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JOHN BYRD, MD: Thank you, Dr. Horning, and the Lymphoma Research Foundation, and all of you for inviting me to speak today. I want to thank the Lymphoma Research Foundation for two reasons -- one, for inviting me, but also, a lot of the work that I'm going to present that other people have been presenting relative to new drugs for lymphoma has come forth through the research grants that the Foundation provides to investigators. So I want to thank them for that support.
So I'm challenged with the big challenge of talking about drug development and what's coming forward for all types of lymphoma. And you've spent approximately two days now talking about traditional therapies of both non-Hodgkin's lymphoma and Hodgkin's disease, and this summarizes that, and I'm not going to talk about that.
The important point I'm going to make is that, as you've heard, the outcome for patients with both indolent or low-grade lymphoma and aggressive lymphoma has not improved a lot over the past 25 years, with the exception of some of the advances of transplant, and, say, some of the new molecules that have just recently come forward, such as rituximab.
I think a common theme is that more of the same therapy is not better in improving the outcome for disease, and similarly, for Hodgkin's disease, while people with Hodgkin's do very well most often, there have been very few new therapies introduced in the past 20 years. So what's really important, if we're going to move forward from where we're at now to hopefully none of you needing to be here in 20 years, is we need to develop new therapies with properties that are selective to the tumor, that have minimal side effects, and that are novel, that work through a different pathway, kill the lymphoma cell, the leukemia-like cell, different than agents than we have now.
So really the goal of the rest of my talk is to describe some of the most promising therapies that are coming forward for each subtype of non-Hodgkin's lymphoma and Hodgkin's disease. I'm going try not to make this a listing of things, and I'm going to talk about individual things, and there will be some overlap between the types of lymphoma that I discuss on Hodgkin's disease.
So what about follicular lymphoma? Clearly, a lot of discussion has been made about the biologic therapies, and I sort of have starred what I think are the most promising things, the antibodies, which you've heard a lot about, rituximab being the first; cytokines with antibodies, because this brings the immune system together with antibodies to really enhance the response; and then vaccine approaches that we're going to hear about later. And I think the vaccine approach is particularly early in this setting of low-grade and follicular lymphoma. It's very exciting. And finally, allogeneic stem cell transplant, particularly the mini-transplant, because that's another form of immune therapy, and when we think about it, say, all of us have lymphoma, cancer that grew up in one or two cells, and it's really tricking our immune system that it's able to manifest its full fury. So harnessing the immune system is clearly the most exciting avenue for follicular lymphoma and many of the other lymphomas.
Monoclonal antibodies in non-Hodgkin's lymphoma, these have been around for a very long time, over two decades. Mouse antibodies that were tried were not effective, but really the humanization, or bringing the technology forth and to adapt new therapies has made this a very exciting therapy for lymphoma. Obviously, the advantages of antibody therapy, particularly, it can be selective to the target cell, and it has a novel mechanism or mechanisms of action. So it kills the lymphoma cell in several different ways.
There are a lot of antibodies of interest that are coming forward or are that in the clinic for CLL. Rituximab, obviously, is approved. It's widely used. Say, Campath 1H, as has been alluded to, very effective, but has problems in CLL, and then other antibodies -- Hu-1D10, which targets another marker that's expressed on a small subset of immune cells, including most lymphoma cells; epratuzumab; and then another antibody called IDEC-144 that targets CD80. The radiolabeled antibodies we've heard about.
What I'd like to talk a little bit about is an antibody called Hu-1D10, which targets, say, an antigen different than CD20 called HLA-DR that's expressed mainly on B cells and most B cell non-Hodgkin's lymphoma cells. It's not on T cells, so therefore it's selective. A humanized antibody was made for this, and it entered clinical trials approximately three years ago.
This is a summary slide of the initial patients with follicular lymphoma that were treated on this study, and what's represented here is the total amount of tumor that they started with. So the total square centimeter amount of tumor, and you see over time that decreased in the majority of patients that were treated on the phase I, or the very early study of this antibody. This generated a lot of excitement, because these responses often occurred late, and there was some preliminary evidence that this antibody was awakening the immune system. So it was generating not only antitumor response, but it was awakening the immune system to generate a secondary response.
