Chapter 03: Research into Treatment for Gynecologic Cancers
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In this chapter, Dr. Freedman discusses his “travels in the lab,” first explaining how his Fellowship work on cell lines transitioned to the development of vaccines for gynecologic cancers. He talks about the prevalence of these cancers, explaining the special challenge of ovarian cancer. He explains the logic behind the vaccine strategies tested (e.g. intra-peritoneal injection) and the immune mechanisms stimulated, and also notes the clinical challenges faced, which led to work on an approach using T-cells. He then details his work with T-cells, describing some of the equipment used, the procedures attempted, and his evaluation of those procedures, concluding that his work added “building blocks” to the understanding of the immune system, as well as the creation of a mono-clonal human antibody. Dr. Freedman then goes on to talk about the relationship between the immune system and the inflammatory system and his work with ecosinoids and inflammatory responses to tumors. It may be possible, he explains, that if the inflammatory response can be stopped, a tumor will stop growing. He notes that his research has given him new respect for how difficult it is to treat cancer, pointing out that mortality rates for cancer has not changed substantially over the past years. He discusses the difference between private practice and academic medicine then describes what it was like to establish his own laboratory after working collaboratively in others’ labs. He offers his views on translational research. Dr. Freedman then talks about how he dismantled his lab and projects when he decided to retire.
Identifier
FreedmanR_01_20120224_C03
Publication Date
2-24-2012
City
Houston, Texas
Interview Session
Ralph Freedman, MD, Oral History Interview, February 24, 2012
Topics Covered
The Interview Subject's Story - The Researcher; The Researcher; Overview; Definitions, Explanations, Translations; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; On the Nature of Institutions; Evolution of Career; Professional Practice; The Professional at Work; Collaborations; Discovery and Success
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
Tacey Ann Rosolowski, PhD Okay, we're recording again after a brief break for tea. And we were talking about the research that you were doing when you were on your fellowship, and you were just kind of describing how you were transitioning from that research into the next phase.
Ralph Freedman, MD I started to think about translating some of the knowledge that we had in clinical trials, and the first efforts were at developing vaccines for gynecologic cancers—cervix cancer and ovarian cancer—along the lines that Dr. [Joseph] Sinkovics had already done in sarcomas and melanoma. And so he did a trial in cervical cancer patients. It was a randomized trial, and the results were not spectacular. There looked like there was a little bit of a difference. Then we, at about that time—also, I think the HPV story started to come out, and it was clear that there would be efforts to produce vaccines to target the virus, and the incidence of this disease would probably go down, which is what's happening today. Not from the vaccine itself, but from the fact that pap smears are being more widely utilized. I think it is only about ten percent in this country that doesn’t get pap smears. The vaccine, of course, would help to eliminate it all together. In fact, today cervical cancer is not— Let's see, you've got ovary, endometrium, and then cervix as cause of death amongst women, and cervical cancer relatively uncommon.
Tacey Ann Rosolowski, PhD The cervical cancer?
Ralph Freedman, MD Cervical cancer. Also as compared to what we saw in South Africa, where eighty percent of the women were with advanced disease, and it was the most common cause of death from malignancy in black Africans. Here it has become the opposite, where eighty percent are in early stages and only a relatively small percentage now of the patients we see at LBJ—we are at work at the moment. And you see people who are coming from over the border or who basically haven't had any preventative care.
Tacey Ann Rosolowski, PhD Just for the record—I'm sorry—you mentioned LBJ, and could you give the full name of that institution?
Ralph Freedman, MD Lyndon Baines Johnson.
Tacey Ann Rosolowski, PhD And it's the public hospital here—
Ralph Freedman, MD Yes. It's one of the two county hospitals—Lyndon Baines Johnson and then Ben Taub.
Tacey Ann Rosolowski, PhD Okay.
Ralph Freedman, MD So I work there once a week, on Tuesday. I help Dr. [Lois] Ramondetta with her clinic. She does a clinic on Wednesday, I do the clinic on Tuesday, and we'll get to that at some point. So then the next— So the real challenge for us was then, and still is, ovarian cancer.Tacey Ann Rosolowski, PhD I'm sorry. Why is ovarian cancer such a challenge? I had read that—that it's just the biggest challenge for—
Ralph Freedman, MD Well, there's not tests for early diagnosis, unlike the Pap smear, which is early—can pick up early changes on the cervix. There is no early test. The CA-125 is not recommended or approved for early diagnosis, and apart from annual examination, that is all they have today. And the majority of patients are picked up when they have advanced disease, when the mortality is highest. So only about twenty-five percent of patients will survive five years when they have this advanced stage. So that is, and still is, the challenge. And we were thinking of immunological approaches, and I started off developing a—using the vaccine approach because we knew there were immune cells in the peritoneal cavity but they were not doing anything. And basically with, I would say, primitive knowledge that we had at the time, which would have been in the early '80s, we developed a strategy for intraperitoneal injection of vaccines. There was already intraperitoneal chemotherapy. So we thought, “Why can't the intraperitoneal route be used to administer vaccines?”
