Dr. Louis Staudt — The ABCs of B Cell Lymphomas

>> Diego (narration): We’ve all had those days, you know, the kind when one tiny mistake seems to make everything else go wrong. The kind of days when waking up past your morning alarm sends you rushing across the room only to stub your toe on the foot of the bed, so that you limp your way to the bus stop, right in time to see the bus drive away.

Small things can quickly escalate to have larger repercussions. It’s what’s commonly referred to as the domino effect, named for the analogy of a falling row of dominoes.

The idea that a single event sets off a cascade of consequences can be scaled up to global proportions. The assassination of Archduke Franz Ferdinand of Austria, for example, is often cited as a catalyst for the beginning of World War I.

In other instances, the first domino can be even smaller, falling at the microscopic level. Cancers in the body result from small changes to DNA, known as genetic mutations. When these mutations occur on oncogenes—or cancer-causing genes—it triggers a chain reaction that causes cells to go awry and spread uncontrollably. And that’s what cancer biology is all about: identifying those mutations and finding ways to stop them before they snowball into a deadly disease.

Dr. Louis Staudt, a senior investigator and the director of the Center for Cancer Genomics at the National Cancer Institute, studies genetic mutations and how they lead to different types of cancer. In 2020, Dr. Staudt was elected to the National Academy of Medicine for distinguishing subtypes of lymphoma based on genetic screening and identifying potential routes for targeted therapies.

In this episode, we walk down memory lane as Dr. Staudt recounts the story of how he discovered different molecular subtypes of cancer in the lab and translated his findings in what resulted as a game-changer for patients during the dawn of cancer precision medicine.

>> Diego (interview): So, Dr. Staudt, for the nonscientists out there, how would you describe your research?

>> Dr. Staudt: Well, I was puzzled by the fact that some patients with aggressive lymphomas we're being cured which was of course, a great medical success while others weren't. And what I thought my basic idea was, there must be something molecularly different about the tumors that patients had that could be cured and those that were unfortunately not and would relapse. So, it was that simple idea. And I started reading up about the cancers of B cells, these lymphomas.

>> Diego (interview): Just to clarify, lymphoma is cancer of basically the immune system. Is that accurate to say?

>> Dr. Staudt: Lymphomas are cancers of a part of the immune system, lymphocytes. Most of them come from what are called B lymphocytes or B cells.

>> Diego (interview): And B cells, those are the ones…

>> Dr. Staudt: Those are the ones you hope the COVID vaccine is going to elicit a very good antibody response from. And we need them. We can't live without them. But there is aspects of how they're made during the normal course of your life that allows errors to occur. And these errors can sometimes make them malignant. And that is why lymphomas are very common type of cancer that we fortunately, how to treat in many cases. But we have a lot of work left to do.

>> Diego (interview): And that's mostly because there are so many subtypes, right?

>> Dr. Staudt: Exactly right. So, the process of developing an antibody response –let’s stick with the COVID metaphor—is first you have a resting B cell that's circulating in your blood. And then it will encounter an antigen let's say from the COVID virus. It will then become activated. That is, it will start turning on various programs of cell division, of metabolic activity, and then go through a process of differentiation in a specialized part of lymph nodes, that's called the germinal center. And I go into this technical aspect because many of the lymphomas arise from germinal center B cells. So, it is in that group of cells that the errors occur and can give rise to different malignancies. And the basic idea is that each of those stages of B cell differentiation has a different molecular makeup. That is the genes that are active in each state of differentiation are different because cells do different things. And as a result, the types of lymphomas arising from different stages of B cell differentiation will inherit different patterns of gene expression. And that's not just a signature that you look at. That changes the biology of those lymphomas. And that is really where I started with subdividing the lymphomas using an early technology to look at these gene expression differences.

>> Diego (interview): I see. So depending on what checkpoint in development certain B cells make it past, that will changes the way they function and possibly disfunction. So how do you go about distinguishing between lymphomas?

>> Dr. Staudt: So, I heard way back in, I think, 1998 from a very good friend of mine Dave Levens at the intramural program. He had just visited a friend of his, Pat Brown out at Stanford who had developed a technology of looking at the levels of gene expression not one gene at a time, but thousands of genes at the same time. This was called the DNA microarray. And the very next day I called up Pat. I had never talked to him in my life before. But I proposed to make a specialized DNA microarray using his technology that fondly we ended up calling the LymphoChip.

