Chapter 8: Putting the Pieces in Place to do a Phase I Trial with MEPACT
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Description
Dr. Kleinerman begins the MEPACT story by discussing her growing collaboration with Dr. Fidler.
She explains the preliminary work required before running a human trial involving the immunotherapy agent, MEPACT. She talks about partnering with Ciba Geigy.
Next, Dr. Kleinerman explains how an individual at the NCI blocked her attempts to develop a trial, noting possible gender bias, followed by Dr. Fidler’s invitation for her to come with him to MD Anderson.
Dr. Kleinerman explains her strategy of constructing “the ultimate clinical protocol.” She describes the ethical issues that arose and research challenges in determining the Optimal Biological Dose (OBD). She notes that she and Dr. Fidler were the first to design a study around this concept and that they have not been adequately recognized for this contribution. She notes that they also ran studies to demonstrate that human patients could respond to the drug.
Next Dr. Kleinerman notes that in 1986 with support of colleagues at MD Anderson. She describes the results and some surprising discoveries.
Identifier
KleinermanES_02_20140529_C08
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 Discovery and Success Discovery, Creativity and Innovation Professional Practice The Professional at Work Women and Minorities at Work Obstacles, Challenges Joining MD Anderson Ethics Contributions
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:
Interesting. Yeah, yeah. Now, you were talking about how he [Dr. Joshua Fidler] saw his next steps, and then what did you do to come together? How did that collaboration first take shape?
Eugenie Kleinerman, MD:
So what he said is, “Okay, we’ve got to show you how to make up the drug and how you assess it.” Then I needed to plan the experiments to get normal peripheral blood and isolate the macrophages in the peripheral blood so that we could do the experiments with the agent. So he taught me how to make up the agent, how to purify it, whatever. We designed an assay. I mean, all he had done is use mouse macrophages, pulmonary macrophages, so it was not really applicable. So we had to design an assay system where we could isolate human monocytes and quantify their ability to kill tumor cells before and after exposure to the drug. We have to work out how do you expose them to the drug, how many hours, you know, do you wash it away. So all of the little details that one needs to do to show that it is applicable with human cells in addition to mouse cells.
Tacey Ann Rosolowski, PhD:
And how did that process go? Were there any surprises or turning points?
Eugenie Kleinerman, MD:
Not really. Not really at all.
Tacey Ann Rosolowski, PhD:
Mm-hmm, pretty straightforward.
Eugenie Kleinerman, MD:
It was pretty straightforward, and I duplicated everything that he had shown in the mouse. At the time, there was an investigator who had identified another immune cell called the natural killer cell, and so there was a debate in the immune world whether what we were describing, Dr. Fidler and I were describing, was really macrophages or whether it was NK cells. So we had to stop and do a lot of experiments to prove that it was indeed the macrophage and not the NK cell. And that’s sort of just the way science goes. So that was all also part of the process. But it was probably—I don’t know how long it was—maybe a year, year and a half, something like that, till—maybe two. I don’t know. Maybe a year, year and a half, we had the data and it was really ready. Dr. Fidler had a relationship with Ciba-Geigy, which was the pharmaceutical company that made the MTP, and we were ready to go into a clinical trial. And, of course, because I was the clinical liaison, you know, I sort of could control what disease. So he and I went to discuss this with the people at NCI to try to set up a clinical trial, a Phase 1 trial, looking at the toxicity and the ability to give this drug. Now, I will also say, in Europe, Ciba-Geigy had already done testing with this drug in accident victims, because the theory was if you could give this drug to accident victims, you could fend off infection. You know, when somebody’s in a car accident, they have a broken leg, it’s the wound, and all this other stuff. So they really had done safety testing, so it wasn’t like this was going to be a first in human. Because whenever you talk about putting drugs into children, they get—you know. So I said, “Look, we can do it in adults.” I mean, I had been on the metabolism branch and took care of adults with immune deficiency. And that’s where the roadblocks started. I believe it was Sam Broder who was head of the Division of Cancer Treatment, DCT, at the time, and it was clear to me that there was going to be no way that he was going to allow me to do any clinical trials with the drug. You know, he would say, “Well, Genie, first you’ve got to do an extra year of clinical fellowship focused in pediatrics. You’ve done immune patients.” I came home to my husband and I said, “You know, I’m never going to be able to get this.”
Tacey Ann Rosolowski, PhD:
What were the issues that were really at work there, do you think, with these roadblocks?
