Chapter 14: Viruses, Genetics, Designer Drugs, and other Advances

Chapter 14: Viruses, Genetics, Designer Drugs, and other Advances

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In this chapter, Dr. Keating talks about discoveries about viral control of cancer and work that shows how genes control enzymes, leading to development of designer drugs to turn off enzymes. Other studies explore how to expand the patient’s immune system. Dr. Keating says he discovered that second cancers are driven by viruses, and he developed a program that takes a patient’s cells, modifies them, then returns them to the patient. He talks about an unusual collaboration with Baylor College of Medicine, where researchers are developing virus-specific immune cells that may target CLL cells lingering after other treatments.

Next, Dr. Keating sketches his other research studies with Rituximab, Lenalomide [Revlimid®], an inhibitor that work on B-cell signaling pathways. He explains how the latter are involved in pathways that can kill CLL cells. He also talks about drugs that interfere with “survival proteins” that keep CLL cells alive. [ [CLIP These are the “new building blocks” in treatment, he says. He anticipates doubling the cure fraction in the next few years and notes how quickly patients respond, with their faces shining like a healthy person’s (in comparison with the sickly appearance of chemotherapy patients). Dr. Keating notes that patients who receive targeted therapy feel sorry for chemo patients with acute leukemia.]

Dr. Keating notes that in the future he wants to write a book on CLL and plans to hand his practice over to his daughter, Dr. Anna Franklin. He expresses his pleasure that his children are happy in their work.

Identifier

KeatingM_01_20140520_C14

Publication Date

5-20-2014

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; The Clinician; Definitions, Explanations, Translations; Patients, Treatment, Survivors; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care

Transcript

Michael Keating, MD:

But the world is better now, and it’s better now because we have very good ideas of the genes that are involved. We have better ideas of the new enzymes that are being manufactured by these mutations, and the ability to develop designer drugs that just are the right shape and size and electrical charge to fit inside this key pocket and turn off the enzyme, so that we have a number of oral medications that are very, very well tolerated now, that dramatically improve the outcome of a whole variety of patients. We now know that there are new ways that we can expand the cells in the immune system so that we can either stimulate them with beads that have stimulating molecules or what are called artificial antigen presenting cells, and you can in two weeks have the number of cells going from 100 million to 100 billion and give the patient’s own cells back and re-expand their immune system. And that’s going to be critical in keeping patients well and allowing their immune system to benefit from these new modifiers of the immune system to help them [unclear].

Tacey Ann Rosolowski, PhD:

Is that work that you’ve been specifically involved in?

Michael Keating, MD:

We found out that a lot of the second cancers are probably driven by viruses. For example, the skin cancers are probably driven by papillomaviruses that cause warts, but in the susceptible cell, it will make it malignant. So we’re now developing a program where we can take the patients’ own cells and expand them up and give them these cells back, and we’re hopeful that it will be—

Tacey Ann Rosolowski, PhD:

What do you do with those cells that you take from a patient?

Michael Keating, MD:

You take them and you put them onto these beads and culture them for a couple of weeks, or on these antigen-presenting cell layers and culture them for that period of them. You then prove that they’re activated. You show that it’s a clean population. You show that there’s no reactivation of bacteria or any nasty cells. Then you just give them intravenously. Fortunately, the body’s smart enough to know to tell them where to go, and they attach to the cells. We’re working together with Baylor, which is not a common feature. I always thought that when you came to the Medical Center that everyone would be collaborating, etc., but there are a bunch of egos that stop that from happening. So that we are now in the situation where the Baylor people have been developing viral-specific immune cells, so that they have taught these immune cells of the patients to specifically kill off one, two, or three different viruses. So that we’re hopeful that this will allow us to eradicate remaining leukemic cells in those that are driven by the Epstein-Barr virus and the papillomaviruses, etc.

Tacey Ann Rosolowski, PhD:

What other studies are you involved in?

Michael Keating, MD:

Well, there are—well, let’s backtrack. We’re very happy that we’re now able to get very good results by the chemo-immuno therapy by adding Rituximab to the FC and making the FCR and having this 30 percent of patients that end up being free of disease at ten-plus years. That’s not bad. But the downside, as I mentioned, were these other agents. So we’re looking at drugs that are not like that, and one of them is a drug called Lenalomide, L-e-n-a-l-o-m-i-d-e, which is like Thalidomide, and it enhances the ability of the immune system to function and it probably kills the cells off by a variety of means, but one of them is by enhancing the immune system, and it doesn’t damage DNA. So we’ve been showing that combined with Rituximab is very, very effective, particularly in older people. It decreases the risk of getting a number of second cancers, and so we’re doing non-chemotherapy regimen.

Tacey Ann Rosolowski, PhD:

And what does that look like, the non-chemotherapy regimen?

Michael Keating, MD:

It’s this Lenalomide, which you give by mouth on a continuous basis, together with the antibody, Rituximab, which you give intravenously. Then there are these inhibitors of what they call the B-cell receptor signaling pathway, so that the normal B-cell is randomly manufactured in the marrow, and then it goes out into the circulation and it gets into the lymph glands and the spleen, and it sits there waiting to see if the virus or the bacteria or the food substance or the chemical that it’s supposed to neutralize comes along and gets into the little pocket that it has. And if it does—

Tacey Ann Rosolowski, PhD:

What does it get activated by?