And it was a little challenging at the time because the human genome project had not been completed. We didn't even know at that time where all the genes were. So, while we're doing this, we were simultaneously defining new genes. Sometimes you have to proceed full speed ahead without perfect knowledge of where you're going. So, that then led to a very clear subdivision of the diffuse large B cell lymphomas into two gene expression subgroups. One we called the germinal center B cell-like DLBCL. DLBCL stands for diffuse large B cell lymphoma.

What does the name imply? The cells are large, not small. They are diffuse in sheets, not in sort of clumps of cells. And as I mentioned earlier the germinal center is a place where many of these lymphomas come from. And these particular lymphomas bear many of the gene expression hallmarks of that normal stage of B cell differentiation.

>> Diego (interview): Uh-huh.

>> Dr. Staudt: Then the other type looked quite different by gene expression. And we called it the activated B cell-like diffuse lymphoma. And we called it that because instead of looking like germinal center B cells it looked like one of these blood B cells that had been acutely stimulated by an antigen. In that process of activation hundreds, and hundreds of genes are turned on. And these lymphomas had these genes on all the time. So, we called the activated B cell type which I really like that one because then we could call it ABC diffuse lymphoma. And I knew that that banding might stick. And then germinal center B cell lymphomas we called the GCB type of diffuse lymphoma.

>> Diego (interview): Alright, so we now have ABC and GCB lymphomas based on genetic screening. What’s next?

>> Dr. Staudt: So, the reason I was doing all this was not to be some sort of stamp collector and put all these tumors into boxes. But I was more interested in developing cures potentially, for the different molecular subtypes. And really the DNA microarray and gene expression profiling were not going to take us there. Because they sort of showed us what you would call the phenotype of the tumor. Sort of what it looks like. But not its mechanisms. Not how it worked. And those mechanisms are important because drugs generally work by blocking molecular mechanisms in cells. And so, I had this general idea that I wanted to find all the genes in the genome that the malignant lymphomas could not live without. So, the genes that cancer cells needed to stay alive.

>> Diego (interview): Got you. And these - so, these mutations or these genes that you're looking at might otherwise be detrimental to like a body or a cell. But in this context, they're actually beneficial because like you said they make them vulnerable.

>> Dr. Staudt: They're beneficial to the tumor, but not beneficial to you, right. What's beneficial for the malignant cell is what's going to kill you. But you raise a very good question, is that some of the essential genes are going to be essential in every cell of your body, right. Things that are involved in intermediary metabolism. Or some sort of cellular processes having to do with creation of the nucleus or the different organelles. Any of those essential things aren't going to make good drug targets because if you interfered with those, you'd have all sorts of side effects.

>> Diego (interview): Sure. And you were saying that you were trying to identify those genes for ABC and GCB cells…

>> Dr. Staudt: Yeah. So, we had cell lines that grew continuous in the lab that for all the world looked exactly like these ABC tumors. And we had other cell lines that grew in the lab that looked like the GCB tumors. So, we very simply imagined, hypothesize if you will, that that if you found a gene that was essential for the survival of the ABC cells but not for the GCB cells, that that might turn out to be a gene that wasn't essential broadly around the body. And that one could interfere with that with a drug. And have what they call a therapeutic window. A dose of the drug that would get rid of the lymphoma in this case, but not touch the normal cells and therefore not give you too many side-effects.

So, we screened lymphoma cell lines and found when we knocked down the expression of a receptor on its cell surface called a B cell receptor, the cells hated it. They died very quickly from a process known as apoptosis.

>> Diego (interview): Interesting, so what did that mean, that these cells died when they didn’t have the B cell receptor?

>> Dr. Staudt: Well, this was the very first inkling that the B cell receptor was essentially the most important oncogene for malignant lymphomas. So, we then tumble to the possibility that these malignant lymphomas would have genetic mutations or other alterations that would affect this B cell receptor pathway. After all, normally it doesn't cause a malignancy.

