Well, thank you for inviting me to speak. I don't know precisely why Ted chose me to do this, particularly right after lunch, but I will get you back, Ted, sooner or later.

TOP

So, to talk a little bit about developing novel IP therapy approaches for ovarian cancer, I guess what I really wanted to start off with is, what do we really know about IP chemotherapy.

It seems as though, from the aggregate of the studies, that the median survival seems to be improved with an IP approach in patients with optimally debulked ovarian cancer by, on average, about 10 months.

What we also know is that some of the trial designs, particularly with the last couple of trials, really sort of confound our ability to attribute the benefits solely due to the IP therapy, although with the first trial that was done with cisplatinum and cytoxin, it clearly was the IP route of delivery that afforded the benefit.

We know that there appear to be subtle difficulties in administering a total of six cycles of chemotherapy intraperitoneally to a substantial fraction of patients.

We are not talking about five to 10 percent of patients that can't complete the therapy, and that the outcome in these patients who do not complete the IP therapy is actually not entirely clear, as these are intent-to-treat analyses.

TOP

I think on aggregate, it tastes great, is more effective, but is not necessarily less filling. It may be more toxic, at least in the short term. So, I think what we want to try to do is to get it to taste even better and be even less filling.

TOP

So, how do we go about trying to improve the therapeutic index of IP therapies for ovarian cancer? I think we can do some of the simple things. I say simple, although I have seen us argue in the GOG ovarian committee for about three or four years now about how to do this, but we are working on trying to change the dose and change the schedule and maybe look at combining IP and IV strategies, using better tolerated agents and improve the supportive care.

I think what we ultimately want to do is sort of look at ways to incorporate the not so simple things, and I think there is a variety of different agents which I am briefly going to talk about today, which may give us some opportunities to see if we can, indeed, improve the therapeutic index of IP therapy, and thinking about it from a scientific and rationale standpoint.

TOP

I am not going to go over all the different agents that have been talked about, but there clearly are several novel therapeutics that we can consider using, that may give us some pharmacokinetic advantage within the IP context.

I think the liposomal taxanes, the taxanes that are bound to small albumens or the nanoparticle technology, and perhaps some of the pro-drug strategies are all important ways by which we could consider using new agents that will give us some sort of pharmacokinetic advantage.

Obviously, Dr. Howell is here, and the expert in this area, and certainly could speak to this in more detail than I could.

TOP

Well, what about the monoclonal antibodies. We have heard a lot about those today, and here is just a whole list, at least a partial list, of both the growth factor inhibitors, the tumor associated antigens, which we really haven't talked a lot about today, and some novel monoclonal antibodies toward other death receptors.

I think it makes a lot of sense to consider combining some of these monoclonal antibody approaches with the IP chemotherapy regimens, both given in an IV regimen as well as to consider whether or not to administer these agents within the intraperitoneal cavity.

For instance, it makes a lot of sense to me that bevacizumab would be an agent that we could consider for development for intraperitoneal administration.

There is a lot of VEGF production in the intraperitoneal cavity, and this certainly could give us some pharmacologic advantages of using this agent intraperitoneally, and that would be just one particular way of using these monoclonal antibodies.

I think we have seen a lot of data that has demonstrated the ability of these monoclonal antibodies to actually synergize the effects of chemotherapy agents.

TOP

Indeed, we have worked at developing a novel antibody toward the death receptor called TRI-8. You can see in this series of primary ovarian cancer cells from two patients, that we have significant effect of the TRI-8 antibody alone and, when given in combination with a variety of chemotherapy agents that are active in ovarian cancer, we actually synergize that particular effect.

So, I think that the challenge for us will be how to choose or prioritize these antibodies, and whether to use them alone or in combination with chemotherapy to see if we can achieve our ultimate objective.

TOP

Now, antibodies can be used alone, and they can also be conjugated to radioisotopes or a variety of different toxic conjugates.

I was really intrigued by this SGO abstract that was presented at the last meeting that, although it was a negative study with respect to overall survival, the time to intraperitoneal relapse and the ability to somewhat sterilize the intraperitoneal cavity was somewhat intriguing to me.

TOP

Indeed, we have done a series of studies looking at radiolabeled CC49 that we are actually further developing to a more humanized antibody using a variety of different isotopes, both alone and in combination with chemotherapy and interferon gamma.

