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Slide # 1
SANDRA HORNING, MD : It's really a special pleasure for me to introduce our last speaker this session, John Timmerman. John is a graduate of the fellowship program at Stanford University, where he distinguished himself as perhaps in the elite group of a very outstanding group. Did his laboratory and clinical work with Dr. Ron Levy. And now it's to the benefit of UCLA that he has come to Los Angeles as an assistant professor and will be discussing today therapeutic vaccines for lymphoma. [APPLAUSE]
JOHN TIMMERMAN, MD: Thank you, Dr. Horning, it's an honor to be here. And I'm very excited to talk to this group. Usually I'm talking to lots of doctors, but it's a real honor to talk to many patients. And I think a number of patients that we treated in our clinical trials at Stanford and elsewhere are here and we've already from some notable representatives of that group, who have stood up and volunteered their success stories.
Now I'm going to talk to you about a very different approach. That is, recruiting the body's own natural defenses to elicit their body to make an immune response against their own tumors. A little bit different than you've heard about in some of the previous talks. And I wanted to emphasize that these vaccines -- and I'll explain what I mean by that -- are therapeutic vaccines, is a term we really like to use. We don't have a vaccine yet that can prevent lymphoma from ever occurring in a patient; these are vaccines that are used to treat people who already have lymphoma.
Slide #2
So what I'm going to talk to you about, it's just first teach you a little bit about the immune system. I know you probably or some of you know some already. Focus on the idiotype or ID-KLH vaccine, since these have reached the most advanced stage of clinical development. Just mention to you some of the new non-Hodgkin's lymphoma vaccines that are under development. And lastly, we'll conclude with what vaccines are now available to patients. Once again, these are all investigational agents; none have been approved by the FDA and so they're all being available only in very carefully controlled clinical trials.
Slide #3
Now just for a point of review, I wanted to just touch on the basic of the immune system. The immune system can most simply be divided into two arms. We say that's the humoral or the cellular arm. Now the humoral arm is the so-called B-cells; these are the cells that become malignant in most forms of non-Hodgkin's lymphoma. And a B-cells expresses an antibody on its surface and when it meets up an antigen -- that is, a foreign substance -- it will become activated and secrete these molecules and these antibodies bind to and inactivate these foreign substances.
The other arm of the immune system -- the T-cell arm -- uses these so-called T-cells that will attach to and see antigen that's expressed only on cells, not antigen that's floating around in the body, for instance. And these T-cells will then kill the abnormal cells -- which is virus-infecting cells or tumor cells. And they make chemical messengers called cytokines that will have mostly negative impact upon these tumor cells.
Slide #4
Now in fact we can use the immune system to target one specific molecule that's expressed on B-cell lymphomas. And that marker molecule is called the idiotype. Now as I showed you before, each normal B-cell expresses and immunoglobulin or what we call an antibody molecule on its surface. And these have portions of them called the variable regions that's different for every known B-cell. And it uses these sequences to bind foreign substances in the environment. But when a B-cell undergoes a malignant transformation and becomes a cancerous B-cell, it maintains this signature, this sequence of protein on the cell surface. And so these B lymphoma cells are then derived from this and they carry this marker with them.
Now we can turn this around and use this antibody that this B-cell was expressing before and use it as a tumor-specific marker. And indeed, that's why the idiotype is really an ideal target for an antitumor response.
Slide #5
So what we're going to try to do then is to isolate this protein from tumors and give it as a vaccine and get the patient's immune system to respond.
So what are the different ways that we can get the immune system to respond? Well, first, if we vaccinate against -- with this protein, the patient themselves, their own immune system, their own normal B-cells will make what we call a polyclonal -- meaning more than one type of antibody -- that would recognize this tumor idiotype here shown in red.
Now also, this tumor idiotype sequences, these tumor-specific immunoglobulin sequences are expressed on special marker proteins called MHC molecules on the B-cell lymphoma cells. And those, in turn, can be recognized by the T-cells, either the helper T-cell type or the cytotoxic killer cell T-cell type. So as you can see, there's three different ways that the immune system can recognize these B lymphoma cells after receiving adequate vaccination against this tumor idiotype.