Unfortunately, as with a lot of phase I studies, this entered phase II testing and was tested in more refractory -- in patients with more refractory disease who had less a intact immune system, and while the treatment was tolerated well, the efficacy relative to the phase I was marginal. And right now, alternative schedules of this are being used, giving more of the antibody and to more selected patients. Similarly, second-generation antibodies -- sometimes we don't get it right the first time and we need to develop better antibodies targeting the same thing, and there are pan-DR antibodies that are coming forward. Preclinical data in mice have shown very promising results. This is one such antibody that we're working with in our laboratory, and this shows here our negative control, and you see Hu-1D10 is a little bit better than that, but it's not curing the mice. And this is mice experiments. These aren't people experiments or trials.
And you see in the majority of the mice treated with this pan-DR antibody, they're being cured with the antibody. So these are moving forward, and over the next four to five years, if these are tolerated in the clinic, hopefully we'll see promising results.
Campath was brought up. While Campath is a great drug for CLL, particularly when other therapies have failed, in low-grade lymphoma, particularly follicular lymphoma, the response rate has been very marginal. While 20% have been reported in the biggest series, most of these were T cell lymphomas, and in fact the response in low-grade lymphoma outside of T cells, or the B cell lymphoma, follicular lymphoma, was only 14%. This antibody targets B and T cells, so it's very immunosuppressive, and another large phase I study looking at follicular cell and other B cell lymphoma showed no responses. So, really, Campath, outside of CLL and outside of cutaneous T cell and the T cell lymphomas, really, outside of a trial doesn't have -- is not a very active agent for this disease as a single agent as we give it right now.
What are some other promising agents? There's the histone deacetylase inhibitors which target genes that are repressed in lymphoma, are active and are entering clinical trials. Depsipeptide, MS-275. There's a whole new class of drugs, the imides, that are very active in multiple myeloma, and they shut off cytokines that keep lymphoma cells alive. A very exciting agent.
And then I've got listed here geldanamycin derivatives, AKT inhibitors and CP-461, and all of these are kinase inhibitors. And kinases are very important to keeping cells alive. The best thing that you can -- Gleevec is a medicine that's used for CML that targets a kinase, and these are new kinase inhibitors, and kinase inhibitors can best be thought of as something that -- like when you turn off the light switch, and if you pick the right light switch with these medicines, you can turn the tumor off. Several of these are entering clinical trials. They're very early, but they're very promising.
Even though I'm talking about new drugs, I think stem cell transplant, allogeneic stem cell transplant in follicular lymphoma is very exciting, particularly if it's done before people have received everything. And this is data from Dr. Flynn, one of my colleagues, showing very good results relative to allogeneic stem cell transplant when it's done relatively early, before two prior therapies.
And you've heard about nonmyeloablative stem cell transplant, and again, as a drug developer, I want to give my plug that this is a new mode of therapy that's very exciting, as exciting as some of the drugs that we were talking about before and that we will talk about.
What about CLL, small lymphocytic lymphoma, the tissue variant of CLL, and another type of lymphoma, Waldenström's? Clearly, there are a lot of new antibodies that are coming forward. I've listed them here. As I said, I'm not going to go through the list, but several of these target markers on the leukemia cell, including IDEC-152, and these four target substances that the leukemia cells, the lymphoma cells require to stay alive. They target cytokines, and all of these, there are antibodies to these, and these are moving forward in clinical trials right now.
I mentioned Hu-1D10 in lymphoma. We're also looking at in CLL. We're doing a trial at Ohio State, the University of Chicago and Johns Hopkins, and we've seen promising results in our phase I study, just as we've seen in the low-grade lymphoma study, including in patients with very resistant CLL that have bad molecular markers. So again, the antibody therapies, there's this theme for both the lymphoma and CLL are very, very promising therapies.
What are some other exciting compounds for CLL? We have sort of that same list of medicines. We have this medicine called Viagra. And that's not a joke, actually. People have taken leukemia cells and small lymphocytic lymphoma cells and exposed them to Viagra in culture, and guess what. The cells die. [LAUGHTER] The problem is, there's not a CLL doctor that's willing to take this to a clinical trial because of a fear of the contracts that are going to be taken out on them by their spouses. [LAUGHTER]
And then, again in CLL, there are a variety of other kinases. So again, kinase inhibitors, just like we said with follicular lymphoma, turning the light switch off. One in particular that targets ZAP-70 is very exciting, and hopefully it will be coming into the clinic within the next year.