Tacey Ann Rosolowski, PhD Could you describe what the purpose is of the intraperitoneal intervention?
Ralph Freedman, MD So the approach was, and there was some evidence that if you—and this is from Sinkovics' work that these cells—these cultured cells—if they were infected with a Puerto Rican strain of the virus, which was an attenuated virus so it didn't cause harm, and then you put this new viral antigen onto these cultured cells and then you produced extracts of the cells—so you killed the cell, so of course it can't grow, and you kill the virus as well by using UV light and the methods to destroy virus. If you use extracts of these cells, you can actually stimulate components of the immune system. And during that period, I actually collaborated with Dr. Eva Lotzova, who was—she was originally from Czech—it wasn't Czech Republic in those days, but from Czechoslovakia. And she was a noted immunologist in so-called "natural immunity"—basically, natural killer cells. And we saw, in a number of these patients who were receiving these vaccines, that it was stimulating their natural killer cell function. So we thought this was fantastic because the natural killer cells—if they can kill cells without recognizing particular antigens on cells—they have such a broad ability to kill tumor cells. Somehow they recognize that the cells are malignant. It is not a specific interaction like you have between the T-cell and the tumor. In other words, the T cell recognizes the tumor cell through its T-cell receptor recognizing an antigen that is presented in the context of the histocompatibility complex. It is a very defined, highly developed mechanism of immunity which you basically only get in mammalians. Whereas more primitive species, like earthworms, they only have the MK system. The MK system was always there in the humans. It was a question of whether you could stimulate them, and we saw that this vaccine could do it. So we did treat a number of patients with intraperitoneal vaccines, and we learned a lot about the immune system.
Then they decided not to stay with that system—and a number of reasons for this. And some people seem to think, "Well, you should have stayed with it." But one of the problems was the fact that it's very difficult to quantify what you've got in the vaccine when you're that type of approach. We couldn’t use the patient's own tumor because it was very—we tried, but it was very difficult to grow them to a point that you could infect them with virus. So we had to use cell lines which had no relationship to the individual. So they were histocompatibility mismatched, and also they were extracts. So when you look at all the requirements today that the FDA would require for producing a biological product that would go into humans, it was going to be an impossible kind of task.
So about that time I had a post-doc in my lab, Dr. Constantin Ionnides who later on became an assistant professor in our department, and he worked with me on getting more information about the immune system. His mentor was Dr. Chris Platsoucas who used to be the deputy chairman of Dr. [Margaret] Kripke. You remember when Dr. Kripke was head of immuno—she was head of Immunology, and Chris [Platsoucas], whom I'm still friendly with to this day, was her deputy chairman. Well he was—he was—brilliant fellow—he came from Greece originally. Got his PhD at MIT, and he was an expert in cellular immunology and also molecular immunology. So he was able to sequence T-cell receptors, and he had a tremendous understanding of the mechanism of T-cell immunity. We decided at that time to try to see if we couldn't understand better and work out an approach for using the T cell, because the T cell is a very specific mechanism, and also there's more of them than there are NK cells. And also, the thought was those T cells could actually migrate and target specifically tumor cells.
Also at that time, Steve Rosenberg, who's at the NCI, was working on adoptive therapy. There were some immune therapy approaches that were available. There was interferon with Dr. Jordan Gutterman. He was working with and under—with Hirsch—Dr. Hirsch. That was the clinical department of immunology. There was a political issue because Sinkovics did not get on with [Evan] Hirsch. I liked both of these people, as it happened, but it wasn't easy when you're a fellow, by the way, to go and cross over, especially if your bosses didn't communicate or if your boss didn't communicate with somebody else. That would be a hostile move to go and do that kind of thing. But that's sort of going backward a little bit. But working with Chris was easy because he was in another department. Sinkovics was already gone by that stage. On the vaccines I'd worked with, Jim Bowen who was—he was Tomasovic's predecessor. But before that, he was the acting—I guess the acting chair of Virology. We had a Department of Virology. Ralph Arlinghaus is still in that department. I guess they may be a section now. I don't quite know whether it is a separate department anymore or not. Jim Bowen and I had a good working relationship, and he was the one that helped me develop the viral oncolysates or the vaccines for administration to patients.