Slide #6
So what are the advantages that this has over some of the other antibody treatments that you've heard about already -- that is, rituximab, for instance? Well, in fact, this treatment would be truly specific for the tumor cell. Because only one B-cell in the body, that is the cancerous B-cell, will have this marker and not all the normal B-cells that are in the host. You can also generate multiple levels of immune attack, as I've told you, to get multi-tumor antibodies and the T-cells.
And very importantly, something you don't get with antibody treatments is you get immunologic memory. The immune system has memory, that's why you only get chicken pox, generally, one time in your life. Because your immune system remembers the next time it sees that. This is a very long-lasting effect and a very potent effect and unique to vaccine therapy.
And lastly, we think that all of these mechanisms would hopefully add up to decrease the chance that a tumor cell would have to escape during the therapy.
Slide #7
Now there have been three phase II studies that have been carried of idiotype vaccination, primarily in follicular lymphoma that are like discussed today. And these have provided the rationale for taking this therapy forward in larger numbers of patients.
First, the basic initial study done at Stanford with ID-KLH. A study also done at Stanford using dendritic cells and a study done at the National Cancer Institute, combining the ID-KLH vaccine with granulocyte-macrophage colony-stimulating factor.
Slide #8
So this is the first study that was done at Stanford; it started in 1988 by Ronald Levy and his colleagues. And what they did is they took a tumor biopsy from a patient with follicular lymphoma and they fused that cell in a process called rescue hybridization to a myeloma cell in the test tube. And there they got this custom-made cell line that produced large quantities of this tumor idiotype protein.
This protein could then be rendered immunogenic -- that is, recognizable by the immune system by chemically linking it to a molecule called keyhole limpet hemocyanin. This is a green protein that we get from actually a sea slug that grows in the waters of the Pacific Ocean out here; we collect this molecule. And it renders this weakly immunogenic molecule, this molecule derived from the body, the idiotype very recognizable by the immune system.
We then formulate it with a variety of so-called adjuvants. In this case, it was a chemical called S-A-F or SAF. And then we inject this protein underneath the skin. So this is like getting a vaccine, like your DPT vaccine or your flu vaccine you get every fall. And the body will then make antibodies and T-cells against this protein and hopefully fight off the cancer.
Slide #9
So in the initial study what was found is that here are 32 patients who had follicular lymphoma. And all of the patients looked the same going into the study, they all got the same vaccine. However, only about half of them -- 14 of them -- responded to the vaccine. Meaning an immune response, this is not a clinical response. They were in remission; they had either no tumor or very little tumor in their bodies that was measurable at the time.
And the people who made an immune response -- as judged by a test, once again, in the test tube, were different from the people who did not make such an immune response in that they had a longer remission time. Here is the freedom from disease progression or the time that they stayed in remission. Was almost eight years when you projected it out, compared to only just over a year, on average, the patients who did not respond to the vaccine.
Slide #10
Now this difference was also reflected in the patient's overall survival. How they did with their lymphoma. And in fact, the people who did not respond, their overall survival mirrored and paralleled of his case-matched group of historical control patients, also treated at Stanford during the same time period. So this suggested -- and once only suggested that this vaccine had a therapeutic effect for these patients.
It wasn't a randomized study and all the patients got the vaccine and we're distinguishing these patients by something we measured in the test tube. But it is related to the vaccine. And so this suggested that this might have therapeutic effect and we ought to look for ways of making this immune response more potent and to see it in more often than half of the patients.
Slide #11
Now one of the next ways that this was done was to add in a component of the vaccine called dendritic cells. So what are dendritic cells?
Here are some of these so-called dendritic cells isolated from the peripheral blood of a patient and these are these stellate -- star-shaped cells that give them their name, that you can see are very unusual-looking. And these are a type of white blood cell that's very, very rare; less than 0.1% of all the white blood cells circulating. And they're the most potent of all so-called antigen-presenting cells. That is, they present antigen to the T-cells and B-cells of the immune system and turn the immune system on.
And the normal job of these cells is to live in the tissues and they collect foreign substances. And when they become activated, when they sense danger, they travel to lymph nodes and turn on the immune system. Now we can isolate these cells, we can coculture them with antigens and then can reinfuse them -- just like a blood transfusion and this is what we call a cellular vaccine.
