Chapter 05: Building A Departmental Focus on Immunological Approaches to Gynecologic Cancers
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Description
Dr. Freedman begins this chapter by sketching the hopes he had as Director and Chief: to understand the biology of the diseases from an immunological perspective and try to identify new strategies to treat ovarian and uterine cancer, with their (continued) dismal outcomes (in comparison to advances made with cervical and endometrial cancer). He notes that the main contribution IMBR made to ovarian cancer was to demonstrate that T-cells can be activated in the patient, a fact indicating that a vaccine approach might potentially be used. He goes into detail about the biological mechanisms of the tumors and of the patient’s immunological system. He notes that it is important for researchers to determine adequate ways to measure clinical benefit of treatments.
Identifier
FreedmanR_02_20120301_C05
Publication Date
3-1-2012
City
Houston, Texas
Interview Session
Topics Covered
The University of Texas MD Anderson Cancer Center - Building the Institution; The Administrator; The Researcher; Definitions, Explanations, Translations; MD Anderson History
Transcript
Tacey Ann Rosolowski, PhD:
I was asked—going to ask you about the role that you served. You were chief and director of immunology and molecular biology research, and could you tell me the difference between a chief and a director?
Ralph Freedman, MD:
I don’t know. It’s–– The departments came up with these titles at some stage, and as I said, we were lots of chiefs in this institution even to this day, and lots of directors and lots of this and that, but basically, what it amounts to is getting the work done. I’m sure that these are also used for budgetary purposes. When a department has an area of research, and they’ve got titles and personnel attached to it, these things can be used in order to expand. I mean, there was really no research in those days ‘til I got there. Now, you’ve got Dr. [Anil] Sood, who’s got a very big program, and Dr. Karen Lu, who got the endometrium program, and each of those people have now got their own space and personnel where they’re doing their research. Each of them will give a title to a lab which they feel suits the area very–– Immunology research, it suited us, because that’s what we did 80-90 percent of the time and the graduate students that we had and the postdoctorals that came, that was the area that they focused on.
Tacey Ann Rosolowski, PhD:
When you took on that role, did you have a sense of your goals that––something you wanted to achieve in guiding the direction of research and all that?
Ralph Freedman, MD:
Yeah, I was hoping–– I was hopeful at that stage that immunology was going to contribute more to the outcomes of disease like ovarian cancer, because at that time and as today, progress was so dismal, and we were looking out for new therapeutic strategies. I don’t know if you know about the history of ovarian cancer therapy, but we started off with drugs like Cisplatin, which is no longer used today because it’s toxic to the kidneys and toxic to the nervous system. But that’s what was approved back in the ‘80s. And then you had the combination with another drug called Cytoxan, and that was standard of care for a long time, and then, suddenly, Carboplatin came along, which was a less toxic version of what had a different toxicity profile to Cisplatin. It was also related to Cisplatin and was much easier to use, and the patients didn’t get so sick with it, so that replaced Cisplatin. But then there was still Cytoxan and Carboplatin until Taxol came along, and that was considered to be a major breakthrough. And in fact, there was what we call an expanded access. At that time, it was called a compassionate protocol. The results were looking so interesting that they wanted to make sure that the drug could get to patients even though it hadn’t yet been approved by the FDA, so they developed a compassionate protocol which allowed patients to be treated with Taxol. And this, I think, was in the late ‘80s, because in the ‘90s, it became approved. And it wasn’t long after that then Taxol was combined with Carbo––first of all with Cisplatin and later with Carboplatin, and that was because of its toxicity profiles. Well, that’s taken thirty years just to get through those several drugs, and the 5-year survival really hasn’t changed all that much. It’s better with Taxol and Carboplatin than it had been with Cisplatin by itself, but there’s still about twenty-five percent of patients who survive five years who have advanced ovarian cancer, so throughout this period, there’s always been a look around for new drugs, new strategies. They tried different chemotherapies––Doxil, hexamethylmelamine–– hexamethylmelamine’s hardly used anymore, although it was approved for ovarian––Gemcitabine. A number of these different drugs have been tried, and the most recent effort now is to combine Avastin––Bevacizumab––with the Carboplatin-Taxol. And from my understanding, it doesn’t improve the survival of patients, but it may improve by a few months of progression-free survival. People have tried different––even things that are non-chemotherapeutic. That’s how we got into immunotherapy. Does immunotherapy have a role? There are logistic issues with using immunotherapy on ovarian cancer. I kind of mentioned to you last time that the large tumor burden that you have, which overwhelms the immune system in these patients, so you’ve got so many tumors secreting all kinds of proteins––a number of which can interfere with the immune response, so it’s hard to deal with that unless you can eliminate or reduce the amount of tumor. People have tried to develop vaccine strategies post-surgery, post-chemotherapy when the tumor burden was small but where the patients are still going to die of their cancer, and unfortunately, none of those have turned out yet to be efficacious, so ovary remains. In cervix cancer fortunately we’re seeing, over the years, a dramatic decrease in the frequency and in the death rate so that in terms of frequency and death rate, it is now number three. Ovarian cancer is number one in death rate. Endometrial cancer is number one in frequency and second in death rate, and then you have cervix cancer, which is, I think, about 1,500 deaths a years. It’s much less––this is––I’m just talking about the US, but of course, if you go outside the US and go to South America and Africa, the disease is still very prevalent, and that’s because of lack of screening, adequate screening. The simple Pap smear has probably made an enormous difference. Only about ten percent of women in this country now no longer have any type of screening, and then, of course, you’ve got the antibodies to the virus, using the vaccine to stimulate antibodies to the virus, which is probably––we don’t know for sure that it’s going to reduce the death rate even further, but we do know that it’s reducing the incidence of pre-invasion cancers, so we can speculate that it may reduce the incidence of invasive cancer even further. But otherwise, for ovarian and uterine cancer, they haven’t seen the same amount of decrease.