Eugenie Kleinerman, MD:
I think I wasn’t in the favored group. I think I wasn’t taken seriously. I think probably being a woman had something to do with it. I think if it had been one of my male colleagues that had been doing research in what was felt to be a really breakthrough field, that they would have made accommodations and seen that it was done. So I do think that played a role in it. I do think that played a role in it, because Sam Broder—I was in the metabolism branch when he was a senior faculty member in the metabolism branch. And you can just tell the way somebody talks to you, jokes with you when you present, whether they’re taking you seriously or not, and he did not. He just did not. And I think it had to do with I was a pediatrician and I was a woman.
Tacey Ann Rosolowski, PhD:
Well, fortunately, you had an exit strategy.
Eugenie Kleinerman, MD:
You know, I really believe that there was some, you know, divine intervention here, I mean with the movie and the meeting with Dr. Fidler, Ralph Snyderman telling me to go see Dr. Fidler, the connection there. Then Dr. Fidler was offered the position here and said, “Why don’t you come with me.” And that’s when I said to my husband, “If I’m going to be able to realize my dream, we’re going to have to leave. There’s no way. They’re going to keep me chained to the laboratory, always excuses with why you can’t do it. I really have an opportunity here to make a difference. It may not work, but I’d like to have the opportunity to try, to give it a go. It makes perfect sense.”
Tacey Ann Rosolowski, PhD:
Mm-hmm. Mm-hmm. So where were you in the scheme of these tests evolving when you came to MD Anderson?
Eugenie Kleinerman, MD:
So where was I in the scheme? So we had already shown that it can be done. Okay, so I guess where we were was thinking about how to construct the ultimate clinical protocol. I said there’s no way that you can ask a patient, a family, to say, “I don’t want to give you chemotherapy. I want to give you this new immune-therapy,” because chemotherapy cures 65 percent of patients, and it is not ethical to say to a patient, “Forgo this chemotherapy for this new therapy that I just believe is going to work.”
Tacey Ann Rosolowski, PhD:
Right.
Eugenie Kleinerman, MD:
So it became very clear to me that we were going to have to combine this with immunotherapy, chemotherapy and immunotherapy together. Well, the dogma at the time was chemotherapy is immunosuppressive, so it make no sense to use an agent that’s going to stimulate the immune system with chemotherapy that’s going to suppress the immune system. So what I did when I first came here was go in to animals and show that you could combine chemotherapy with MTP and you still got activation of macrophages and you still got tumor regression, that you did not interfere with the activity of the chemotherapy, and the chemotherapy didn’t interfere with the activity of MTP. So we did that both in vitro and in animal models. I was trying to also look at the mechanism. How does MTP stimulate macrophages? What does the macrophage produce that is a signature of a cell that’s going to kill a tumor cell? So we defined cytokines, you know, proteins that are produced by immune cells, because we also needed to have a marker. At the time in Phase 1 trials, which are first in—well, not first. Yeah, first. So it wasn’t first in human, but, you know, when you’re trying to design what the maximum tolerated dose is, what dose are you going to use? Do we use a little? You always have to start low, see what the side effects are. At the time, the dogma was you want to give as much drug as you can, because in cytotoxic chemotherapy, you want to give the most, because more drug means you’re going to have a higher concentration and that’s going to kill the cell. Well, with immune-therapy, immune-therapy doesn’t do anything towards the tumor cell. I mean, I could take a tissue culture of tumor cells and put a high concentration of MTP, it’s not going to do anything to the tumor cell. You’ve got to have the immune cell in there. So what Dr. Fidler and I said is, “We don’t want the maximum tolerated dose. We need the optimal biologic dose,” OBD. And we were really the first to present this as a concept for a Phase 1 trial. I think people don’t give us any credit for that. It’s accepted now. But anyway, so we needed to have a way. How are we going to determine what the optimal biologic dose is? Because toxicity may not be the same as the optimal biologic dose. So we had to know what were we going to measure, what were we going to look for. So one of the things that we showed could happen was that we could give the drug and we could take samples of blood before the drug was given and various time points after, and actually show that the peripheral blood macrophages developed tumorsidal activity. So I gave the drug, took blood before, one, four, twenty-four, seventy-two, took the blood back to my lab, and immediately had to isolate the macrophages and put them with tumor cells.
Tacey Ann Rosolowski, PhD:
Now, just to clarify, this was you were working in animal models at this time, or you were in humans?
Eugenie Kleinerman, MD:
No, this is humans. This is humans.
Tacey Ann Rosolowski, PhD:
Wow. Okay.