Slide #12
So this is the way we did the study. It was somewhat modified from what I showed you previously. We performed the same type of rescue fusion. We got the idiotype protein. But instead of linking it to KLH and then just simply injecting it in -- beneath the skin, we took these cells that we collected, these dendritic cells, collected by a procedure called leukophoresis. You hook up to the machine, we get the red blood cells back, we take the white blood cells. And then we purify these dendritic cells and mix them with this protein and culture them for several days. They then uptake this antigen and we wash the cells off and reinfuse them back into the patient -- into the vein.
And this therapy is very well-tolerated. There are some patients that had side effects, just like any other blood transfusion. We give them Tylenol and Benadryl before we give this.
Slide #13
Now after we did this, we noticed that in some of the patients -- in fact, in four of the ten patients that it was initially studied in who had measurable lymphoma, we saw direct antitumor effects. So here is one patient that had lymph nodes growing in the axillary or armpit region. This is a CT scan; here's the back, the lungs. This is underneath the left arm. And these are lymph nodes that completely disappeared eleven months after the vaccination. And this patient remained in complete remission for almost five years after this; this is the only treatment that they received.
Slide #14
Here is another patient that received CVP chemotherapy. And all the disease went away except for there was a collection of fluid around the lung -- this is the liver; it's again a CT scan. And this is a abnormal collection of fluid around the lung; this is some contrast, that yucky stuff that you have to drink sometimes before you get a CT scan. And this fluid collection and the tumor that was around here disappeared nine months after vaccination. And this patient also had disease in the bone marrow that was quite heavily involved. And that also disappeared following vaccination.
Slide #15
Here's another very interesting case of a woman who got this therapy after CVP chemotherapy and for her first remission. And the disease was gone after the first CVP chemotherapy and then came back about a year and a half later. It then continued to grow over the next year and a half and it was recommended actually that she get a bone marrow transplantation -- autologous stem cell transplantation.
What we decided to do for her -- since she had already gotten the dendritic cell vaccination -- is just simply go back and give her the ID-KLH protein vaccine as a booster injection. The old-fashioned way with the SAF adjuvant that I described to you before. And rather remarkably, this patient called me up two weeks later and told me that all of her lymph nodes that were all throughout her neck, underneath her arms and her groin regimens had all disappeared. And I thought that was amazing, but in fact when she came back at the end of a month, that was true.
And here are the CT scans that showed a complete remission four months after vaccination. I'm not showing you all the lymph nodes that went away, but this is largest one. And it's easiest to see. A big lymph node mass in the pelvis that had completely gone away four months after the vaccination.
So she received a booster vaccination after dendritic cells with the same idiotype protein that we had stored in the freezer. And we got a response, even though she had apparently escaped and her tumor had grown after this initial vaccination.
Slide #16
So this was a very compelling series of observations. It just summarizes our dendritic cell vaccination study. As I mentioned to you, four of the ten patients that had measurable tumor that had relapsed after chemotherapy had tumor regressions after this therapy and 23 of the first of remission patients that completed this therapy after getting CVP and -- or CHOP chemotherapy. 18 of the 23 patients had residual disease, like that pleural effusion I showed you. Two-thirds of the patients made immune responses. And this residual tumor regressed in 22% or four of these 18 cases.
And as a group, this patient has continued to do well. It is a selective patient population, so we have to be careful about interpreting that. But 70% of those patients remained without disease progression at a median or an average of 43 months' followup from chemotherapy.
And I showed you several examples of this ID-KLH protein boosting after the dendritic cell vaccination. In fact, three of six patients treated this way had tumor progressions. And we saw a boosting of immune responses in all three of these. And this latter observation forms the basis of a trial we're now developing at UCLA, where we will routinely give the dendritic cell vaccine, followed by a series of five booster vaccinations with ID-KLH. And we hope to start that early in the coming year.
Slide #17
Now, there's other ways to boost the immune response of these vaccines, and one way is by using colony-stimulating factors; one of those is called GM-CSF. And this is a hematopoietic growth factor that's related to the Neupogen that people sometimes receive after chemotherapy. Of course, as its name suggests, it stimulates the proliferation of granulocytes and macrophages. But it also stimulates the maturation, growth and migration of dendritic cells.