But at that time, too, he was— There were changes taking place in his section, and I guess he had been tapped in order to become the Vice President for Academic Affairs, which would mean he would have a limited role. But fortuitously, at that time, I met up with Platsoucas who was a basic scientist and, as I said, had a very fundamental understanding of the immune system. Jim was a virologist, so that was important for the development of the viral vaccines, but Chris Platsoucas was an immunologist—cellular immunologist and molecular immunologist. So we decided to go after the T cell, and along the lines that Rosenberg had developed but this time for ovarian cancer and to try to expand T cells that were sort of—that were activated and to put them back into a patient. And we actually developed—we spent a lot of time on this, and we had funding from the American Cancer Society, and then later we had funding from the National Cancer Institute to actually develop a clinical trial for adoptive immunotherapy. We had some very good preclinical information, obviously, to support it. We developed a technique for growing the cells to very large numbers, and we were able to develop—grow something like ten to the ten—between ten to the ten and ten to the eleven activated T cells from these patients. It had to come from the tumors. So, in other words, these patients had to be candidates for surgery in order to get them. And we did find, though, that it was difficult to grow them from the solid tumors, but we could grow the cells quite nicely from the fluid around the tumors.
Tacey Ann Rosolowski, PhD What were the special dimensions of your technique?
Ralph Freedman, MD Well, we used a device—a special culture device that had media flowing through it, and it had to be monitored so many times a week to measure its glucose because you couldn't wait until the cells were dying. You had to come in sometimes on the weekend. I had dedicated technicians who would come in on a Saturday and Sunday and check the cells, and then if the cells were ready, we had to call the patient in to go and be treated. So it was a laborious and very labor intensive—but very good personnel—actually one of them was Steve Tomasovic's wife, Barbara [Tomasovic].
Tacey Ann Rosolowski, PhD No.
Ralph Freedman, MD Barbara—she's retired now. And she was fantastic because she kept every single detail and with all of that information, we were actually able to describe our technique in Journal of Immunology Methods. So it is there for everyone to read and see—how do you do these things? What types of cells do you get out of it? But essentially there was a little bit of activity but really nothing remarkable, and it was very costly. It cost in time, and it cost a good few thousand dollars per patient. Now, Steve [Tomasovic] is still doing it, and Patrick Hwu, who works in Immunology here, is still doing it for melanoma. But for ovarian cancer it really—there were logistic issues in that the patient had too much burden. Really, what you wanted to be able to do was to reduce the tumor burden to the point at which you could use the cells. That meant you would have to freeze—you would have to grow the cells up at some point and freeze them down, and then when the patient was in remission from the chemotherapy, you could use the immunotherapy. Logistically this was just too much. You're looking at having facilities to store large numbers of cells. You wouldn't know whether you could even use those cells later on.
And I still believe that the immunotherapy approaches which people are still talking about for ovarian cancer are potentially useful, but you would have to use it at a time when the tumor burden had been reduced by surgery and chemotherapy to the point at which it was minimum tumor burden so that the ratio of immune cells to tumor cells was satisfactory. And also, the problem that you have to deal with in ovarian cancer was that the immunosuppressor systems that are in place, and which we now know a lot more about, actually mitigate against using these approaches. So you really have to reduce the tumor burden so that you reduce the amount of tumor suppressive factors that are in the system. We’ve also tried with IL-12, and we had a grant from theNCIto do that because IL-12 was supposed to drive both NK cells and adaptive immunity. And we tried that in patients with the intraperitoneal approach, but, again, the results were not enough to drive this effort. We also tried whole autologous cells, where we took the tumor cells out of the patient. And we got a grant—anNCIgrant—for that study as well. We took the tumor cells directly from the patient and then we put a gene inside those cells to express a factor on the surface that would co-stimulate the immune system. This was developed by Jeffrey Schlom at theNCI. And basically we got the material from him to do it. But, again, we proved that it was not efficient enough to work, and the same problems developed.
So, at that particular point, that went on for several years. It supported my academic contributions, if you will—papers and things like that. And the intellectual side of it, which is—you know—you asked me the question, “Why was it better to be in academic practicing than—
Tacey Ann Rosolowski, PhD Private practice.
Ralph Freedman, MD
—private?" It is a different philosophical— It's a different environment. It's a different way of life. It's different philosophy. Everything is different about it. And one of the good things about an academic practice is that you can ask these questions and you've got time to do this and to think about things and to interact with other scientists and to get excited about things. So I shared—and that was one of the major contributions that Anderson has been to my life is to give me that resource—give me that access to that environment where you can interact, and, of course, to interact with others, even outside the institution. Because Anderson was becoming recognized, as it is today, as a major center. So none of my work contributed to any breakthroughs, but I think we did contribute some building blocks. We learned something about the immune system. Along the way, we developed a monoclonal human antibody to ovarian cancer.
