Chapter 7: An Introduction to MEPACT and a New Research Collaborator for Study of Osteosarcoma Treatment
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Description
Dr. Kleinerman speaks in detail about her pioneering work on the immunotherapy agent, liposomal muramyl tripeptide–MTPE.
She describes the drug and the mechanisms of its interaction with macrophages, as well as the technique she used to sheath the drug in lipids that would result in attacks on cancer cells. She sketches Dr. Isaiah Joshua Fidler’s [Oral History Interview] work on this agent in mice and describes her “Eureka moment” in understanding the implication of his results for osteosarcoma. She also talks about her first interaction with Dr. Fidler, whose reaction to her idea was “Let’s collaborate.” She explains why she was a good partner for him in translational research.
Next Dr. Kleinerman explains why the NCI was resistant at the time to running clinical trials on children. Sketches her own experience with osteosarcoma and how she discovered that the disease, though rare, is a big problem.
Identifier
KleinermanES_02_20140529_C07
Publication Date
5-29-2014
City
Houston, Texas
Interview Session
Eugenie Kleinerman, MD, Oral History Interview, May 29, 2014
Topics Covered
The Interview Subject's Story - The ResearcherThe Researcher Influences from People and Life Experiences Discovery, Creativity and Innovation Evolution of Career Definitions, Explanations, Translations Critical Perspectives Discovery and Success On Research and Researchers Understanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient Care
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:
All right. So we are recording, and the time is about four minutes after ten. And I’m in the Main Building of the Division of Pediatrics, talking to Dr. Eugenie Kleinerman for our second session. Thanks very much for making time.
Eugenie Kleinerman, MD:
My pleasure, of course.
Tacey Ann Rosolowski, PhD:
And we talked a little bit before the recorder was on, that it kind of made sense to talk about your research. We’d just gotten to the point at the end of the last session when you come to MD Anderson. I don’t know, does it—you mentioned your work with Dr. Fidler at the NCI, but I was hoping you could go into more detail about exactly what Dr. Fidler had discovered and what you saw as being so significant to the potential treatment of osteosarcoma.
Eugenie Kleinerman, MD:
So what he presented at the American Association for Cancer Research, AACR, at the national meeting, was that he had this immune modulator, this drug that is called liposomal muramyl tripeptide. It is like a fat globule that is made up of lipids that are the same lipids that make up an old red cell. One of the immune cells in the body called the macrophages is a scavenger cell. It’s an immune cell that recognizes self from non-self. When you get infected with bacteria or viruses, these are the immune cells that say, “Woops, this is not good,” and they ingest the bacteria or the virus, and they kill it. Through research, it was found that when these macrophages are activated by viruses or bacteria, not only will they kill the virus and the bacteria, but they will recognize tumor cells, attach to the tumor cells, secrete proteins across that membrane interaction, and kill the tumor cell. And it’s selective. They don’t kill normal cells. So there’s some kind of recognition between the tumor and the normal cell, and to the day, we do not know exactly what this is. So because the macrophage is a cell that ingests things, one of the other properties in the human bodies is it is able to detect old red cells from new red cells. The lifespan of a red cell is about 120 days. And you would say, well, how does it know that it’s 120 days old or 12 days old?” Well, what happens to the red cell as it ages, the phospholipid called phosphatidylserine, PS, flips from the inner leaflet to the outer leaflet, and this recognition of PS on the outer surface of the red cell says to the macrophage, “This is an old cell. I’m going to ingest it and get rid of it so the body has fresh cells.” So what Dr. Fidler did with his collaborators was to create a lipid vesicle with PS on the outside, and then inside the vesicle he put an agent that was derived from a bacteria. So this is an ingenious way to trick the macrophage and say, “This is an old red cell.” The macrophage ingests it, starts to break down the lipid wall, and once inside the macrophage, the activating agent is released, so you get selective activation and you don’t get exposure of this bacteria. It’s not live. It’s been modified, so it’s not infectious or anything. It’s really the protein, but no normal tissue is exposed to this agent.
Tacey Ann Rosolowski, PhD:
Yeah. So it’s not a systemic thing like chemotherapy that’s—
Eugenie Kleinerman, MD:
Well, it is systemic, but it selectively goes to areas in the body where the macrophages are.
Tacey Ann Rosolowski, PhD:
I see.
Eugenie Kleinerman, MD:
And that’s lung, liver, spleen. So there’s uptake in the lung, and what Dr. Fidler did was create a mouse model, a melanoma mouse model, where he injected the melanoma into the limb, let the tumor grow, amputated the limb. At that time, if you looked at the mouse in the lung, there were tiny micro metastases, and if you didn’t treat the animals, they would be dead very shortly. Ninety percent of them would be dead. So what he showed in this presentation is if he injected the melanoma cells, let the tumor grow for a month, amputated the leg, and then started treatment with this drug, liposomal MTP-PE, he was able to cure about 70 percent of the mice and completely eradicate the micro metastases in the lung. But they had to be small micro metastases. You couldn’t have a bulk tumor. Well, when I heard this and saw his data, I said, “This is osteosarcoma.” You’ve got a tumor in the limb. We either amputate or resect the tumor. Then we give combination chemotherapy to address the lung metastases, and we can cure about 65 percent. But we’ve been stalled at that 65 percent point, and treating kids with seven drugs or two drugs or four drugs for eighteen months, for twelve months, made no impact on the survival. So my idea was what if we could add an immune modulator where the chemotherapy could get rid of most of the tumors, the metastases in the lung, and then you could use this immune-therapy to activate the macrophages to mop up the cells that were left behind in chemotherapy. So that was my sort of eureka moment. So it took me about a month to get up the courage to go meet with Dr. Fidler, and I told him my idea, and, of course, he—again, here I was, a new faculty member at the National Cancer Institute. And he said, “A great idea. Let’s collaborate. But I’ve only shown this in mouse macrophages. What we really need to do first is show that human macrophages will take up the liposomes and become activated and kill tumor cells and not kill normal cells, before we even think about whether this can go into a clinical trial.”