So it's thought that if we inject this protein locally, it might recruit dendritic cells to the site of the ID-KLH vaccination. And in fact, local injection of this cytokine, GM-CSF, with ID-KLH in an animal lymphoma model has shown improved T-cell and antibody responses and improved survival in those animals.
Slide #18
So that prompted Dr. Larry Kwak and his colleagues at the National Cancer Institute to do a study in twenty patients with untreated follicular lymphoma. They got a chemotherapy called ProMACE. And the patients in the study -- they only treated patients who had a complete response with a goal of trying to maintain that complete response. What they did is they gave the same ID-KLH link to ID-KLH protein I described to you before, given together with this GM-CSF that was injecting beneath the skin at the identical site of the vaccine daily for four days.
They demonstrated that this was safe therapy, it caused a little bit of local inflammation, some flulike symptoms that were expected that were due to the GM-CSF -- we've seen this before. And then the T-cells against tumor were seen in nearly all patients, 19 of the 20 as measured by these assays.
And very interestingly, they measured the bcl-2 PCR test on cells in the peripheral blood to try to detect small numbers of circulating bcl-2-positive tumor cells, as the patients had no other evidence of disease. And they found that in eleven of these cases, in eight of eleven cases, they eliminated this minimal residual disease after the vaccination. And these patients were all doing well at an average of 42 month, post-chemotherapy.
Slide #19
So to summarize these three studies, I hope I've shown you that there's evidence for clinical activity of this approach in follicular lymphoma. It was certainly safe in all three of these studies. And that we have elicited immune responses, a variety of types, in most of the patients on these studies. However, these are tests that are done in a test tube, in a laboratory. We don't know which type is most important for each patient, whether a patient needs more than one type to have a clinical response, an important response. And we'll come back to that at the end when we discuss the eligibility criteria for these trials. But certainly, this work has provided the rationale for studying this in a phase III or randomized setting.
Slide #20
So in fact, this therapy has gone forward and now there is two very large phase III randomized controlled studies of idiotype vaccinations for follicular lymphoma going on in North America at this time. One is sponsored by the Genitope Corporation, one is sponsored by the National Cancer Institute. And these studies are multicentered. The Genitope is taking place at 25 centers around North America. NCI has, I believe, more than six centers now, including the National Cancer Institute.
What they're all treating is follicular non-Hodgkin's lymphoma. Patients need to come in essentially untreated or they may have had some local X-ray therapy to a small site of prior disease. They can have these various histologies of follicular lymphoma. And a tumor sample does need to be taken prior to any therapy; either a small lymph node or, in some cases, we need a biopsy or we can get the cell from the peripheral blood.
The idiotype protein is a custom-made product that is developed either by the traditional rescue hybrid method or in the Genitope case, by a molecular genetic technique. We you don't think it really matters which way the protein is made.
The pre-vaccine chemotherapy is different in these studies. The Genitope study, they use a traditional CVP chemotherapy -- that is, cyclophosphamide or Cytoxan, vincristine and prednisone for eight cycles. And they will treat patients who either have a complete or partial remission.
In the NCI study, the patients received a little bit more aggressive chemotherapy that has prednisone, adriamycin, Cytoxan and VP-16, with the goal of trying to get only complete remission patients and only those patients with complete remission will be eligible to proceed on in this study.
These are both randomized studies, so some patients get the full vaccine with the idiotype, the tumor-specific component. Two-thirds of the patients get that and one-third of the patients will get the KLH alone. And neither the doctors nor anybody knows who's getting which; the patients certainly don't know who's getting which. And these studies together will accrue over 1000 patients and accrual is going very well for these studies and they're about a third to halfway through in each of the trials.
The vaccine is just as I described to you before. It's ID-KLH plus GM-CSF injected beneath the skin. There is five monthly vaccinations -- there is actually two months beneath the fourth and the fifth vaccine.
Slide #21
Now the endpoints, what are we actually studying in this trial, what are we trying to look at? The most important is the time to disease progression. From the time patients finish chemotherapy 'til the disease comes back; we're trying to lengthen that period, to prolong the remission of these patients and keep them away from the need to have other, more toxic therapies. Of course, we'll look at the safety of these treatments. We think that they will be very safe.