Tacey Ann Rosolowski, PhD What does—? Could you describe what that means?
Ralph Freedman, MD A human antibody is a—up to— Well, I guess in the '80s, most of the antibodies that were used for diagnosis and even for in vivo therapy were raised in mice. And the technique of producing antibody—monoclonal antibody—won Milstein—Cesar Milstein—the Nobel Prize in 1977. And basically what they did is they took immune cells from a mouse and they fused them with the myeloma cell line, which is from a human, so that you had a hybrid cell which had the machinery to make the antibody, but it also had a human genetic—some human genetic machinery in that. And those were the early antibodies. That was the beginning. And it was very appropriate that they received the Nobel Prize because today that same principal has been adopted totally human antibodies. There's no mouse antibody in the system anymore. It's just human antibody, which means that when you put it into the patient they don't get an immune reaction to the antibody. You can use it without getting— Whereas when you used to put the old antibodies into patients, they got what they called HAMA—human antimouse antibody response—which interfered with the activity of subsequent doses. So it was a limiting factor. And today we don't have to deal with that. We did make one antibody—but it was an IgM, and the best antibodies are IGg because they are smaller and they can get into them much more easily. And we had a patent for it, though I think the patent is expired now.
Tacey Ann Rosolowski, PhD That was in 1995.
Ralph Freedman, MD Yeah right. Early on. And that was— We got funding from the state of Texas—what's it? Texas Technology, I think. So we actually produced it, and it was available. And we sent it toATCC for anybody wants to use the hybridoma or the—in producing—the antibody producing hybridoma so they can get acces to it. So again, this—
Tacey Ann Rosolowski, PhD I'm sorry. Could I just—? What does IgM and IGg stand for?
Ralph Freedman, MD Well IG is immunoglobulin. And it's immunoglobulin-G. The first is an IgM response. It is a larger antibody, and it has a short phase, but it's a large molecule. So when you talk about molecules of that size getting out of the vascular tree and into tumors, for example, it's not going to be too helpful. You've got to be able to use an IGg. IGg is what happens when you get a memory response so you get a long-term immunity to a particular infection or a particular antigenic challenge. So IGgs are more useful in practice. Now, today there are molecular techniques for changing IgMs into IGgs, and industry is much involved in that type of thing.
Tacey Ann Rosolowski, PhD Uh-hunh (affirmative).
Ralph Freedman, MD So that carried me through a phase. I think the important thing is a lot of work that's done in the lab is dependent upon collaboration—interaction with others. It's the rare scientist who can do any of this on their own. I think one can always be a little suspicious when you find that a piece of work comes out of one laboratory and there're no collaborators. Because in today's world there's just so many areas of expertise that's needed in order to produce—you know—to advance an idea to the next phase. So I depended—my—as I always say, my career was sort of locked—dependent with the careers of others. Whether it was Sinkovics or whether it was [James] Bowen or Platsoucas, there were always others that were part of this development. We started to get interested—unfortunately it was late in my career—on the inflammatory reactions. Discovered that a lot of—a lot of the changes that take place within tumors actually involve inflammatory changes—inflammatory cells like monocytes and macrophages. And the release of products of the immune response such as eicosanoids—and this is the area, I think, that Dr. [Raymond] DuBois is interested in. I haven't spoken to him about it. And we did some studies. We went back, working with, first of all, researchers at NIH—Franco Marincola and his staff. We actually did microarray studies showing the genetic profile—the RNA genetic profile of ovarian tumors. We were one of the first really to do that. And we focused on the immune and the immune inflammatory environment. So a lot of this supported the work that we had done. And then, also, we saw that there were a lot of inflammatory signals coming out of these tumors. So that led me to look at the eicosanoid story. And actually I worked with Bob Newman who was a pharmacologist at MD Anderson. He left about a year or two ago. And we actually did eicosanoid profiles of ovarian cancer, and actually these profiles—papers published in Clinical Cancer Research. And they took some of our work and they put it on the cover sheet of the journal. Because those pathways could be targets for new therapies. We haven't gotten into that area as yet. There's a very close relationship between the immune system and the inflammatory system. They're sort of part of one big system. But the inflammatory system can drive a lot of these tumors, and if you can find a way to interrupt the inflammatory processes, it may be possible that you stop the tumor from growing. Just like people have spent a lot of effort on angiogenesis.
Ralph Freedman, MD This could be another area of similar importance. And there are about fifty products—I read an article—about fifty products that industry has developed that can interfere with inflammatory processes within tumors. So far we haven't seen many of them coming into—well, there were some like the COX-2 inhibitors that they used in colon cancer.
