"THE HEART OF THE MATTER"
a special program of the National Emergency Medicine Association (NEMA)


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Week: 598.6 

Guest: Dr. Scott Freeman/ assoc. Prof. of pathology, Tulane Univ. Med. Center. 

Topic: Cancer vs. Cancer 

Host/Producer: Steve Girard  

NEMA: Thanks for joining us. A while back we brought you the story of the gene bomb, where researchers from Johns Hopkins were introducing a gene into cancer cells, in the hope of delivering a substance that the gene could turn toxic in the cancer cells, killing them and those around them. there's another wrinkle coming in this area...using irradiated cancer cells to carry a virus that will make the new tumor cells sensitive to a common antiviral drug. Our guest is Dr. Scott Freeman of Tulane University Medical Center.... 

GUEST: We started this work about eight years ago and it's termed suicide gene therapy. But what we try to do is to obviously kill the tumor cells, and it started because we wanted to look at ways to treat tumors that were chemotherapy resistant. So basically since about fifty percent of the patient's relapse with their disease after chemotherapy, after each treatment we know that fifty percent of all cancer patient's tumors contain chemotherapy resistant tumor cells. And what we planned to do, or wanted to do was to provide a new drug sensitivity that was different than the standard chemotherapy, to the tumor cells, so that there would be a new agent that would kill the cells when they relapsed. And there have been previous studies that have shown that if you take tumor cells and put a gene in it from the herpes virus, what happens is it sensitizes those cells to an antiviral drug, the drug Ganciclovir. So in effect, the reason why you can treat herpes infections with the drug Ganciclovir is because that virus carries this particular thymitis kinase gene and then makes the cell sensitive to that drug. So it had been show that if you take that gene, the herpes thymidine kinase gene and put the tumor cells and expose the cells to Ganciclovir you could kill tumor cells. The problem in that was that using current gene therapy technology it's virtually impossible to genetically modify every cell in the tumor so in addition if you have a population of tumor cells but one hundred percent of them expressed the herpes thymidine kinase gene again you would find cells that were resistant against Ganciclovir. So pretty much with any drug therapy, there seems to some cells that are drug resistant. So the discovery that I made was that if you take these tumor cells that express the herpes thymidine kinase gene and expose them to the Ganciclovir...not only do they die, but they also kill near by tumor cells. So, back about seven or eight years ago we described what was called, what we termed a bystander effect. And based on that effect was the ability of tumor cells expressing this gene the herpes thymitis kinase gene to become sensitive to Ganciclovir and in the process of dying, killing nearby tumor cells. So that now allows a potential therapeutic approach, because you need less than all of the tumor cells to express the gene that's become genetically modified with the herpes thymidine kinase gene. 

NEMA: Is it important that the cells that you reintroduce are cancer cells... because they bond better with the tumor cells?  

GUEST: It appears that way... there have been some studies looking at other types of cells but there is a couple of advantages to using tumor cells. One is that they appear to home to tumor deposits better, but also it's easier to work with them in culture and grow them to large enough numbers to inject in. So there are several advantages to using tumor cells. And one of the other issues that needs to be worked out in gene therapy is the ability to target the genes to a specific organ. So we're currently using the technology that's available, using what we call vectors, or viral vectors, to deliver a gene. Those vectors are usually are not specific for a particular tissue type. And what we find is that by using cells in many cases, these cells could actually, in effect, target tissue better then some of the viral vectors. So we're taking tumor cells, and as we inject them into the peritoneal cavity or the stomach cavity, we find that there are tumors in the peritoneal cavity that these cells will actually home to and coat the tumor, and in a way deliver this gene to the tumor. I also wanted to mention this other technology that we're beginning to use that was developed by Dr. James Weigle, who's at the NCI, that uses endothelial cells and these are cells that line blood vessels. And what he found is that if you take those cells out and genetically modify them - in one case with this herpes thymidine kinase gene - you could then take those cells and inject them intravenously, and those cells target to sites of angiogenesis...and angiogenesis is the process whereby blood vessels form. And tumors have that capability to stimulate angiogenesis or growth of blood vessels to supply the growing tumor. In affect you now can target those growing blood vessels with these endothelial cells which carry a therapeutic gene, in this case the herpes thymidine kinase gene, to the tumor. Those endothelial cells then now line the tumor blood vessels that are growing, and you can the treat with the drug Ganciclovir and get this same "bystander" effect. 

