of proteins.
Figure 18.
Young investigators John Connolly, PhD, Damien Chaussabel, PhD, and Hideki Ueno, MD, PhD.
Damien Chaussabel, our young bioinformatician, has been essential in the development of our genomics program. He has developed sophisticated approaches to analyze the expression of genes in blood samples. We are trying to establish another start-up company focused on genomics-based diagnostics. Virginia and Damien have been fundamental in the development of this company. Karolina and our collaborator from UT Southwestern, Octavio Ramilo, as well as many others have also been contributing to this program.
I would also like to talk about Hideki Ueno, a pediatric oncologist from Kyoto University in Japan. He came here as a senior postdoctoral fellow and now is an assistant investigator. He works in two areas. First, he is the director of the immunomonitoring core facility, which analyzes the immune response of patients who receive our dendritic cell vaccine. Second, he is developing a research program centered on CD4+ T cells, including regulatory T cells, which are detrimental in cancer and infectious diseases. These cells might, however, be lacking in autoimmune diseases and might prove useful in the transplant setting.
Michelle Gill, a young physician-scientist, is an assistant professor at UT Southwestern whom I have trained here during the past 3 years. She is a pediatrician specializing in infectious disease. She will soon have an independent lab at UT Southwestern, and we will continue to collaborate.
Recently, we recruited SangKon Oh from the National Cancer Institute (Figure 19). SangKon is very involved with the Zurawskis in the development of our next-generation vaccine, where we are making fusion proteins that target dendritic cells. We are now concentrating on flu H5, the avian flu, and we are also getting started in generating novel vaccines against melanoma and prostate carcinomas. We plan to start to work on an HIV vaccine in the next few months. We would like to go to the Bill Gates Foundation once we have formally proven that our methodology is promising.
Figure 19.
SangKon Oh, PhD.
Last but not least, I want to make special mention of the phenomenal support team that we have with Cindy Samuelsen, Carson Harrod, PhD, and Nicolas Taquet. Carson, the head of scientific communications, prepares, among other tasks, our nearly monthly press releases, which show our successes in grant awards, recruitment, and published papers. Cindy works in all aspects of the institute, while Nicolas takes care of all of the technical issues.
Ramsay: You have trained a lot of scientists as well.
Banchereau: Over the past 20 years, I have had the privilege of recruiting and training many students, postdocs, and young faculty. Most of them are very successful. I would like, however, to give a special mention to my close friend, Yong-Jun Liu, whom I recruited as a young faculty member at Schering-Plough in 1991 and with whom I worked for 5 years until I came to Baylor. We published more than 50 papers together, and we still interact a lot as he is also in Texas now. He is the very successful chairman of the Department of Immunology at M. D. Anderson Cancer Center in Houston.
Ramsay: You collaborate with a number of academic institutions.
Banchereau: We do collaborate, almost worldwide actually. I was fortunate to work at Schering-Plough when I was in France, and my close colleagues were in California, in Palo Alto. It is almost home for me, as I went there so many times. We managed to work in spite of being 10,000 miles apart, and we have had so many accomplishments together. In French we say, “Far from the eyes, close to the heart,” which could mean that you work better with colleagues that are 10,000 miles away than with those next door.
Ramsay: That's very good.
Banchereau: One of our weaknesses is that we don't yet have the critical mass of necessary expertise at BIIR. I would like some of my close friends to join Baylor, but it is difficult to move top talents away from major research institutions. So, to get the necessary expertise and to work with top talents, we have established formal collaborations with scientists at Rockefeller University (Ralph Steinman and Michel Nussenzweig) and at Yale (Ira Mellman). We also collaborate with people in New Mexico and at UT Southwestern, as well as with groups in Japan, France, and Mexico and wherever else it takes. We are in the process of establishing a partnership with the leading immunology institute in France, the Centre d'Immunologie de Marseille Luminy. The expertise of both groups is remarkably complementary, as their institute focuses mainly on basic immunology while we focus on human immunology. Collaboration is actually part of the fun of scientific life. You now understand how I earned executive platinum status on American Airlines!
Ramsay: The young scientists that you work with and the students seem to be a fairly international group.
Banchereau: The group is very international, and we think that is tremendous for multiple reasons. We think that science progresses by having people look at things differently, and this comes from having different educations. Doctoral and postdoctoral training is very fundamental in science. It allows you, in your younger years, to establish many friendships, and then 20 years later, when you have become a senior scientist, you have friends all around the world. These friendships that you developed when you were a postdoc are going to be there the rest of your life. These are the many important reasons for a good research center, which, among other functions, has the vocation to train the new generation of scientists, to welcome people from everywhere in the world. Actually, Dallas is an amazing melting pot, by the way.