And so, we had discovered mutations in the B cell receptor, and we knew they were interesting and exciting. But we hadn't publicly spoken about them. We had a paper that we had submitted to Nature and they had asked us for a number of hard experiments to do. They liked the paper but they - there were some challenging experiments, and we were working through them. But hadn't gotten it accepted. And I was asked to speak at a major international conference which was the AACR - American Association for Cancer Research meeting. And this was around 2009. And I was having a chance to say whatever I wanted to say. And so, I said, well, just go for it. I'll just - even though it's not certain this will be published. It's exciting and I want people to know about it. So, I gave my talk, and I was bum-rushed at the podium afterward by a group of scientists from a small company that I had never heard of called Pharmacyclics. And they said have we got a drug for you. They had developed a way to inhibit B cell receptor signaling. And so, this drug at the time was called PCI-32765. I remember it to this day. Just doesn't trip off the tongue the way the current name, ibrutinib…

>> Diego (interview): Oh, either way, that's kind of an alphabet soup.

>> Dr. Staudt: All these drug names are alphabet soup. But we now know and love the drug ibrutinib. So, I was excited by that possibility. And I said well let's do something. They gave me a sample of the drug a nd we showed that when we treated ABC cell lines with this drug they dropped dead. They hated it. And the GCB cell lines laughed at it. They couldn't care less whether they were bathing in this drug. So, that was very encouraging.

>> Diego (interview): That is promising.

>> Dr. Staudt: Now, another aspect of the intermural program came into play. That is, I had developed a close working relationship with some of the clinical researchers who study lymphoma and have been doing so from the early days of the Cancer Institute. And my friend and colleague Wyndham Wilson was interested in what I told him about this new drug. But I would say, pretty skeptical. He had seen a lot of drugs come and go. And everybody thought they were great, and they didn't pan out. So, he was rightly cautious. But he said, look here's what we'll do. We will get 10 patients in that have this ABC type of tumor and we'll give it a try. And in record time he was able to get a clinical protocol established to do this. And the first patient did well and had some very good response to the tumor. The second patient, the patient's tumor went away. Just by giving this drug. Now, what's remarkable about that is these patients had relapsed and refractory disease. That is on average, they had received three different chemotherapy regimens. And their lymphomas came back after each one of those.

>> Diego (interview): Wow. So, tthe first two patients responded really well. Was that the case for the rest of the 10 people in this trial?

>> Dr. Staudt: So, in our first group of 10, we had three responders.

>> Diego (interview): Okay.

>> Dr. Staudt: That was as we say in the business, a clinical signal that that is an active drug. And remember, these patients, had they been given another chemotherapy would only live for two or three more months. So, we then led, Wyndham and I, led a national phase two trial of ibrutinib in diffuse lymphoma. And we took all types of diffuse lymphoma because we wanted to directly test the hypothesis that the ABC tumors would respond, and the GCB tumor would not, right?

And that's pretty much what we found. We found that there was a 39% response rate in ABC lymphoma. And only a 5% response rate in the GCB lymphomas. So that is, if you will, a success in precision medicine. Precision medicine now is something we talk about all the time but did not really have a name until about that time. And so, what you want to do in precision medicine is find by some diagnostic method a group of patients—doesn’t have to be cancer, any kind of human illness—a group of patients that when identified will have a high rate of response to drug X. And another group of patients who might not respond to drug X but would respond to drug Y. So, that's precision medicine in a nutshell.

>> Diego (interview): I see. But that process, which you’ve basically illustrated with ibrutinib for lymphomas, is pretty painstaking. I mean, it must be incredibly difficult and time-consuming, not to mention expensive, to sift through all those variations in a whole bunch of people in order to find a common denominator and begin to distinguish those different subtypes.

>> Dr. Staudt: That is a very astute comment. Every tumor is different. Every tumor has gone through a Darwinian evolution in your body that was selected based on all different types of aspects of your own genetic makeup, having to do with your exposures to different substances; whether you're a smoker or you're not a smoker. So, in every patient, you'll have a different evolution of that tumor. And in detail every patient's tumor is different.

Do we need to slice and dice these tumors infinitely? That's obviously untenable. You don't want to have a something where you need to do a thousand different treatments for different patients. So, there's some sort of sweet spot in between. So, the strategy will be to, I would say, develop a clinically useful way of subdividing patients to receive one type of treatment versus another type of treatment. But in as much as our information is never perfect and clinical disease of any type is heterogeneous. We'll never be at 100% certainty that somebody will respond and a 0% certainty that someone else will respond. I mean, the future does not look like the perfect treatment for every particular patient.