Tacey Ann Rosolowski, PhD:
Were there other goals that you had guiding the search when you were directing the activities of the lab?
Ralph Freedman, MD:
Yeah, the important goal was to understand the biology of these diseases from an immunological standpoint, and we did discover––my lab discovered that there were T cells that were activated in this disease, but you had to take them out of the body and show that they had the potential to be activated. And from that, they’ve now developed strategies to use peptides, which are parts of proteins, which kind of fit into the little cleavage areas on the T cell and are able to stimulate those cells to kill target tumor cells. So we did a lot of that type of work and published a Journal of Immunology, Clinical Cancer Research. At the time, I had a postdoc that came from Dr. [Chris] Platsoucas’ lab, Constantin Ionnides, who worked on that aspect in my lab. He identified the peptides, the particular sequence that had the capacity to stimulate the activated T cell, so what it is is a very small proportion of these T cells that are in the circulation. And what we’ve tried to do was to expand the––in those bio-reactors that were–– And we were able to expand the cells to something like ten to the ten cells, so we thought with that large number of cells we’re sure to be able to wipe out things, but there were two major difficulties that we came across. One was that you had to be able to grow those cells from tumor, and so you had to have access to a large amount of tumor in order to do it. Well, that’s not also a good condition to be able to treat those patients, see, and have some way of storing those cells or keeping them going in culture or storing them until the patient’s tumor had collapsed. So these are logistic issues that we came across. We found that directly treating them––the patients––with the expanded T cells, and they had high tumor burden, you got a lot of interferon being released, which indicated that they were producing cytokines. But we didn’t see any appreciable shrinkage, and I think part of that is the fact that–– And we even put the cells directly into the abdomen, where the tumors were, in the hope that they would go there and would go actually into the tumors, but the problem is that you’ve got the host is––that the cancer is like a parasite. It basically utilizes the resources of the host in order to support itself, so all these suppressor factors are released. Amy Loercher, who was a PhD student with me, she did her research on IL 10 and the macrophage. We found there were very large numbers of these monocyte macrophages in patients that secreted IL 10, and these were immunosuppressant—these cells behaved in immunosuppressant form—so we speculated or postulated that, in fact, in ovarian cancer, where we saw large numbers of these macrophages, they were secreting IL 10. They were probably primarily the source of the IL 10 that we saw secreted in these patients, and they probably contributed to an immunosuppressive environment, so you would have to find a way to overcome this immunosuppression either by effective debulking the tumor or by finding a technique to inhibit those immunosuppressive cells. And that’s not—it’s not a trivial issue because there are multiple mechanisms that the tumor uses to suppress the environment to the tumor. IL 10 is one, and another is IL 6, and they actually suppress T cells, and the suppressor macrophages seem to be expanded in conditions of malignancy. So in other words, you have to be able to knock each one of these and the more pathways that there were for immunosuppression, the more complicated it became from a logistic point of view. So I think that our main contribution was the fact that, yes, we demonstrated that in ovarian cancer, there were activated T cells produced in the host, and they were kind of sitting there in a dormant fashion, probably suppressed by this immune environment that they could be taken out of the host and expanded into activated cells. There was a possibility that if you were able to shrink the tumor down to very small amounts––we don’t know what that amount actually is––that you could use a vaccine approach potentially to target these. This hasn’t been effectively done at this stage because there are multiple peptides and multiple T-cell clones, basically, that can only be activated by certain peptides. And then of course, the description of the immunosuppressant environment and this is providing new channels of research for many others, such as our recent progress in cancer research. I’m listed as a collaborator because they used samples from my lab and expanded on some of the ideas that we had developed to actually demonstrate the suppressor T regulatory cell. It’s a small subset of T cells that has a highly suppressive effect on the T-cells bonds, and these cells have been isolated from ovarian cancer patients from tissues. You can demonstrate them actually in the tissues in the vicinity