Michael Keating, MD:

Well, the—

Tacey Ann Rosolowski, PhD:

I’m sorry. I didn’t—

Michael Keating, MD:

There’s a random process of reorganizing the DNA that makes antibodies. B-cells make antibodies against viruses and the flu. When you get the flu vaccine, you get antibodies against that particular vaccine, which is not a perfect fit for the virus, but it’s a good enough fit. So this randomly sends out about 15,000 families of cells, and it’s a very redundant process, and most of the cells actually just die off in about seven days, but if you get attached to the right molecule, it stimulates the body to make many, many copies of that cell, and they survive and they become very quiet functioning cells that just keep on pumping out antibodies to neutralize the virus, for example, if it comes on again. So that’s one of the situations, though, it has to be activated by this thing called the B-cell receptor, and the B-cell receptor looks very similar to the antibody, so that it’s stuck to the surface, and as soon as it gets attached, it switches on a whole cascade of enzymes so that there are three or four different enzymes that are now able to be inhibited by these oral medications along what they call the B-cell receptor signaling pathway. Ibrutinib has been approved, the other one is Idelalisib, which will be approved soon, and there’s another one which doesn’t work in that particular fashion. It’s called a Syk inhibitor, S-y-k inhibitor, that is along the same pathway. So as I said, they usually die off in about seven to ten days, and what happens is in chronic lymphocytic leukemia there are a variety of survival proteins called the BCL-2 family, and they’re present in all cells in the body to a different degree and in all cancers to a different degree, so that there are drugs that have been manufactured to specifically inhibit the activity of the survival proteins. And you now get to the point where they’re so potent that when we give them to CLL patients, patients go into the hospital and get a 20-milligram tablet, and they sit there while we watch how quickly the cells disappear. So we measure the levels of the toxic breakdown products every two hours and dialyze them if we need to and do all these heroic things. But within a matter of weeks, all of the lymph glands are gone, the white count’s normal, and you can eradicate the signs of disease from the marrow as well. So I think that these are the new building blocks for the combination, one that stops the cells being born and the other accelerates the dying process. And then you can start figuring out, well, if you give an antibody, that’s probably going to make the cells weaker and more susceptible to being killed, so that I anticipate that we’ll probably be doubling the cure fraction in the next, oh, two to three years.

Tacey Ann Rosolowski, PhD:

What are the side effects from these drugs, if any?

Michael Keating, MD:

Well, the Ibrutinib, you can get a little bit of bruising on the skin. It’s not a dangerous thing usually. A few patients will develop an irregular heartbeat, about 3 to 5 percent. Some people eventually develop some diarrhea, some people, aches and pains. But it doesn’t make your hair fall out, it doesn’t make you nauseated, and you go about your business, and in about four to six or eight weeks, family members are saying, “Boy, you look good, Dad.” And they really—their face begins to shine like a healthy person. So that’s one of the spectacular parts about the things that have come along. The Idelalisib is about 20 percent of the patients can’t continue because they get very significant diarrhea or lung toxicity, and so it’s not quite as easy as Ibrutinib. The ABT is very well tolerated and perhaps the least difficult to give after you get past that enormous dissolving in the cells that is early. The antibodies are usually very well tolerated except for the first infusion, because the first infusion is of a foreign protein, and patients get fever and sometimes chills and their blood pressures go up and down. But again, as opposed to people that come out from the old chemotherapy and they were bald and skinny and their skin looked miserable, that just doesn’t happen with these people. So we have two groups of patients in our waiting rooms with leukemias, and the chronic leukemias have these targeted therapies and they keep on saying how sad it is to see these sick people out there, which are the ones with acute leukemia, particularly if they’re older, that they don’t respond very well to treatment and they look really as though they’ve been beaten up. So one of the amazing things about MD Anderson is that we get to see so many patients and we document them so well that I think that my future is probably to write a book on my experience with one disease, just from the point of view of where we started and where we are now and observations that have been made and clues that we have, hiccups along the way, etc., and who were the important players in that. So rather than an oral history, we might have a written history of that, and it would be nice to just sort of close the book on it when most people end up being cured of the disease.

Tacey Ann Rosolowski, PhD:

You’ll be doing your own interviews and maybe using this archive of the oral history project as research material. (laughter)

Michael Keating, MD:

Well, I’ll also probably be handing over my practice to my daughter.

Tacey Ann Rosolowski, PhD:

Wow. I didn’t realize she practiced in the same area.

Michael Keating, MD:

Yeah, she works in childhood leukemia. She runs the Adolescent and Young Adult Program. So when she went to talk to some of the hematopathologists and then she was going through and talking about things with them, and then she said, “Oh, yeah, my dad talks about that.” And they said, “Who’s your dad?” And she said, “Dr. Keating.” They said, “Oh, why don’t you use his name instead of just Dr. Franklin?” And she said, “Well, some people really like Dad and some people he’s really annoyed, so you have to be really careful who you’re talking to.” The interesting thing is that I went down to the Peter McCallum Cancer Center in Melbourne, and, as I said, Anna runs the Adolescent and Young Adult Program here. So we’re going in there, showing me around there, and I went into this house where they have it set up so that the adolescents and the young people sit there and wait to be called into the clinic, because they don’t like hanging around getting bored and seeing all these sick people, etc. So they get paged. They said, “This is where we run our young people’s thing.” And I said, “Oh, yeah, my daughter runs our AYA Program at Anderson.” And they looked at each other and said, “Anna Franklin?” I said, “Yeah.” They said, “You’re Anna Franklin’s dad?” So all of a sudden, she was the famous person and I just happened to be a relative along the way, so it was a nice flip of the coin to look at it in that direction.

Tacey Ann Rosolowski, PhD:

Something to make you very proud indeed.

Michael Keating, MD:

Yeah. I’m very happy because my kids are happy in the jobs that they’re doing, and that’s the most important thing. I tell the young trainees coming along, “You’d better be happy in your job, because you spend more time with your job than any other activity in your life. So to make your mind happy, you’d better also hang around with people that make your emotions happy, and if you can get that balance, you’re doing okay.”

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