Tacey Ann Rosolowski, PhD I'm sorry. I missed the name of that.
Ralph Freedman, MD COX-2 inhibition—and these agents were used to antagonize adenomatous growths in patients with pre colon cancer. So basically that is the—my sort of travels in the lab. We had—over the years we had—I supported I think three or four PhD students, and one was an MD/PhD. We did work on the monocyte, macrophage, in ovarian cancer. Amy Loercher got her PhD for papers published in Journal of Immunology on the monocytes in ovarian cancer. Sheri Butts—she was a PhD student who did the work on dendritic cells in ovarian cancer. And then I had some excellent postdocs from outside. And I can single out Dr. [Gabriella] Ferrandina who was from Italy. And she was from the Pope's hospital in Rome. She was outstanding. She got some good papers—nothing to do with immunology, but just looking at some pharmacology of certain drugs. And then Dr. [Robert] Melichar—he came back a couple of times to work with me, and he's now the chair of Medical Oncology in the Czech Republic, so he has his own department. And he got his PhD, basically, with the work that he completed in my lab. Actually, we went to visit him recently, him and his wife and kids, and they took us around Prague. Phenomenal guy—he could speak— I know a lot of Europeans are able to speak many languages, but he could speak five languages. And I had a Japanese student in the lab. And I saw one day he had a Japanese dictionary. So he was busy studying Japanese while he was working with me.
Tacey Ann Rosolowski, PhD He had a real gift.
Ralph Freedman, MD Yes. And he produced some very important—good papers—while he was there. So it was fun to work with the students, fun to work with the postdocs and have this interaction. And there was always interaction with somebody—on a collaborator scale or whatever. That was that aspect of my career. I don’t think we— I think, basically, we contributed some components of knowledge to the disease, but nothing in terms of any earth-breaking treatments. It's fun to look at. It gave me a bit of perspective on how difficult cancer is. Cancer is a difficult disease to treat. And if you can't prevent it, and you've got a disease that causes a significant mortality—and in fact that mortality hasn't changed in the last ten to twenty years—it's a tough road to get into. I know there's a lot of hope that personalized therapies and identifying all these mutations and that be able to— So far what I've seen at the FDA is—because I serve on this Oncology Drug Advisory Committee. It's my third year on it. And a lot of these new drugs come, and they give incremental changes. There are incremental benefits. But you don't get something that wipes out the disease and the patient is cured. So it's been eye-opening to get that side of the picture.
Tacey Ann Rosolowski, PhD
Well, I was really glad that you've described the intricacy of that process by which you were growing those cells, because I don't think the ordinary person who doesn't spend time in a research lab that's related to cancer understands just how delicate the cells are and what you have to do to kind of create the facsimile of a physical environment in order to grow those tumor cells so that you can work on them. It really gave me a real appreciation for the challenge of how to create something to investigate. And I just don't think most people understand how that works and how laborious it is and how complicated the physical systems are that you're trying to tease apart.
Ralph Freedman, MD These cell lines are basic to any type of understanding. And, of course, now we have a registry at MD Anderson of all these lines which we didn't have before. And Ty Hoover who works in the IRB office which I also participate in, he has developed a phenomenal registry now. All these lines that were sitting in people's fridges and so forth have now been identified and catalogued, and they are potentially useful. We have to understand, of course, that a cell line is a little bit artificial because it's been taken out of the host and expanded under culture conditions, and you've selected out certain parts of this—certain cells from that tumor—that are able to grow. And then some of them can't. They don't grow very well. And they may be very important or may be more important than the ones that you actually have in the test tube. So the cell lines are important for studying basic—getting basic information. But at some point you've got to move from them to the tumor itself.
Tacey Ann Rosolowski, PhD You know, I would like to do a quick sound check because we have one of these dreadful leaf blower things.
(end of audio 2)
Tacey Ann Rosolowski, PhD Here we go. Okay. I don’t know why the record didn’t take. So let me ask you again. I neglected to ask you earlier whether—when you shifted from your fellowship to your academic appointment—whether or not you established your own lab or whether you worked collaboratively.
Ralph Freedman, MD Initially, I was with him, and then—
Tacey Ann Rosolowski, PhD This was Dr. Sinkovics.
Ralph Freedman, MD Sinkovics. Then at some point, I got my own lab after that, and it was after that that I remained with my own lab assignment. He was there for a few years, and then he moved to Florida— Sinkovics did. So, let me see, the next phase was I occupied part of Jim Bowen’s lab, and then after that, I got my own assignment, which remained like that for years after that. We were finding that we had support from external and internal sources.
Tacey Ann Rosolowski, PhD And what was that like, shifting from sharing space to having your own lab? Did that make a difference in the type of work you did?