In the Genitope study, since some patients will have a partial response, we'll be able to look for regression of tumor, as I showed you before. Conversion of a partial response to a complete response. If they have any leftover tumor, can it go away after the vaccination?
We'll also be looking at immune responses retrospectively, the so-called molecular responses. That is, the bcl-2, PCR test. Quality of life, very important, and survival.
Slide #22
So the idiotype vaccines are the most well-advanced of all the -- most well-developed of all the lymphoma vaccines, but I will mention some others that are undergoing various stages of development. There are some gene-modified tumor cell vaccines that are being studied in lymphomas and related cancer. Investigators at Johns Hopkins are studying multiple myeloma cells that have been -- GM-CSF gene has been introduced into the tumor cells and then the cells will secrete this growth factor that I described that will attract dendritic cells and hopefully elicit an immune response against the tumor cells.
The CD40 ligand gene can be inserted into the tumor cells. This is a gene that activates the immune system through some very interesting mechanisms, and this has been studied by Dr. Thomas Kips in San Diego, and a phase II study in chronic lymphocytic leukemia is now underway.
There is also another vaccine that's available for low-grade lymphomas, being studied at MD Anderson. And this is so-called heat shock protein vaccine. Heat shock proteins are small proteins that are inside tumor cells and actually all cells. And they carry antigenic proteins, proteins that might be small peptides, pieces of proteins that might be recognizable by the immune system. And what they do is they take a tumor biopsy, they extract and purify these proteins and then inject them beneath the skin as a vaccine.
And lastly, you can take the whole tumor cells or kill them or radiate them or make -- coat them with antibodies and feed these whole tumor cells the dendritic cells. And this approach is being studied for a variety of lymphoid cancers at UCLA and in Stanford and a number of other institutions around the country. And hopefully you'll be hearing more about that in the coming years.
Slide #23
Now I wanted to remind you once again of this -- of the potential three types of immune responses we can get after vaccination with idiotype. We think we can get antibodies, which we think an important part of this response as well as the T-cells.
Slide #24
And I wanted to remind you of one thing that will happen if the patient gets rituximab before they get vaccinated.
And that is that rituximab -- since it depletes your normal B-cells, it will abrogate or diminish the ability to mount a primary antibody response. So you will not be able to make an antibody response against a new vaccine if you get rituximab first. And for this reason, rituximab is not allowed in all the phase III studies I described to you earlier, because it felt that prior exposure to this agent might damped the effectiveness of the vaccine. It will knock out the ability to make antiidiotype antibodies.
Slide #25
Thus, we think that it may be - and we don't really know for sure. But we think it may be best to give rituximab after the vaccine, after you've already been able to establish an anti-idiotype antibody response due to the vaccine. And then you might have the opportunity for these two antibodies -- those elicited by your own immune system and those given to the patients through the rituximab -- to work together to fight the cancer.
However, if you give the vaccine in this situation, once again, you'll still be able to get a T-cell response. So it really remains to be seen which type of these responses are most important and the proper sequence, giving these two together.
Slide #26
And so I'd like to summarize then and tell you about studies that are addressing this. These are the lymphoma vaccine trials that are now open and available for patients.
I mentioned to you in some detail the phase III randomized trials for follicular lymphoma that are actually very similar. Favrille, as a company, a biotech company in San Diego that's performing a study of idiotype vaccination. And they're addressing issue about rituximab. In fact, they're taking patients with relapsed follicular lymphoma and they will give rituximab first and then give the vaccine afterwards. And so it's expected that these patients might not make many antibodies against their idiotype protein, but they should be able to make the T-cell response. So this is a very interesting study that's available to patients who have relapsed low-grade lymphoma, to investigate this interesting combination and sequence of these drugs.
Genitope is also looking into expanding this treatment for patients with diffuse large-cell and mantle-cell lymphoma. And this is a study that's ongoing. The National Cancer Institute has a similar study that they've just recently completed accrual for mantle-cell lymphoma. And lastly, Antigenics is another outfit that's looking at these heat shock protein vaccines and these are available to essentially any patient with low-grade lymphoma.