Ramsay: So what are the essential tasks of the institute now?
Banchereau: What do we need to do in the short term? I see three areas: 1) a reinforcement of the institute's senior group and management; 2) a development of our scientific and medical missions; and 3) a development of our relationship with industry. Regarding management, we need to recruit one or two strong individuals who are going to share some of the responsibilities for the institute's goals. I am thinking of establishing a BIIR executive committee with experts in different specialties—a leader in infectious disease, a leader in cancer. As we are working at developing the Baylor Cancer Center, there might be an opportunity to do something really integrative between the cancer center and BIIR. In some ways, I see BIIR growing like biotechs do, with a chief executive officer/chief scientific officer and several senior vice presidents who will each be in charge of a selected area.
Regarding the development of our scientific and medical missions, we want to attract and recruit more physician- scientists. That means people who are going to see patients and who are going to be in the lab. We are very flexible in terms of the expertise. We focus on highly talented individuals. We want that bridge between the laboratory and the clinic to happen. The recruitment of Wenru Song helps build strong ties with Texas Oncology, which is very important for Baylor's long-term plan of becoming a major cancer care provider in North Texas. Of course, Virginia, our rheumatologist, has been with us for a long time. We want to attract more physician-scientists in the field of autoimmunity. The recruitment of Dr. Matsumoto for our islet cell transplantation program is an important step in this direction. My ambition for next year is to compete for an autoimmunity center of excellence grant from NIAID. I think that we have a good chance, but we need to bring strong clinicians who want to do lots of clinical trials in autoimmunity. Actually, we are planning a retreat this fall with all of the scientists and clinicians involved in autoimmunity research at Baylor.
Hopefully for the infectious disease position, we are going to find a strong person. The search is open. A recruitment committee has been established and will be chaired by Dr. Bill Duncan.
As for the development of our relationships with industry, we need to strengthen both our patent output and patent licensing. We are currently exploring partnerships with a biotech as well as a larger organization, but we do not have the in-house expertise to do it efficiently.
As you see, we are not short of tasks to make BIIR better.
Ramsay: One of the exciting things that you do is the genes of health program. Talk a little about that.
Banchereau: Thanks for asking! That is a very exciting program at the institute which we started 5 years ago. We have invested quite a bit of resources on the vision that is only now becoming accepted by the scientific community. In a nutshell, we are convinced that the analysis of the expression of genes in your white blood cells will replace the traditional counting of these white blood cells, the complete blood count. Compared with white blood cell counts, this gene analysis will be far more detailed. It will tell you which disease you have. For instance, with systemic arthritis in children, it takes us 3 days to diagnose the disease with this methodology. The average time for diagnosis is otherwise between 3 and 5 months, at a time when children start to have swelling in their joints. Therefore, we can now start treatment earlier, before joint lesions appear. The methodology that we have developed has been applied to Virginia's practice at Scottish Rite Hospital but needs to be extended and validated in a much larger community of pediatric rheumatologists.
In lupus, Virginia and Damien have found that microarray analysis of blood leukocytes can predict whether a child is going to have nephritis, which is a dramatic phase of lupus (Figure 20). This will allow us to start therapy earlier and prevent kidney damage. What we don't know yet is how to treat the patients who have a bad prognosis. Virginia and her colleagues, pediatric rheumatologists at Scottish Rite Hospital, will be performing studies on treatment in the next 5 years.
Figure 20.
Using microarrays to identify blood gene expression patterns in lupus patients. Reprinted from Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 2003;197(6):711–723 with permission from Rockefeller University Press.
We believe microarrays can be applied to many other diseases. For instance, as part of our U19 Center for Human Immunology and Biodefense, we collaborate with Octavio Ramilo, a professor of pediatric infectious disease at UT Southwestern. The problem that we are trying to address with him is how to diagnose children arriving in the emergency room. Forty percent of them come with a fever of unknown origin. Five percent of those should go immediately into the intensive care unit. Ten percent to 15% more require standard hospitalization, and the other ones should go back home. The initial symptoms are very similar, so doctors don't know which ones should go where. We believe that this technology will permit doctors to make that determination. The methodology assesses the immune response and indirectly permits us to identify the virus or the bacterium responsible for the fever. Now it takes us 2 days to assess the expression of 40,000 genes. We are working extremely hard to reduce it to 5 hours. To reach this goal, we need to build a start-up company as a vehicle to raise money that does not come from the same pot of money as academic funding. NIH puts money into start-up companies through a specific program called Small Business Innovation Research/Small Business Technology Transfer. Furthermore, venture capitalists invest money into companies but not into an institute like ours. We do think that we have made remarkable progress in identifying diseases by just looking at the genes expressed in the blood cells. This is going to be a tremendous tool that will help physicians in the diagnosis and prognosis of diseases. Indeed, I believe that every one of us will have our blood drawn every year for a gene expression analysis. This will permit early diagnosis of disease before clinical symptoms appear. Furthermore, this will permit us to measure the level of exhaustion of top athletes or to determine whether they are doping!