Ralph Freedman, MD 00:01:15
I think yes. It probably did because you could bring people in to work. For example, you could bring students and postdocs at your own decision, and it wasn’t dependent upon somebody else deciding for you.
Tacey Ann Rosolowski, PhD Where was the lab located?
Ralph Freedman, MD The lab was located—let me see—Sinkovics was up on the—was it the seventh or eighth floor of the old Central Core Building? And then we moved around the corner, closer to Virology. I know the area, but I can’t describe it to you exactly. But it’s in the Central Core of the old building. Then we moved down to four, at the back, behind the operating room area, and actually it was there until I closed my—the lab—before I retired.
Tacey Ann Rosolowski, PhD I was wondering if you could comment on the ways in which the sort of phases in your research career dovetailed with changes in just the understanding of cancer and how cancer as a disease was approached over those decades.
Ralph Freedman, MD Yeah, I think that in some ways it’s a seamless process because our knowledge influenced what people did, like when we started with the cellular vaccines. There was a lot of interest in cellular vaccines at that time, a lot of excitement because this came after interferon. Interferon started off with using leukocyte interferon in which about two percent of the extract was active interferon that was used by Gutterman. And in the next phase, when they developed the recombinant technology, they shifted from leukocyte interferon to recombinant interferon. And then once they got recombinant interferon, then they made recombinant IL-2 and recombinant IL-12, and the cytokines that they used in vivo today are all recombinant cytokines. So all of these things—and then you had the monoclonal antibody development after ’77, I guess the 70s. During the 70s, you had monoclonal antibody development, but first it was mouse antibodies. And then later on people started to develop human. The techniques with doing things in the labs also changed because of the evolving. And depending upon what you wanted to do, the expertise might or might not be available in your lab, and then you had to go to others. And that’s why I say that you really today, in today’s world, you cannot do this kind of work anymore without interacting with others. I had Platsoucas who was a very important contributor to the research that we did. There was Newman on eicosanoids. There was Franco Marincola from NCI. We were not doing any type of consistent microarrays, so I had the NCI group to do the microarray work and then doing the interpretations of that. I had proteomics. It was a biochemist from Japan, Dr. [Koichi] Kobayashi, who we did proteomics with, and we actually did proteomics analysis on fluids to see what was in them.
Tacey Ann Rosolowski, PhD What is a—? What are proteomics?
Ralph Freedman, MD Proteomics is the study of proteins. There are hundreds of thousands of proteins in our bodies, and these proteins do different things, and they may be involved in signaling. And we actually found one which was called the zeta protein—14-3-3 zeta—and that was an important adapter protein. And that has multiple activities in cellular proliferation. We had a proteomics laboratory at MD Anderson, so we made use of that in order to find out about this protein and its unique pattern in ovarian cancer. So a lot of the work that we did here was absolutely dependent upon the expertise in other labs at Anderson or outside of Anderson, and I think that’s a practice that goes on today.
Tacey Ann Rosolowski, PhD That’s leading me to my next question. I believe in one of the materials that Mary Jane shared it talked about sort of characterizing your research as translational research, and I was wondering what your response to that was, because that’s all about crossing those disciplinary boundaries and communicating with other—
Ralph Freedman, MD Translation unfortunately has become a funding buzzword. It became incorporated into the NCI funding programs or external funding programs. You know, I served on the National Cancer Advisory Board, so we saw a lot of the things there that it was supporting. And translational research, and maybe it still is now, implies that you take things from the laboratory and then you take it through to the clinic, and I guess the best example would be Dr. [John] Mendelsohn’s work with his ImClone product—Erbitux. He started working in collaboration with others in California, and he carried it over to New York, and then eventually he had an antibody that he could use in patients. And then trials were done with an antibody, and then, of course, it’s now commercially available. So that is, perhaps, the best example of translation work—that it starts and does end up somewhere where you’ve got something that’s either useful or marketable, but a lot of it is research that’s done and is contributing something to understanding the disease, understanding potential targets, but maybe doesn’t reach the final point of producing. And then even products that are produced and that are commercialized, they have to be replaced in a few years by a small molecule here that does the same thing without these toxicities. So it raises the whole point about what should be the focus of the academic scientist. And I think if we get too obsessed or too taken up with trying to produce a successful outcome, particularly when you’re dealing with cancer, it just may be too ambitious for the nature of the disease that we have to deal with. That doesn’t mean that you should give up, throw up your hands, and say, “Well, this is just impossible. I’m not going to do it.” I think if we accept the fact that each block is a building block to understanding the nature of the disease, and maybe somebody in a few years will take that information and say, “Well, this is another direction that we can go in, in developing a new therapy.” Because I strongly believe that most cancer therapy from here onwards is likely to be incremental in this outcome. I don’t think we should expect a magic bullet that’s going to suddenly wipe out the disease. It’s different when you’re talking about something like HPV vaccine because there you got one simple target—the virus that you know contributes to the change of a normal cell into a cancer cell. And you know there is a very high probability that that virus is responsible, so if you can prevent that virus from getting in there, it’s going to work, but once the cancer is already established, it’s got multiple mechanisms for getting around. I think pathologists always used to say that cancer has almost got a mind of its own—that a human being tries to make a strategy towards defeating it, and then it develops another mutation. And that seems to be what happens, because even in patients that have been targeted with drugs like Gleevec or imatinib, they eventually get resistance.