But, what we want to do is lump together in the largest lumps possible, tumors that have the greatest chance of responding to a particular kind of therapy. This is what medicine is through the ages. Medicine started out by just observing clinically various aspects of the disease based on a physical exam. Then all of a sudden you could look under the microscope.

>> Diego (interview): Right.

>> Dr. Staudt: And then there was a different way of putting patients into groups. And if you have these little squiggly spirochete then you should get treated with an anti-syphilis drug. So, that is precision medicine. It's just with a different tool. So, this is what we continue to do just with ever-more sophisticated tools.

>> Diego (interview): Definitely. Well, we've been talking about COVID and cancer and how those alike. I know you've been working on some COVID stuff during the pandemic with Dr. Wyndham Wilson, which you mentioned.

>> Dr. Staudt: Oh, I'd love to mention that. So, Wyndham and I are colleagues that talk almost every day on the phone about one matter or the other. And we were talking about the fact that COVID had to with an inflammatory reaction. So, lightbulbs went off that maybe this very same drug that we were using might help quell the cytokine storm—this hurricane-like mix of immune stimulants and reactivity that you see in this bad COVID.

>> Diego (interview): And that usually leads to hyper inflammation, right? The cytokine storm.

>> Dr. Staudt: Hyperinflammation often in the lungs, but also elsewhere in the body. And there was another drug called acalabrutinib that we'd also studied. And it probably has somewhat fewer side-effects which we thought would be a benefit when we were proposing to treat otherwise healthy people with this drug. So, we had this idea on a Friday. We had a very great clinical colleague, Mark Reshefski [phonetic], who conducts the majority of our clinical trials. And we got Mark on the hook and got him excited. And within the course of the weekend, Mark had written up a clinical prospectus of how one would use acalabrutinib to treat patients with this disease. Usually, the normal medical research process is slow and deliberate. It takes a fairly long time. And that was not - so The World Health Organization has said if you plan to use an existing drug that has been shown to be safe, and that there's a mechanism that makes sense, that it might help people in a pandemic. And you're willing to publish and disseminate the results of your investigations, it is ethically acceptable and actually, you know encouraged to do such of investigation.

So, Wyndham and I and Mark initially teamed up with some physicians at Walter Reed and the first patient that we treated said the following morning, "I feel a lot better." We then proceeded to expand that and saw very frequent responses. And these responses seemed to make sense because they were associated with not only better oxygenation—so that's why you feel better, you're getting more oxygen—but also, a decrease in inflammation as we could test by blood markers. And in patients that were not already in the intensive care unit and had you know very, very bad off, we did very well. And among the 11 there, 10 of them ended up eventually doing exceedingly well and going home. And these are patients who were quite sick and in the hospital for that.

It was not a controlled clinical trial. It did not have a placebo arm to it, but we had a lot of science that we incorporated that made us think that the drug was hitting its target. So we do still think that our data, which we published in Science Immunology, is correct. So, time will tell. I do think that that was also something that was quite special that we were able to move so quickly here in the intramural research program

>> Diego (interview): Yeah, and I think it's such a great testament to the all-hands-on-deck approach that this public health crisis has spurred.

>> Dr. Staudt: Yeah, exactly. I mean, if you're not doing that you're not really listening because people were suffering. And we had some, we thought, knowledge that we were maybe among the few in the world to appreciate the possibility that this drug could be repurposed in this particular way, because this is a tough situation we find ourselves in.

>> Diego (interview): Unfortunately, yeah. But in lighter news, you were recently inducted into The National Academy of Medicine. So, how does it feel to get that recognition and hit that milestone?

>> Dr. Staudt: Feels real good, because, you know, if you're a young scientist you have your heroes. And those heroes - you go to meetings and they give great talks and you say, I don't know, could I ever do that? And am I capable of doing that? And the same people then who were my heroes now are also in this academy. And I get to see them when we have our meetings and I know them very well now. And that's really an amazing feeling.

>> Diego (interview): Yeah, to be in that company. When mentors or, you know, heroes become peers, that’s pretty special.

>> Dr. Staudt: Whenever anybody asks me this question, I say quite honestly that the work is its own reward. The fact that you can move the ball down the football field you know 10 yards and help some patients with some illness is very motivating.

>> Diego (interview): Yeah. Well, I’m sure they appreciate it and I appreciate you taking the time to chat with me today. So, thank you so much.

>> Dr. Staudt: It was great talking to you.