DR. SANDA: There are a couple of themes I think that ran through the advanced prostate cancer session, and perhaps I'll just start with Dr. Beer, since his presentation is fresh in our minds.

Dr. Beer, it's interesting, you had a paradigm shift there were you undertook your phase I study in hormone naive patients, it appeared in one of your earlier studies. Is that correct? It was published in Cancer. I was curious. I had two questions related to that, and I think I would like the audience to keep this paradigm shift in mind, because I think ultimately it's going to be an important facet for the immunotherapy and other alternative therapy studies.

How did you find that patient acceptance was in terms of a phase I study, where their alternative was to simply go on hormonal therapy? In other words, were patients eager to undertake a phase I highly experimental study, when they simply could have gone on to hormone therapy instead? And in this context, was that well accepted by the patients? Did you find that accrual was a problem or not?

DR. BEER: I think our experience in Oregon has been that there is a large population of patients who have a detectable PSA after an initial curative attempt.

DR. SANDA: That never happens in Michigan, by the way.

DR. BEER: Yes. And are seeking alternative to androgen deprivation. So we have conducted several trials in that population who are currently participating in the dendrion vaccine trial, and have found that it's really a pretty easy sell. These patients are eager to find something that might delay the need for hormonal therapy.

DR. SANDA: Now, in that context, it was interesting that you then shifted to the androgen refractory, the hormone refractory prostate cancer patients for your subsequent phase II and phase III study. If so, when would you plan to return to the hormone naive group in terms of your strategy for a sequence of clinical trials?

DR. BEER: In the hormone refractory setting we were testing the hypothesis that the combination with chemotherapy was a reasonable idea. And clearly, that is the population for which we had data for docetaxel as a single agent, where chemotherapy is reasonably well accepted and so forth. So that was the setting where we wanted to test the concept.

One of the areas that we are very interested in exploring is this regimen in combination with surgery. That might be the first place where we would go. We are currently conducting a pre-operative chemotherapy trial with docetaxel and mitoxantrone, which we developed before we had this regimen tested in advanced populations.

But what we are thinking about doing next is a phase II randomized trial of docetaxel with and without calcitriol prior to surgery, because that is where we are going to get interesting biologic data from the tissue. And it would also give us an idea about the activity of this regimen in a hormone naive setting, because we would have the PSA, and of course pathologic endpoints to follow it.

DR. SANDA: Great, thanks. Along those lines, Dr. Bander, as interesting as well, it looked like your studies as well have focused on hormone refractory prostate cancer. And you seem to be quite a way along now, moving toward multi-institutional phase II studies. And you have been moving forward in the hormone refractory population.

But it seems that the therapy is relatively well tolerated, and toxicity is low. And so similarly, I pose a question, when do you foresee, or do you see a role in terms of experimental drug development for targeting hormone naive patients? And in the context of Dr. Beer's comments about patients who are doing functionally well after prostatectomy have a rising PSA, those patients often times want to avoid hormones.

Do you foresee the radio-immunotherapies such as with J591 as potentially serving a role? And how would you envision getting those types of trials underway, where the urologists would be more actively involved than in hormone refractory disease?

DR. BANDER: Well, you know I think one of the great advantages we have in the setting of prostate cancer, and the application of immunotherapy is the ability to identify patients who have minimal extent of disease. And I think that's where ultimately we stand the greatest chance of having the most significant impact.

I look forward to being able to treat those patients, but in the early stages of drug development, particularly when you are using something like a radio isotope, where there is potential for toxicity, or where you are conjugating highly cytotoxic agents, which we have just started some trials with, in my opinion, you really have to start with patients who don't have therapeutic alternatives, because there is potential for toxicity.

In addition, you have regulatory issues where the FDA is going to -- well, they are not going to accept at least as we sit here now, they are not going to accept PSA responses. They are going to want survival data. And clearly, to do trials in patients who are early PSA failures, to do a survival trial in that setting is arduous, to say the least.

We have the advantage that we are pretty confident that we are seeing significant biological activity in patients with very extensive disease, and in patients who not only failed hormonal therapy, but have failed chemotherapy, those patients have relatively short survival expectations. So from a regulatory point of view, that's going to be our first target.

And in fact, the phase II trial of radio immunotherapy that we'll start in the not too distant future will actually be restricted to patients who have not only failed hormonal therapy, but have failed chemotherapy.

I would expect that as we have all more toxicity data, et cetera, that we'll rachet back and treat patients who are earlier in the stage of disease.

DR. SANDA: That's a good comment. One of the things that then poses a hurdle for Dr. Schlom and Dr. Vieweg's approaches is they are a little bit different approaches than those discussed by Dr. Beer and Dr. Bander. One of the key facets that distinguishes the dendritic cell and recombinant vaccine approach is that these are active immunization approaches. They require and rely on a very robust and intact immune system of the host or patient.

And it is a real Catch-22, because animal model studies have clearly demonstrated that although strategies such as passive immunization, such as the antibody techniques that Dr. Bander is pursuing, or other systemic treatment approaches can be accomplished quite well in animals with perhaps late stage cancers, who are relatively anergic.

Immunization strategies using vaccines, like recombinant vaccines or dendritic cells really are very sensitive to the even subtle effects of perhaps early or late stage disease, as compared to primary and early post-primary cancers.