NEMA: Is there a toxicity effect?  

GUEST: So far we have seen fairly minimal toxicity - mostly fever, nausea - within a couple of days of injecting the cells, and it appears that the toxicity is relatively localized to the killing of the tumor and relief of factors during that process. Normal tissue for the most part seems to be relatively spared. 

NEMA: What about the body's immune response to the application of these irradiated cancer cells and the virus inside? 

GUEST: Depending on which virus or virovectors you use. Some of them induce sort of an immune response more then others. That doesn't particularly occur on these cells or when it does occur on these cells we believe that part of this whole bystander effect is based on the immune response. And so, we want the immune system to target these cells and target these tumors. The other advantage to this approach, in general the suicide gene therapy, is that you only need short term gene expression. So a lot of this killing affect occurs within several days of injecting the cells...whereas the immune response, the body's response to some of these foreign agents, is over several weeks. So, the advantage is that the effect happens fairly quickly... and it's probably one of the reasons why some of the gene therapy treatments for genetic diseases are still really in their infant stage, while this has advanced a little further... although it's still in experimental approach. 

NEMA: Ok. What is next?... what is the next step for you, and where do you see this heading? 

GUEST: We have had evidence for awhile that the immune response is involved in this, the bystander affect. So, we are completing our phase one trial to look at toxicity of injecting these herpes t-k modified tumor cells into patient's with ovarian cancer. And what we now want to add to that is a vaccine or tumor vaccine in combination with this treatment. I think tumor vaccines have been around probably a century now, they were first started in the early nineteen hundreds and I think one of the limitations of the tumor vaccines is that the tumors, especially the tumor environment, has a way of suppressing the immune response to the tumor. So even if you vaccinate patient to their tumor, these immune cells have to go into tumor...and I think at that point become inactivated and is the whole reason why the body never recognized the tumor from the beginning. We found when you use these thymidine kinase cells plus Ganciclovir, in the process of dying and killing nearby tumor cells, they also can activate an immune response, and activate an immune environment within the tumor that allows immune cells that recognize the tumor to actually function in that environment. So, what we are planning to do is first vaccinate patients to their own tumor so those immune cells are in the body and then treat with thymidine kinase Ganciclovir to not only kill some of the tumor, but activate the tumor environment to allow those immune cells now to traffic into the tumor, and have the appropriate environment to kill the tumor. 

NEMA: I first heard of this experimental therapy last year and you can never tell which way things are going to turn... but your seems like a good turn. 

GUEST: Right. Yes... it's certainly been a very exciting system...initially from the animal models, and now we're trying to translate it into helping patient's with ovarian cancer. Ovarian cancer unfortunately is a difficult disease and, in particular, most patient's have their disease confined to their peritoneal cavities. For the most part it's a localized disease, and only about fifty percent of the patients actually achieve long term survival with Taxol, and so what I want to stress is that chemotherapy has been a standard approach, and has really helped a lot of patients over the last several decades. But I think the discovery phase in chemotherapy has plateaued, and I think most of the agents are there and the majority of the effect is probably there, although they're changing and looking for new regiments that may be a little more effective. But I think at this point there is fifty percent of patients that relapse with their tumor and for the most part, as I said in the beginning, are resistant to chemotherapy. I think molecular medicine will be the new horizon that hopefully will provide therapeutic potential for those patients who are chemotherapy resistant.

I should say that this is still a very experimental phase and that chemotherapy developed over the last fifty years...and it still will take many years before some of these gene therapy treatments become readily available and actually are no longer experimental. But I think it is an exciting beginning. 

NEMA: Our thanks to Dr. Scott Freeman, a professor of medicine at Tulane University Medical Center. 

SPOT: 15 years in the prevention of heart disease, stroke and trauma - The National Emergency Medicine Association. This show is just part of what NEMA does. We send out millions of pieces of prevention information to people around the country, give grants to organizations in research, public information and emergency services, and have been instrumental in the creation and expansion of the Chest Pain Emergency Room movement. To play a role, call 800-332-6362. 

NEMA: Thanks for joining us for today's program. If you have any comments or suggestions, contact this station. Or visit our home page at:www.nemahealth.org/...for a look at transcripts of this or past programs, or to find out more about the National Emergency Medicine Association. I'm Steve Girard at The Heart of the Matter.