Slide #27
So just to summarize, I hope I've informed you that therapeutic idiotype vaccines for lymphoma represent a clinically active modality that has minimal toxicity. And we believe that ultimately this should be applied early in the disease course in an attempt to perhaps delay the need for more toxic or immunosuppressive agents. Fludarabine and adriamycin that's used in the CHOP chemotherapy are very active agents, but ultimately we like to get away from these combinations. And if indeed these vaccines were shown to be effective, we might use these agents later on only when we needed to.
It's important to emphasize that drugs like fludarabine are very suppressive to the immune system, so we wouldn't want to give the vaccine after these agents, but more introduce the vaccines earlier. But these are scientific questions; we've yet to prove that this is the right strategy to do and that's why our -- randomized studies are very important to complete.
I've told you that rituximab after vaccination will at least preserve your ability to make antiidiotype antibodies, which we think are important effectors of this vaccine. Although you will have T-cells preserved after the rituximab, so you can still get the vaccine, this is a scientific question that's being addressed and we hope to have an answer to that sometime soon. And in the meantime, we'll continue accrual to the phase III studies.
And lastly, I'd just like to thank many investigators at Stanford that have contributed to these studies over the year as well as many biotechnology companies that have been very forward-thinking in developing novel strategies for producing these vaccines on a mass basis to make them available to patients. And lastly, of course, to thank the Lymphoma Research Foundation, who has been a long-time supporter of this work. Thank you. [APPLAUSE]
SANDRA HORNING, MD: Five minutes for questions. So we have time for a few minutes for a few questions for Dr. Timmerman before our break. Go ahead.
Q: Doctor, have these vaccines been tried with Waldenstrom's patients?
JOHN TIMMERMAN, MD: They have not been tried with Waldenstrom's yet, but we hope to do that very soon. I shouldn't say "we." There is a group in Boston that is at the Dana Farber Cancer Institute that is trying to start a study, I understand, in Waldenstrom's. This was mentioned to me several months ago. So you might contact Dr. Munshi at Dana Farber Cancer Institute to see if they're going to be starting their study.
Waldenstrom's macroglobulinemia is a very attractive disease to target -- to use this therapy in. But one of the unfortunate things is that small numbers of patients -- is getting people interested in studying this rather rare disease. And I would like to eventually study this disease with this approach; I think I would work very well.
Yes?
Q: [OFF-MIKE/INAUDIBLE]
JOHN TIMMERMAN, MD: Yeah. So the question, for those that didn't hear it is: In the dendritic cell or any kind of vaccine, patients -- do they have to have an immune response to have a clinical response? And the answer is they probably -- they have to have an immune response, because this treatment works by getting the immune system activated, but we may not be able to measure that response. We think that the techniques we use in the test tube, in the laboratory are imperfect.
And there is one patient on our trial that had a very nice tumor regression in whom we could not measure an immune response in the laboratory, but clearly something happened there. And we think that that's an immune response that we simply couldn't measure.
So we need to get better and that's why future studies will be focusing on very detailed immune response analyses that are more comprehensive than those studies that we have done before to really try to learn what type of immune responses and the combination of immune responses that are associated with regression of the tumor, the tumor's going away.
Q: The other question is regarding the tobacco vaccine phase I trial and how the results of that look compared with the other existing vaccine trials.
JOHN TIMMERMAN, MD: Yes, she's mentioning another technology, that is Ron Levy and his colleagues are using another technology to make these vaccines and they're using -- in a wonderfully ironic turn -- the tobacco plant to manufacture these vaccines. The tobacco plant is genetically engineered to produce high quantities of this tumor protein. And those studies are being completed; I cannot comment on them that time. They have shown that there's immune responses can be generated against those products and you'll have to ask Dr. Levy and his colleagues when that study is completed.
Q: Could you tell me if any work is being done on CLL on the vaccine programs?
JOHN TIMMERMAN, MD: There is some interesting work being done, as I mentioned. Tom Kips and his colleagues, there's a group in San Diego and I believe they may also be working in Boston now. This gene-modified -- the genetically engineered CLL cells, taken out of the body. A gene is inserted into them that will activate the immune system. Then they're reinfused back into the body.
Other people are developing these type of vaccines I described, these idiotype vaccines that -- custom-made vaccines for CLL and I think that's a very -- it's an unmet need, it's a setting that we need better treatments for and, yes, that is being done. I'm not aware of any open studies that are accruing patients. But, yes, we are working towards that goal of using this treatment for CLL.