Ramsay: When you finally decide to retire, what do you think that Jacques Banchereau should be remembered for? What would you like Jacques Banchereau to be remembered for?
Banchereau: Wait a minute, I am still here for a while! What would I like to be remembered for? Two things. First, I am very concerned about my students and postdocs as well as young faculty. I want to be remembered for that effort that I spend with them, that mentoring. Both of my parents were teachers, and education is very important to me. Second, I hope to be remembered for having made a difference for patients. I feel strongly that the study of humans and patients generates much more information in regard to human diseases than the study of mice. Now, I think that we need to study animals, we need to have model systems, we need a lot of basic science, but I think today we are in an amazing position to make a huge difference with respect to disease management because the tools that are available today permit us to study patients in great detail. These tools were not there 15 or 20 years ago; now they are, and I would like to encourage a lot of people to get into studying humans. This is why I am organizing a keystone meeting just on human immunology in early 2007. So that is what I would like to be remembered for. Hopefully, in the next few years, we are going to find some very critical new treatments for the disease scourges of the current times.
Ramsay: Do you see any generational differences in the young scientists coming up in how they approach science, in how they apply themselves, in how they work, or in their work ethic? Because there are clear changes in medicine.
Banchereau: That is a tough question. I speak to a lot of young scientists that have a great enthusiasm. But I am not sure that I can do a proper analysis of whether they approach a problem differently now than we did 20 years ago, particularly since the first part of my career was mostly in Europe and the second part is here. The key to being a successful scientist will continue to be high enthusiasm and hard work. I give many postdocs the book The Agony and the Ecstasy by Irving Stone. It describes the life of Michelangelo. It could have been written about a scientist. I love interacting with people who are fascinated by science, by life, by the mechanisms of life and disease. You have it in you or you don't. I think that it's something that burns inside you for life. One of our latest young postdocs, a Chinese guy, is just unbelievable in this regard.
Ramsay: What will you do when you retire?
Banchereau: Science. I am going to step down as director within 10 years. I am extremely busy attending to the demands of the growing institute, and I realize that I have less and less time to do the in-depth thinking that I have done in the past. I would like to go back to this in-depth thinking, which pleases me and makes me a productive scientist. Now I have to dedicate a lot of my energy to raising money. I have to confess, however, that it is a lot of fun to see the research progressing so fast at the institute. The institute today is really an exciting place. It doesn't stop.
One other thing that we need to do, Mike, is to establish a scientific advisory board. This board will serve several functions. It will advise you, Bill Duncan, and me about our progress. Should we invest more here? Should we cut this program that is not as productive? The board should also help us in the recruitment of new faculty and the evaluation of the current ones. It is very fundamental today as we are growing. We need one meeting every year when our scientists will present their past year's progress and next year's goals to a panel of respected scientists.
But, back to the original question, I am going to do science for another 15 years, until my brain doesn't work anymore (Figure 21). Everything that I have done is for science. Everything is science for me. I see Arthur Kornberg, who was one of the founders of DNAX. He was a Nobel laureate in 1959 for the discovery of DNA polymerase. He published a paper 5 years ago in Science at the age of 83. I hope that I will be able to do that.
Figure 21.
Jacques Banchereau shortly after coming to Baylor.
Ramsay: Is there anything else that you want to say—a personal message or anything that hasn't been stated yet?
Banchereau: I came to Baylor rather than a more established research institute because of two other examples. One is St. Jude Children's Hospital in Memphis. The other is San Rafaelle in Milano, Italy. San Rafaelle Milano was built by a Catholic archbishop who said 20 years ago, “I am going to put a lot of resources to develop science in San Rafaelle Hospital.” This is now the top scientific institute in Italy. I think that Baylor has taken such a path and will benefit tremendously overall.