So we're going to talk about a medicine called depsipeptide. This is going to come up over and over again. This is a histone deacetylase inhibitor. Why are we excited about this in CLL? In other diseases -- as you'll hear later, in T cell lymphoma, this is one of the most active new agents coming forward. But what's exciting about it is it's very selective against CLL cells versus the normal immune cells, so we're looking at a two-log difference in sensitivity. So it's much more -- it kills the leukemia cell much better than the normal immune cells or the bone marrow cells. There's a three-log difference there.
And this is some data from our initial phase I study showing that the substance that it's targeting, the chromatin remodeling, the histone acetylation, we see very little acetylation, and as we treat the patient with the drug at four hours and 24 hours, it goes up. Here you see the white blood cell count of the patient being treated. So, pretreatment, and then it goes down, and within each treatment it comes up a little bit, and with each treatment it goes down.
Well, how about mantle cell lymphoma? This is a disease that is a very challenging disease. We've heard a lot about it. What are some exciting new therapies in addition to some of these agents we've talked about? Well, flavopiridol, an agent that targets cyclin D1, the gene that's overexpressed in mantle cell based on the genetic abnormality present. And while this was initially tested in mantle cell lymphoma, it had no activity when given as a 72-hour continuous infusion. It's sort of a theme of drug development that often we don't get it right the first time. And really, when we looked back, there was no chance that we were going to attain levels that killed the mantle cell lymphoma cells from the data that was generated later in the laboratory.
A new bolus schedule has moved forward that still is probably not optimal. This agent still needs schedule work done on it. But a study done by the Canadians -- you have 25 patients with mantle cell lymphoma -- showed responses, but what was exciting is, even in the patients that didn't respond, about 72% had disease stabilization for a prolonged period of time. This is exciting, because this agent doesn't cause myelosuppression. It's main side effect is it can cause diarrhea that's short-lived. So it provides a new medicine to build on our current therapies for mantle cell lymphoma, and that's how we make progress. We find something that works, and we build upon what we have.
I think really the true benefit of this drug is going to be giving it in a more optimized schedule, but this is something for mantle cell lymphoma that should be on the radar.
For T cell lymphoma, we mentioned depsipeptide in CLL. This targets something called histone deacetylase, which turns off cytokines that keep T cells alive, including the T cell lymphoma cells. Dr. Bates at the NCI has done a small -- has done a phase I/II study that was reported in peripheral T cell lymphoma, which, I think, Dr. Horning will agree, is a very difficult type of lymphoma to treat. Two of the six patients have responded. One patient with single-agent therapy had a remission that's ongoing beyond two years. Nine of 11 patients with cutaneous T cell lymphoma who are very refractory responded to this, and this is probably one of the most active agents coming forward for T cell malignancies of this type.
The main problem with this drug is it causes fatigue, nausea and vomiting, and again, I think we're going to need to work with the schedule of it more, but this is a very exciting therapy for T cell lymphoma.
Similarly, another medicine, GW506U78 -- that's made by Glaxo -- is very active in adult T cell lymphoblastic lymphoma, and is being tested in these other T cell diseases.
What about Hodgkin's disease? We said that while most people are doing well with Hodgkin's disease, we need new therapies for this, particularly less toxic therapies. There's one study by the MD Anderson group looking at rituximab. They treated 24 patients with this. They know that 23% of the patients responded, and the majority of patients have resolution of their B symptoms. This does not depend on the Reed-Sternberg cells expressing CD20. Clearly, these are interesting, provocative data that need to be confirmed by other studies.
There's a Medirex antibody targeting CD30 that's entering clinical trials, and in Hodgkin's cells, in Hodgkin's cell lines, at least, this antibody, as well as in anaplastic large cell lymphoma, it appears to be very effective in the laboratory.
And then finally, the CD80 and the class II antibodies are very exciting options for Hodgkin's. So for Hodgkin's we have several antibodies coming forward, which, again, just like you've heard earlier with CHOP and rituximab, may offer the potential to augment our chemotherapy approaches for Hodgkin's. Other therapies targeting cytokines such as the small molecules and the histone deacetylase inhibitors also offer promise for Hodgkin's.
What about large-cell lymphoma? I think here the basic biology of the array studies that have been published by several groups are giving us guidance as to what type of molecules we should bring into diffuse large-cell lymphoma in addition to the antibodies that you've heard about. And Dr. Davis did studies on the activated diffuse large-cell lymphoma that was shown with the microarray, which is a very sophisticated laboratory test, and showed that what distinguishes that bad type of lymphoma is over-activation of NF-kappa-B. And what's exciting is, there are molecules such as PS-341 and second-generation molecules that target that, so there are trials moving forward with PS-341 and EPOCH and other types of chemotherapy for the subset of lymphoma.