Q: All right. The other part of my question. Is there an age limit for any of this?
JOHN TIMMERMAN, MD: I don't believe there is an age limit for the follicular lymphoma studies.
Q: But for the CLL.
JOHN TIMMERMAN, MD: Oh, as I said, there's no --
Q: Oh, they're not going on, yeah.
JOHN TIMMERMAN, MD: -- open studies at the time. And I believe -- you would have to contact investigators at UC San Diego to ask about the CLL study.
Q: Thank you.
Q: Yes, doctor, are there any clinical trials going on right now for previously treated patients with CVP and Rituxan, that have been previously treated with CVP and Rituxan?
JOHN TIMMERMAN, MD: Yes, as I mentioned, the Favrille study that's being carried out in a variety of institutions around the country, including several here in Los Angeles -- Cedars Sinai and we hope UCLA soon -- that will take most patients who have been previously treated, there's a limit on the numbers and types of chemotherapies you can have had. But if you want to talk to me afterwards, we can work out a way to learn more about that for any patient's particular case.
Q: Thank you.
Q: Excuse my ignorance on the subject, but on the antiidiotype vaccines, are those patient-specific or is it -- are all idiotypes for follicular B-cell lymphomas the same? And if they aren't the same, then why aren't they done on a individual patient basis?
JOHN TIMMERMAN, MD: I'm sorry if I didn't make that clear. This is a custom-made therapy that's made for each individual patient. It's made form their tumor cells and is only -- will only work in them. So every patient has their own vaccine made that's stored in the laboratory and is used.
Q: Thanks, okay.
Q: First a request: If you could put up one of your last slides that showed the current vaccine trials? It was a list. Yeah, because I wanted -- my question is: My understanding is that the techniques used to produce the idiotype vaccines can be quite tedious and complicated. And as more vaccine trials open up, how important is it that the institutions have experience making those vaccines?
JOHN TIMMERMAN, MD: Okay, that's a good question. The institutions, the treating doctors or the hospitals are not making the vaccines. The vaccines are manufactured -- in one case by the National Cancer Institute in collaboration with a biotechnology company that's making these vaccines for patient-grade use. And obviously there are pharmaceutical -- you know, biotechnology companies that are making these things under the strict FDA guidelines. So they are made to exacting standards.
There are about five or six different companies that are making these two. These are the two largest studies that are ongoing now and so they're not made by any hospital. And I think each individual entity that's making these vaccines is making them to very strict standards.
You ask a very question, though, is are these all created equal? And we really do not know that they are. We think that the chemical structure and the general principles that are involved in making them lead to a very similar product, but there are some subtle differences, and this is going to be a very important question to answer. And it's being addressed, to some degree, in some animal-model studies that we're doing. And we're going to have to await the clinical trials.
But, for instance, if somebody shows that one of these vaccines works long-term and improves survival and three other new ways of making the vaccine come along, it's going to be complicated to know whether they're equivalent. We believe that they should be, but we'll have to do additional studies to find it out. But you can rest assured that the Food & Drug Administration and that large groups of investigators are asking some very tough questions of the people making these to make sure that they're made to exacting standards.
Q: Thank you. Any work being done in -- or any studies being done in the earlier work to try to figure out why some of patients didn't have an immune response? Was it because of the manufacturing process? Maybe because the specific idiotypes were not targeted correctly?
JOHN TIMMERMAN, MD: Well, this is -- yeah, this is so important is why does some people respond to this vaccine and others not? And this is the question that bothers me every day, because people always ask me and I'm very curious about it. We'd like to know why people respond, what are the components of their immune response and can we manipulate that? And can we bring that type of response on in more patients? If we understand how it occurs, we might understand how we can make it better.
Nobody knows in any given patient exactly what lead to their tumor's regression. We have some patients, though, that make only antibodies that we can measure. Some patients that don't make antibodies that make T-cells. And in either of those cases, there are at least several examples where beneficial things have happened; tumors have regressed or stayed away. So we really don't know the answers, but hopefully detailed studies in these randomized studies and in further studies we're doing in our group will help to answer some of these questions. It's a very good question.
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