of the tumor, so we know they’re there. So you’re looking at this, you’re looking at angiogenesis, you’re looking at mutation, and you’re looking at inflammatory processes that support the tumor that are recruited from the patient––from the host––in order to support the tumor. So it sort of raises a little pessimism, I guess, about being able to overcome those tumors that are so very heterogeneous. The more heterogeneous the tumor, the more likely that you will have multiple mechanisms that will support the growth of that cancer. Where you have monoclonal tumors––certain lymphomas, certain leukemias––you’ve got a better potential for targeting the cancer, but if the cancer has a habit of mutating and changing––changing its face all the time––that’s going to be a difficult problem to keep up with, and that’s where we have to see now with the new patient-directed therapy whether you’re going to be–– You see, I think that the only way that you can defeat cancer is to eliminate it. We’ve talked about making it into a chronic disease. I think there’s a little bit of glibness in that hypothesis because it seems that the relationship between survival of the cancer and survival of the host is so tenuous unless you totally destroy that disease. In other words, if it gets out of control, how do you control it? So that’s where I think we contributed understanding of the immune system, natural killer cells that we did with Eva Lotzova and the T-cell environment, the immunosuppressive environment in this disease—the fact that in spite of that all, there is a state of immunization that takes place in these patients but it’s overwhelmed by the immunosuppressive environment that you have, so it’s possible that in the future multivalent vaccines can be developed which target different types of cells. But it’s that one clone of cells that might escape and grow that’s ultimately the concern.
Tacey Ann Rosolowski, PhD:
I just wonder how much of the general public understands the many faces that cancer can present. I think that I’ve mentioned before that when I started doing research for this—and I had no idea how complex the disease was and what you’ve just described, the way it can morph and present these very, very different challenges to any attempt to control it, let alone eradicate it, so—
Ralph Freedman, MD:
If you don’t try, you can never learn.
Tacey Ann Rosolowski, PhD:
Well, certainly.
Ralph Freedman, MD:
And that’s why I think we have to keep on trying, and of course, we don’t want to destroy people’s optimism and present a totally pessimistic view of things to the public. I think generally those patients who develop these terrible diseases that have low cure rates, they search for areas of optimism, and we’ve got to try to keep the optimism, but do it in a truthful manner, because some patients are happy with a few months. When they’ve got that disease they’re happy with a few months longer that they can have with their families provided, of course, they’ve got good quality of life. What’s missing in a lot of our trials is adequate ways to measure clinical benefit. It’s not sufficient to just show the tumor shrinks here. We’ve actually got to know how the patient is benefiting. They have these quality-of-life instruments, and we have some researchers that are working in that area. From a regulatory point of view, they fall short because they don’t find sufficiently the symptoms or the complex of symptoms that goes into creating those instruments like you may have pain. You may have just feeling good or not feeling good, but each of these is separate. If a drug is approved on the basis of improved quality of life, you’ve actually got to show it, and a good example would be, for example, esophageal cancer. If a patient can’t swallow, and as a result of their treatments now they can swallow, that’s clear evidence of benefit––clinical benefit. And unfortunately, there may be half a dozen or so drugs that have been approved by the FDA and actually have been approved using patient-reported outcomes or from quality of life improvements. That’s an area that the agency is struggling with now, and they’ve provided guidances.
Tacey Ann Rosolowski, PhD:
Which conference is it?
Ralph Freedman, MD:
This is the ECOR Conference that’s–– ECOR stands for Ethics Compliance in Oncology Research and will be in October.We’ve got Pazdur from the FDA, people from OHRP, and we’ve got a panel on patient-reported outcomes, because it is so important that our trials not just provide end points that are satisfying to the physicians, but end points that are meaningful to the patients, and that’s where we fall short with a lot of trials up to now.
Recommended Citation
Freedman, Ralph MD and Rosolowski, Tacey A. PhD, "Chapter 05: Building A Departmental Focus on Immunological Approaches to Gynecologic Cancers" (2012). Interview Chapters. 945.
https://openworks.mdanderson.org/mchv_interviewchapters/945
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