Similarly, the group at the Farber has used that same c-DNA microarray test and has shown that certain protein kinase C subsets are overexpressed, and molecules are being developed to target that.
Finally, something that's been ignored in diffuse large-cell lymphoma is methylation. And again, this is another way that cancer cells turn off genes that keep the cancer cells -- that tell the cancer cells to die, and agents that target methylation are, again, like light switches. They turn it on. So they remove the methylation, the genes are expressed, and the lymphoma cell dies. And there are a variety of genes that are methylated -- P57, 14 and 16 -- that contribute to the pathogenesis of lymphoma, so targeting people that have these genes silenced may offer a very exciting option for this disease.
But it's sort of a two-handed sword, because this is a normal process by which genes are silenced, and sometimes genes that are advantageous to response can be silenced by methylation. So we're going to have to individualize our therapy, and that's sort of a theme that I want to finish with, is that for all the types of lymphoma, CLL, Waldenström's, everybody's an individual, and as we move forward with our new therapies, targeting the individual with our individualized therapies is going to be very important. That's where medicine is going in the next 10 to 15 years.
So my conclusions, I'd like to say that basic science work that the Lymphoma Research Foundation, the NIH and others have supported has really led to a better understanding of non-Hodgkin's lymphoma and Hodgkin's disease and has given us guidance of how to manipulate therapies. The combination of chemotherapy with antibodies, as you've heard, in diffuse large-cell lymphoma and low-grade lymphoma is leading to good responses. The long-term impact is uncertain, and certainly moving forward with targeted molecules, including the small molecules, such as the kinase inhibitors, new antibodies, new biologic approaches and mini-stem cell transplant, offer the opportunity that we're going to move step by step forward to our ultimate goal of curing lymphoma. Thank you. [APPLAUSE] No questions?
Q: I think in the beginning of your talk, you mentioned that Campath was not good for low-grade non-Hod... to expression?
JOHN BYRD, MD: I'm sorry, I didn't hear the last part of your question.
Q: Is the reason Campath not being good for low-grade non-Hodgkin's lymphomas, is that regardless of the amount of CD52 expression?
JOHN BYRD, MD: I think it's possible that Campath will be effective for low-grade lymphoma, because most lymphomas express CD52. We just don't know, perhaps, how to correctly give it for that disease, because Campath in general does not work well for bulky or nodal disease. It's better for clearing the bone marrow out. It may be possible as well that the signaling that Campath does to kill CLL cells is not going to be same that's present in low-grade lymphoma. But there's just not -- because of the side effect profile off clinical trials, Campath is not something that I typically give to my patients with low-grade lymphoma.
Q: I have a question about clinical trials. I was in a clinical trial up in Nebraska, and I went through the six months of CVP and was not responsive to it, and so then was dropped from the trial. So my question -- well, and then, of course, since then was told I needed a more aggressive chemotherapy and radiation. Instead I went to Burzynski Clinic and have been in remission for six months now. But my question is, for those who get dropped from the trials, where are they in the numbers, as far as the results go, and rather than dropping them, couldn't they outside the trial be given the -- in my case, it was the vaccine that they made from my particular tumor -- couldn't they go ahead and give them the treatment, but keep them outside the trial?
JOHN BYRD, MD: I'm a very big advocate that when we know something works -- and that's really the key. Some of the medicines we've talked about are new. We don't know the side effect profile completely in lymphoma, and we're not certain that it's going to work. But if we know something is going to work, I'm a big advocate of trying to get -- when I'm working with pharmaceutical companies, for instance -- to get them to have a compassionate use study, so if someone, say, starts at the low dose in the phase I, and then we see later on that it's working that they can receive the drug compassionately at a later time, because that's what everybody that's speaking here is about. If we have a therapy that works, we want to provide it to you to make you feel better.
Q: Okay, thanks.
Q: Since I don't understand all of your terms, I'll ask this question. My wife has MALT. Now, is there any of this stuff that looks promising for that?
JOHN BYRD, MD: Yes. A lot of the molecules, a lot of the medicines that I talked about for both follicular lymphoma and small lymphocytic lymphoma-slash-CLL and Waldenström's are equally promising for MALT. [APPLAUSE]
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