We have seen some patients who have extended long-term survival, and all of these patients were actually patients who were found to either have a disease at the time of second look, or were in their first relapse.

TOP

I think the pre-targeting strategy actually affords us the opportunity to see if we can actually improve the therapeutic index of using radiolabeled monoclonal antibodies.

This is a strategy by which we use streptabaden in combination with single chain antibody genes that will self assemble into a quantinary structure, and then it can be actually cleared free, streptabaden-labeled with the SFE can be cleared with a biatin-labeled clearing agent, so that you are left with just antibody that is bound specifically to your target, and that being on the tumor cells, and then come back and deliver a biatin-labeled -- either radiolabeled biatin or other sort of toxic conjugate, so that you won't have so much leaching into the bone marrow whereby you would have untoward hematologic toxicity, giving us ability to further improve the therapeutic index with this particular approach.

TOP

Last of all, I wanted to briefly talk a little bit about gene therapy. These are the number of gene therapy trials that were conducted in the 1990s.

We certainly know that there is a variety of vector strategies that have been used as well as a number of different approaches.

We have seen, actually, the success of these not live up to the hype.

TOP

And, indeed, over the course of the last decade, we have seen them go from a high of 91 clinical trials down to about seven trials at the beginning of this particular year.

TOP

There are some hurdles that have been just recently recognized, obviously, by Dr. Kirn in the Journal for the American Society for Gene Therapy.

We certainly have to improve our ability to deliver these agents systemically. We have to improve our ability to target and distribute these agents directly to the tumor cells, augment the effect of gene transfer, overcome tumor heterogeneity, and enhance our clinical trial testing.

TOP

You will see that these are the active clinical trials currently ongoing or plan to be going within the country, to the extent that I know. I think these are the entire list.

M.D. Anderson is using E1A in combination with Taxol. We just opened up a trial looking at IL-12 expressing-liposome.

I think these two trials actually demonstrate the ability of the gene therapy movement in a direction where you are not required to actually transfect each and every tumor cell, that you are actually using a gene therapy strategy to deliver a biologic that will ultimately give you the desired antitumor effect.

There are replicative viruses being used. This is a measles virus used by the Mayo Clinic, and we are working on an enhanced targeting strategy.

So, the field is actually moving, and yet it is still in its infancy, and much remains to be developed, in order to see us achieve the desired success.

TOP

These are just some slides looking at the measles virotherapy for ovarian cancer done in Mayo Clinic, and this is a measles virus that has actually been modified to express CEA so that you can measure replication by means of measuring CEA in the serum.

You can see the effect on uninfected cells versus infected cells, and in this animal model, achieving enhanced effect. This is an active trial right now in GOG, at Mayo Clinic.

TOP

We have developed a replicative adenovirus that has a deletion in the delta 24 region of the E1A gene, that allows for replication within cells that are defective in the RB and P16 pathway.

We have incorporated, within this adenovirus, an RGD motif within the knob component of the fiber of this particular virus, that we have been able to demonstrate will enhance the ability of the virus to infect ovarian cancer cells.

TOP

In this particular animal model, you can see we had significant improved survival compared to controls. We are in the process of completing biodistribution and toxicology studies, so that we can initiate this phase I clinical trial next year.

TOP

So, I think there are a number of different strategies and agents that can be explored within the intraperitoneal context, but I think there are a lot of different channels.

How do we prioritize which of these agents we will use? How do we select which chemotherapy to use in combination with these agents?

Can we use them in combination, both intravenous and intraperitoneally, or a combination of different agents?

More important, how do we assess the biologic effects in vivo? I know we have talked a lot about the hassles with obtaining issue, as well as the delays in developing non-invasive strategies.

I would say that, at least in the context of gene therapy, there are developing strategies now by which you may be able to look at viral replication or tumor cell transfection with non-invasive means.

How do we best assess response? We have talked a lot about looking at biomarkers for such, and the importance of stabilization of disease.

I think lastly, how do we make these therapies more cost effective. Certainly these take a lot of time and effort and dollars to develop and move forward into the clinical trial context.

TOP

I think that the most important thing is that we really not stop questioning. So, there are a lot of questions to ask, and I think the struggle would be to define the right priorities and the right context by which we do this, and the right clinical trials to do this.

I will look at it as a time of lots of opportunity and a way by which we can move forward to address this important issue. Thank you.

TOP