Let me also take this opportunity to thank all of the doctors and patients that have taken part in our clinical trials. They have been and remain an integral part in the progress that we are making. I would also like to thank the institutional review board office and all of the administration for their hard work on BIIR's behalf. Thanks also to the Baylor Foundation and everyone involved in fundraising. A special and heartfelt word of thanks goes to all of the philanthropists who are doing so much to make BIIR a world-class research institute through their financial contributions.
I want to close by emphasizing my vision. Within the next 10 years, I see Baylor becoming the Mayo Clinic or the Cleveland Clinic Foundation of the Southwest. I imagine a new, futuristic-looking building hosting the Baylor Molecular Medicine Institute, where physicians and scientists will be working together to provide personalized therapies to patients coming from all over the world. I see this building as a glass bridge between Gaston Avenue and Live Oak.
Ramsay: What came across very well is your enthusiasm for science and where science can take us. Thank you, Dr. Banchereau, for taking this time to share with me and the readers the exciting things that are going on at BIIR.
Banchereau: It was my pleasure.
Acknowledgments
Thanks to Carson Harrod for his help in organizing and editing this interview.
KEY ORIGINAL PAPERS AND REVIEWS FROM BAYLOR INSTITUTE FOR IMMUNOLOGY RESEARCH
Key original papers and abstracts
1. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas
Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, Valladeau J, Davoust J, Palucka KA, Banchereau J
J Exp Med 1999;190(10):1417–1426. Reprinted with permission from Rockefeller University Press.
We have analyzed the presence of immature and mature dendritic cells (DCs) within adenocarcinoma of the breast using immunohistochemistry. Immature DCs were defined by expression of CD1a–, Langerin–, and intracellular major histocompatibility complex class II-rich vesicles. Mature DCs were defined by expression of CD83 and DC-Lamp. Breast carcinoma cells were defined by morphology and/or cytokeratin expression. We demonstrate two levels of heterogeneity of DCs infiltrating breast carcinoma tissue: (a) immature CD1a+ DCs, mostly of the Langerhans cell type (Langerin+), were retained within the tumor bed in 32/32 samples and (b) mature DCs, CD83+DC-Lamp+, present in 20/32 samples, are confined to peritumoral areas. The high numbers of immature DCs found in the tumor may be best explained by high levels of macrophage inflammatory protein 3αβexpression by virtually all tumor cells. Confirming the immature/mature DC compartmentalization pattern, in vitro–generated immature DCs adhere to the tumor cells, whereas mature DCs adhere selectively to peritumoral areas. In some cases, T cells are clustering around the mature DCs in peritumoral areas, thus resembling the DC-T cell clusters of secondary lymphoid organs, which are characteristic of ongoing immune reactions.
2. Cross-priming of naive CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells
Berard F, Blanco P, Davoust J, Neidhart-Berard EM, Nouri-Shirazi M, Taquet N, Rimoldi D, Cerottini JC, Banchereau J, Palucka AK
J Exp Med 2000;192(11):1535–1544. Reprinted with permission from Rockefeller University Press.
The goal of tumor immunotherapy is to elicit immune responses against autologous tumors. It would be highly desirable that such responses include multiple T cell clones against multiple tumor antigens. This could be obtained using the antigen presenting capacity of dendritic cells (DCs) and cross-priming. That is, one could load the DC with tumor lines of any human histocompatibility leukocyte antigen (HLA) type to elicit T cell responses against the autologous tumor. In this study, we show that human DCs derived from monocytes and loaded with killed melanoma cells prime naive CD45RA+CD27+CD8+ T cells against the four shared melanoma antigens: MAGE-3, gp100, tyrosinase, and MART-1. HLA-A201+ naive T cells primed by DCs loaded with HLA-A201– melanoma cells are able to kill several HLA-A201+ melanoma targets. Cytotoxic T lymphocyte priming towards melanoma antigens is also obtained with cells from metastatic melanoma patients. This demonstration of cross-priming against shared tumor antigens builds the basis for using allogeneic tumor cell lines to deliver tumor antigens to DCs for vaccination protocols.
3. Immune and clinical responses in patients with metastatic melanoma to CD34+ progenitor-derived dendritic cell vaccine
Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, Taquet S, Coquery S, Wittkowski KM, Bhardwaj N, Pineiro L, Steinman R, Fay J
Cancer Res 2001;61(17):6451–6458. Reprinted with permission from the American Association for Cancer Research.