Tacey Ann Rosolowski, PhD:
Can I ask you—I’m sorry to just go back a little bit, but, you know, I just wanted to go back to that moment when you figured this out. I mean, that must have been really exciting. Was it really a eureka moment, like, “Oh, my god, here it is,” or—
Eugenie Kleinerman, MD:
Yeah, it really was, really was. It was a eureka moment saying, “Now I understand.” I’d been having these thoughts about this movie and about osteosarcoma. What was that all about?
Tacey Ann Rosolowski, PhD:
And this was Whispers in the Dark you talked about last time.
Eugenie Kleinerman, MD:
Yes. Promises in the Dark.
Tacey Ann Rosolowski, PhD:
Promises in the Dark, yeah.
Eugenie Kleinerman, MD:
And I said to myself, “Here’s the connection.”
Tacey Ann Rosolowski, PhD:
Yeah. Where were you when you made the connection?
Eugenie Kleinerman, MD:
I was in the audience. It was in Washington.
Tacey Ann Rosolowski, PhD:
So you were right there.
Eugenie Kleinerman, MD:
Yeah.
Tacey Ann Rosolowski, PhD:
So it was very immediate.
Eugenie Kleinerman, MD:
Yeah. Oh, yeah. Oh, absolutely. Absolutely.
Tacey Ann Rosolowski, PhD:
Wow.
Eugenie Kleinerman, MD:
I saw that, and a light bulb went off and said, “This is osteosarcoma,” and recalling the movie where she was on the phone to the NCI saying, “There must be something. This is a young girl. Don’t tell me you have no clinical trials.” And the response was, “Well, it’s a rare disease, and, you know, it’s not going to make that much impact. Nobody’s interested in developing anything.” Now, when I met with Dr. Fidler, of course he was interested in using this for melanoma. Melanoma at the time was not a big killer of children, but the cancer was not a big cancer. So I said, “Well, I’m really interested in osteosarcoma.”
Tacey Ann Rosolowski, PhD:
But he was very game to [unclear].
Eugenie Kleinerman, MD:
Oh, yes. Oh, yes, yes. I think he also had been searching for someone that could give him the clinical connection. I mean, he was a vet, he was a PhD, but in order to translate it, he really needed to have a clinical collaborator. So I think what he saw in me was the opportunity to really translate his basic research into the clinic, and he was always very translationally oriented.
Tacey Ann Rosolowski, PhD:
Right. Now, I just remembered that I had forgotten to ask you last time, because one of your frustrations was that the NCI was unwilling to take children into clinical trials. Why was that?
Eugenie Kleinerman, MD:
Well, pediatric cancer is a rare disease. I think it’s a poor perspective, because if you look at what the impact of curing childhood cancer in terms of years of lives saved, in other words, how many life years will you gain by curing childhood cancer, it’s about the same as curing breast cancer. So if you look at the number of years, if you cure a child of osteosarcoma when they’re fourteen, and you figure they’re going to live till they’re seventy, so that’s, what, fifty-four years, whereas if you cure a woman of breast cancer when she’s fifty, that’s twenty years. And if you add it all up. But at the time—and osteosarcoma is one of the rarer pediatric cancers as well. Leukemia is the most common, relapsed leukemia is the second most common, and brain tumors is the most common solid tumor. There are probably only 1,500 to 2,000 new cases of children with osteosarcoma.
Tacey Ann Rosolowski, PhD:
Now, how many cases of osteosarcoma had you encountered throughout your clinical practice?
Eugenie Kleinerman, MD:
Before I heard Dr. Fidler, not a lot. So I was in my last year of fellowship, actually, when I—it took me—you know. So the cancer meetings are now, and I wasn’t going to start my faculty position till July. So during that time when I went back as a fellow, I started to look for all of the cases of osteosarcoma, and it was amazing to go through the history, to sit and listen to all the cases that presented. At the time, there was a national clinical trial randomizing children with osteosarcoma to receive surgery alone or surgery and post-op chemotherapy, because there had been a study at the Mayo Clinic that said that surgery alone was as good as surgery plus chemotherapy, and why are we using chemotherapy if it’s not effective and there’s all these side effects and long-term sequela. And so there was a national study, and, anyway, a lot of children died because of that study. But anyway. So in the sitting in the meetings, listening to Sally presented with osteosarcoma, was randomized and treated, and then is now presenting with metastases in the lung and metastases in the lung and metastases in the lung. So that just validated my eureka moment hearing Dr. Fidler and what was in the movie, that this indeed was a big problem. Even though the numbers were small, this was a big problem, and that adding an immune-therapy could make a big impact in a lot of children’s lives. So really, prior to hearing Dr. Fidler, I maybe had one or two patients.
Recommended Citation
Kleinerman, Eugenie S. MD and Rosolowski, Tacey A. PhD, "Chapter 7: An Introduction to MEPACT and a New Research Collaborator for Study of Osteosarcoma Treatment" (2014). Interview Chapters. 1403.
https://openworks.mdanderson.org/mchv_interviewchapters/1403
Conditions Governing Access
Open