Tacey Ann Rosolowski, PhD I didn’t know that.
Ralph Freedman, MD And they get resistance. They might get resistance because they are developing mutations, so that same drug is not working anymore, and you have to change to another drug. Well, how many times are you going to have to do that before you actually get rid of those cancer cells? And it will be interesting to see what happens with the personalized therapy approach, because by analyzing the tumor and identifying these different mutations, one has to prioritize them. One has to have a drug that will target it. And even if you have that drug, what’s to guarantee that you won’t get another mutation to come along and another line of cells that develops that’s resistant to that drug? Can you have enough drugs available that can actually annihilate that tumor? So I think we have to see—it’s an experiment that’s being done now with the IPCT, and we have to see how that works out.
Tacey Ann Rosolowski, PhD You mentioned that you’ve done both the basic research and research with clinical trials as well. And that’s a theme that’s come up in a few interviews—it’s that connection between basic science and clinical research and how there’s kind of a feedback loop between them. I wonder if you have any observations about their respective contributions. How are they related?
Ralph Freedman, MD You know, it’s interesting. The previous National Cancer Institute director—actually, he was there when I joined the NCAB. Dr. Richard Klausner said that basic research is a lot like a Lewis and Clark expedition. They didn’t really know what they were going to accomplish on this thing, but they had some belief that there was something at the end, but it’s not always clearly hypothesis-driven. So we are so used to only look at the research protocol—what’s the hypothesis? What’s the underlying hypothesis for this label research? Same thing when you talk about translational research. You expect there to be a clear hypothesis. But I think there’s a lot of basic research where it’s not clear that there’s going to be a link. It may provide more understanding of the disease or some component of a disease or some mechanism, and again, it’s one of these building blocks, but it’s not so clear that it’s translational at that particular point. And I think that research is also important. Not all research necessarily has to translate into a new treatment.
Tacey Ann Rosolowski, PhD When you were describing the value of— A little bit earlier we were talking about the kind of research that simply opens up a new pathway that maybe the direction of it will become clearer later. It really reminded me of the kind of post-war spirit of doing research where it was just—you’re doing research to do research, to just find out what’s out there. Then it was really later on in the ‘70s and the early ‘80s that the commercial goal of—at least I don’t know about it in medicine, but I know in some of the other sciences, the commercial goal became much more powerful, and that started to change. You had to have a purpose for doing your research.
Ralph Freedman, MD Well, there is purpose. This may be hypothesis-generating. So you have hypothesis-based and hypothesis-generating. In other words, you’re looking at an area—perhaps you’re looking at, to give an example, all these trees that are dying from the summer’s heat. We don’t know at the time; we just say it’s the heat, but somebody assumes that there’s some stress involved. So getting information about the environment that these trees are in, where they’re growing, how close to water, so forth—maybe this provides important information that can save trees in the future. So it doesn’t look directly relevant. It may be because it’s a very isolated area, but I don’t think you can discount it because, for one thing, it supports intellectual effort. There is some theory behind it, and the hope is that it will, perhaps, provide a number of pathways for further looking at a particular question. But it shouldn’t be that we should only consider an effort that starts here and that we already planned that it’s going to end up there because that, in biology, it’s so complex that you could go in different directions.
Tacey Ann Rosolowski, PhD I was going to say, if you could see that pathway, you wouldn’t need to do your experiment. (laughs)
Ralph Freedman, MD Yeah, right. Exactly. Really, you’d go straight there. So I think it’s something— I’ve thought about this often. If we commit every faculty in the university to developing a new drug or a new treatment—that means their whole career will be spent just on that objective—is that necessarily productive for that individual or even for the community of scientists? Especially when we’re dealing with diseases that are very complicated and that we know so relatively little about.
Tacey Ann Rosolowski, PhD What is your most memorable research experience?