Immunization to multiple defined tumor antigens for specific immune therapy of human cancer has thus far proven difficult. Eighteen HLA A∗0201+ patients with metastatic melanoma received injections s.c. of CD34+ progenitor- derived autologous dendritic cells (DCs), which included Langerhans cells. DCs were pulsed with peptides derived from four melanoma antigens [(MelAgs) MelanA/MART-1, tyrosinase, MAGE-3, and gp100], as well as influenza matrix peptide (Flu-MP) and keyhole limpet hemocyanin (KLH) as control antigens. Overall immunological effects were assessed by comparing response profiles using marginal likelihood scores. DC injections were well tolerated except for progressive vitiligo in two patients. DCs induced an immune response to control antigens (KLH, Flu-MP) in 16 of 18 patients. An enhanced immune response to one or more MelAgs was seen in these same 16 patients, including 10 patients who responded to >2 MelAgs. The two patients failing to respond to both control and tumor antigens experienced rapid tumor progression. Of 17 patients with evaluable disease, 6 of 7 patients with immunity to two or less MelAgs had progressive disease 10 weeks after study entry, in contrast to tumor progression in only 1 of 10 patients with immunity to >2 MelAgs. Regression of >1 tumor metastases were observed in seven of these patients. The overall immunity to MelAgs after DC vaccination is associated with clinical outcome (P = 0.015).
4. Induction of dendritic cell differentiation by IFN-αβin systemic lupus erythematosus
Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J
Science 2001;294(5546):1540–1543. Copyright 2006 AAAS. Reprinted with permission from the American Association for the Advancement of Science.
Dendritic cells (DCs) are important in regulating both immunity and tolerance. Hence, we hypothesized that systemic lupus erythematosus (SLE), an autoimmune disease characterized by autoreactive B and T cells, may be caused by alterations in the functions of DCs. Consistent with this, monocytes from SLE patients' blood were found to function as antigen-presenting cells, in vitro. Furthermore, serum from SLE patients induced normal monocytes to differentiate into DCs. These DCs could capture antigens from dying cells and present them to CD4-positive T cells. The capacity of SLE patients' serum to induce DC differentiation correlated with disease activity and depended on the actions of interferon-α(IFN-α). Thus, unabated induction of DCs by IFN-αβmay drive the autoimmune response in SLE.
5. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood
Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V
J Exp Med 2003;197(6):711–723. Reprinted with permission from Rockefeller University Press.
Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients' white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P > 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.
6. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6
Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J
Immunity 2003;19(2):225–234. Reprinted with permission from Elsevier and Cell Press.
Dendritic cells (DCs) initiate and control immune responses. Plasmacytoid DCs (pDCs) represent a unique DC subset able to promptly release large amounts of type I interferon (IFN-αβ) upon viral encounter. Here we report that depletion of pDCs from human blood mononuclear cells abrogates the secretion of specific and polyclonal IgGs in response to influenza virus. Furthermore, purified pDCs triggered with virus induce CD40-activated B cells to differentiate into plasma cells. Two pDC cytokines act sequentially, with IFN-αβ generating non–Ig-secreting plasma blasts and IL-6 inducing their differentiation into Ig-secreting plasma cells. These plasma cells display the high levels of CD38 found on tissue plasma cells. Thus, pDCs are critical for the generation of plasma cells and antibody responses.
7. Cross-regulation of TNF and IFN-αβin autoimmune diseases
Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J
Proc Natl Acad Sci U S A 2005;102(9):3372–3377. Copyright 2005, National Academy of Sciences, U.S.A. Reprinted with permission.
Cytokines, most particularly TNF and type I IFN (IFN-αβ), have been long considered essential elements in the development of autoimmunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-αβ plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-αβproduction in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-αβ, from CD34+ hematopoietic progenitors. Second, it inhibits IFN-αβrelease by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-αβsecretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-?-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.
8. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade
Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J
J Exp Med 2005;201(9):1479–1486. Reprinted with permission from Rockefeller University Press.
Systemic onset juvenile idiopathic arthritis (SoJIA) encompasses ∼10% of cases of arthritis that begin in childhood. The disease is unique in terms of clinical manifestations, severity of joint involvement, and lack of response to tumor necrosis factor blockade. Here, we show that serum from SoJIA patients induces the transcription of innate immunity genes, including interleukin (IL)-1 in healthy peripheral blood mononuclear cells (PBMCs). Upon activation, SoJIA PBMCs release large amounts of IL-1β. We administered recombinant IL-1 receptor antagonist to nine SoJIA patients who were refractory to other therapies. Complete remission was obtained in seven out of nine patients and a partial response was obtained in the other two patients. We conclude that IL-1 is a major mediator of the inflammatory cascade that underlies SoJIA and that this cytokine represents a target for therapy in this disease.
Key reviews
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