Eugenie Kleinerman, MD:
This is humans. Actually, let me back up. So first I had to show—because also people said that cancer patients have a depressed immune system, so it makes no sense to give them an immune-therapy. So what I had to do was I had to collect blood—and this all required protocols that went through the IRB—blood from children with osteosarcoma, and take their blood back to the lab, isolate the monocytes, incubate them with MTP, and show that I could stimulate their macrophages just like normal macrophages to kill tumor cells. So there wasn’t an inherent macrophage defect in these patients. They could respond to the drug. I also then took blood samples of children who were undergoing chemotherapy, so they would get their chemotherapy and then I would take blood samples and take it back to the lab, and showed that actually with some chemotherapies, the drug worked better. Adriamycin was one of them. So we don’t understand that, but anyway. So I showed that children with osteosarcoma, their macrophages responded to the drug, and when they were getting chemotherapy, there was no interference. So not only did I do that in animals, then I did it in patients with osteosarcoma.
Tacey Ann Rosolowski, PhD:
It sounds like this research is also creating new understanding about how the immune system works.
Eugenie Kleinerman, MD:
Yes.
Tacey Ann Rosolowski, PhD:
Pretty amazing.
Tacey Ann Rosolowski, PhD:
Yes, yes, yes. And so that research with the patients was funded by a grant from the NCI. That was my first grant from the NCI, was to obtain the translational data that would allow us to go into clinical trials. So I came here in ’84. So in ’86, we were ready to go into a Phase 1 trial. But again, you couldn’t do a Phase 1 trial in children first, so, again, the collaborative spirit of MD Anderson. I collaborated with one of the adult oncologists, Dr. Lee Murray, who used immunotherapy in the clinic, and so he was the principal investigator on the Phase I trials, so it was done all in adults. And this is where we defined the optimal biologic dose. We said, okay, we’re going to start low and see what the side effects are, but we’re also going to collect blood from these patients, and I’m going to take it back to my laboratory and look at what proteins are being stimulated to be released, what is the dose that gives the highest levels of these proteins, and what is the dose that gives the maximum activation of the macrophages in the blood. And so we determined that the maximum tolerated dose that we could give was 6 milligrams-per-meter-squared, and the side effects were fever, shaking chills, fatigue, and muscle pain. The fever and the shaking chills usually lasted an hour or so, could be easily controlled with Benadryl. At the time, we couldn’t pre-medicate because we wanted to look at the side effects. The fatigue lasted about twenty-four hours. The fever could last a little longer, and the muscle pains lasted about a day. So by twenty-four hours, patients were fine. But based on the protein levels in the blood and the macrophage activation, the optimal biologic dose was two, and, in fact, if you went above two, you saw suppression of the macrophage activity, which showed how important it was to determine the optimal biologic dose [OBD] and not assume that the maximum tolerated dose, when you’re talking about an immune-therapy, would be what you need to do.
Tacey Ann Rosolowski, PhD:
What were the side effects with the optimum biologic dose?
Eugenie Kleinerman, MD:
You still got fever and chills. You still got the same. But with six, patients just couldn’t tolerate it. You had to stop. They couldn’t get more than one infusion or so.
Tacey Ann Rosolowski, PhD:
Interesting. Huh. Now just a little side question here. It sounds like these were—this was not a randomized trial [unclear]?
Eugenie Kleinerman, MD:
No, no, no. Phase 1 is never. It’s always in patients who have exhausted all therapy, and it’s never disease-specific. All you’re looking at is feasibility to give it and toxicity. Now, as part of the Phase 1, we also wanted to know where this drug was going. In the animals it was going liver, spleen, lung. Where is it going to go in humans? So we treated a few patients with technetium-labeled liposomes.
Tacey Ann Rosolowski, PhD:
[unclear].
Eugenie Kleinerman, MD:
Technetium is something that you can use that will be picked up on x-ray, so it has some radioactive—not radio, but—so we treated—the company made up technetium-labeled liposomes with MTP, and so in the first, I think, four patients, we gave them the drug, and we found that, again, it went to liver, spleen, and lung. But actually, interestingly enough, it also went to the nasopharynx, which we were very surprised at, which could mean that eventually this drug could be used in cancers that are in the nasal area. But, again, those are not biggies in pediatrics.
Tacey Ann Rosolowski, PhD:
Right, right, right. I had a question and lost it. Sorry. It will come back to me. (laughs) So, next steps?
Recommended Citation
Kleinerman, Eugenie S. MD and Rosolowski, Tacey A. PhD, "Chapter 8: Putting the Pieces in Place to do a Phase I Trial with MEPACT" (2014). Interview Chapters. 1404.
https://openworks.mdanderson.org/mchv_interviewchapters/1404
Conditions Governing Access
Open