Ralph Freedman, MD Well, of course, we had these blips of excitement with the production of the antibody, and that was exciting that we had that. Actually, I would say providing patients with some hope in the trials that we did. And when patients, I would say, who did respond and benefitted, and I think that means a lot. I would think—I don’t know. As I said, we didn’t really accomplish any what I would consider breakthroughs in treatment, but we learned a lot of things. And I think some of the things that we’ve learned could be useful today.
Tacey Ann Rosolowski, PhD Was there a handful or—you know—one or two discoveries you had in the lab that really kind of shifted your paradigm and how you looked at the disease?
Ralph Freedman, MD I think finding the— When we were able to look at the molecular aspects of these tumors like ovarian cancer, particularly, because most of my career at Anderson was spent on ovarian cancer after the initial few years. And seeing the molecular profiles of these tumors—how many complex interactions there were between cytokines and inflammatory processes and the linkages between all of these factors. The fact that there were so many macrophages which are normally considered to be phagocytic cells—cells that eat up other cells that are damaged or dead—that there were so many of them in the environment of the ovarian tumor was, I think, quite fascinating, even more than the population of T cells. And then we studied them further, and we found that they had so many functional factors that could contribute to tumor promotion. And we constantly thought, “Isn’t there a way of possibly harnessing these or trying to control them?” And we found that those cells were dysfunctional to an extent that they couldn’t—they weren’t as effective as we hoped in killing tumor cells. And was this because of the tumor, the environment that it was in, or was it because they contributed to the tumor promotion—promoted the tumor growth? And these changes we found all in the vicinity of the tumor. When we took biopsies from the lining of the peritoneum in the vicinity of these tumors—the tumor metastases—we frequently found these inflammatory changes already there. So the question was, was the tumor doing it? It was a chicken-and-the-egg situation. Or were these predisposing now to further growth of the tumor? And if that’s the case, then really we should be targeting the inflammatory changes around the cancers in the same ways people have been targeting the angiogenesis factor. But—you know—you have so much time to do these things and think about them before your research career is over. But we published—
Tacey Ann Rosolowski, PhD So you were saying then that when the research career is over—
Ralph Freedman, MD Yeah, and then it’s—you come to a point when you say, “Well, this is as much as I can do, and now I need to step down from it.” And at the point that I retired, I made sure that we completed everything, that it was done. And I don’t think we left any loose bits lying around, but the idea was to publish everything that had—the way patients had contributed. I think that the important thing is that the patients who contribute tissues and cells—we act in a fiduciary role or we act in a role where we’re protecting the interests, and I hate the thought of discarding stuff that they have given you to complete. So we did make arrangements to transfer our bank to another investigator who was able to use and, in fact, just sent a paper to me the other day to look at a manuscript from work that we had collected several years back. And it’s a big issue today—what happens when a lab does close? What happens to those specimens? And I told my IRB colleagues, I said, “I really think that the patient expects that that work goes on or that something comes out; people continue to work with what they’ve donated, and hopefully it will be some useful information.” So we’ve worked out a system where that can happen. The IRB gives authorization to transfer that material to somebody else.
Tacey Ann Rosolowski, PhD 00:25:06
When did you begin thinking that way about the specimens that patients have contributed?
Ralph Freedman, MD Oh, probably several years. I mean, we worked out systems, I guess, several years back for transferring banks into the institutional tissue bank or to other investigators. I think investigators have the wrong idea. They think that they own this tissue. They really are given privileges over using it, and they have to be respectful to the people, the donors, who’ve given them those tissues. And if they can’t use them anymore, there needs to be a way of giving them another function. Now, of course, people argue, “Well, maybe somebody can do something that the patients or the subject didn’t authorize or wouldn’t have liked to have done with it.” So we do give subjects an opportunity to withdraw the tissues or their consent. This is getting into IRB business. And we do have restrictions on them doing anything that could affect their families— certain genetic diseases, for example, they might be affected by or a family member could be affected by. But most of the research that’s done at Anderson doesn’t have any bearing on that. It’s basically asking questions about cancer, and that’s what I think the donors gave the tissues for, so I think to respect their wishes—we should treat it as donations but continue to make sure that it’s properly utilized.
Tacey Ann Rosolowski, PhD It’s almost 3:30, and would this be a good time to stop? I mean, we can start up with IRB next time and see how the other roles—(talking at the same time)
Ralph Freedman, MD Yeah. Sure. Sure.
Tacey Ann Rosolowski, PhD Okay. So I’m going to be turning off the recorder right now, and it’s about twenty-two minutes after 3:00.
Recommended Citation
Freedman, Ralph MD and Rosolowski, Tacey A. PhD, "Chapter 03: Research into Treatment for Gynecologic Cancers" (2012). Interview Chapters. 943.
https://openworks.mdanderson.org/mchv_interviewchapters/943
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