With that in mind, and I will get to your second in a second there, I would like to kind of pose to Dr. Schlom, where recombinant vaccinia and recombinant pox viruses in general now, really there is a wealth of safety data available, and it's quite recognized that this is quite a safe approach in terms of therapies. So some of the issues Dr. Bander has alluded to, perhaps the vaccinia approaches are already beyond that step of establishing a safety profile.

So along the lines, and in the background of the active immunization hurdles, two questions for you. Have you had any opportunity within the multiple studies that have been done, to compare T cell responses from patients who were treated on some of the early stage trials, compared to T cell responses of patients who might have been treated with later stage cancers in analogous trials using similar dose profiles?

And as a follow-up to that question, what exactly is going to be the target population for the phase III prostate cancer study?

DR. SCHLOM: Your point is well taken, that there clearly is an indication that with increased -- let me put it this way, there are two factors that we are looking at. One is increased disease burden, and the other is once the patients enter into the trial, how much prior therapy have the had?

Now, there are two published studies with these vaccines in colorectal and other solid tumors, showing that there is an inverse correlation between the amount of prior therapy regimens, and the ability to mount a T cell response, and the time since the last chemotherapy.

So clearly, previous therapies will influence the ability to mount immune response. But not all therapies will do that. It depend on the therapies, such as the docetaxel seems to have no effect. Adriomycin in another trial had no effect in a solid tumor. So there's that.

But we have been seeing robust immune responses in these trials, similar responses in the early patients, and the late patients in the prostate cancer. But the other factor is the tumor themselves induced suppressor factors, as was mentioned. And there are many different strategies where one can reduce the suppressor cells.

So I think the field is maturing to learn how to deal with this problem, but it's a point well taken.

DR. SANDA: And the patients with the phase III prostate cancer trial, do you have know off the top of your head by any chance?

DR. SCHLOM: No, that is still being developed.

DR. SANDA: Well, I vote for hormone naive in that trial, myself.

Dr. Vieweg, your presentation was really some very exciting work regarding dendritic cell maturation effects, ways to deal with suppressor cells, a variety of issues. A lot of the studies that you are undertaking at Duke are using really complex technological approaches in terms of purifying the dendritic cells.

You have highlighted the importance of -- or alluded to at least-- the importance of how the dendritic cells are prepped. There is a lot involved there. Do you foresee this dendritic cell therapy such as RNA loaded DCs that you are developing at Duke, do you foresee it as a bridge to simpler technologies? Or do you foresee that the dendritic cell technology will become sufficiently efficient, that it could be done on a multi-institutional basis at the level of rigor that you have pursued at Duke?

DR. VIEWEG: I think my last slide clearly showed actually one of our goals is enhance and simplify. And the process, as complex as it seems, it's a fairly simple FDA compatible seven day process, which actually some other companies are currently implementing that one.

So I think it can be done. Nevertheless, I think it relies on certain experience, which needs to be learned. On the other hand, as I said, the process is not mature enough really to fully predict how complex and simple this can be.

I just would like to allude to Jeff Schlom's answer. What we are lacking at the moment, or at least the fundamental principle in cancer immunotherapy is that immune response can be therapeutic. And we have not really proven that as of now. What we are lacking are prediction models. What are the variables which impact on the -- when does an immune response become therapeutic?

So we can say, okay, it depends on T cell frequencies, but we really don't know what we measure right now. It's not the T cell frequency alone, because I have seen in regressions and let's say favorable outcomes, even with low frequencies of antigen T cells after vaccination.

And I think that the challenge that lies ahead now is to identify these factors. As Jeff said, it might be pretreatment, it might be age, it might be tumor burden. But it's not just a single factor. It's an array of factors which impact on our ability of inducing a clinically relevant immune response.

DR. SANDA: I think that's a good take home point on my comment.

A comment from the floor, a question?

PARTICIPANT: A quick comment relative to regulatory approval, which is probably premature. But about two weeks ago the FDA gave an approval for taxotere within lung cancer. It was very interesting. Rick Pasteur had a press release that accompanied that approval. And it was based on non-inferiority.

And I think that is a very important regulatory issue. I noticed that you said a little bit earlier that we have to prove a survival advantage. We may be moving into an era from the FDA perspective, where survival advantages need not be demonstrated, but rather non-inferiority in appropriately powered trials.

With this immune approaches, you have opportunities to diminish toxicity in comparison to conventional therapies. And I simply want to open your eyes to perhaps a new regulatory environment that may very much change the way we approach individual patients and individual drug approvals.

DR. SANDA: Thank you, that's a point well taken.

PARTICIPANT: I enjoyed everybody's talk very much. This is directed mostly to Johannes. A couple of quick technical questions. First, maybe I missed it. Did you amplify the RNA before you loaded it?

DR. VIEWEG: Not in this trial. I think we have done this in a subsequent trial, which is ongoing at the moment. I think here in this case we used a total tumor from a nephrectomy specimen.

PARTICIPANT: And what technique did you use to load your DCs? And do you know how efficiently the DCs were presented?

DR. VIEWEG: Right, I think is a question what I commonly get. The issue is what we had done in this trial was loading the dendritic cell with naked RNA. And that is for a traditional gene therapist, very hard to understand, because unlike with traditional gene therapy, where you have to achieve a high level of transgene expression, with dendritic cells you only need a minimal amount of maybe 800 MHC molecules in association with a peptide to elicit immune response.

We actually have compared different transgene expression levels or dendritic cells transfected with different methods, which yielded different transgene expression levels. And we did not observe an immune response in a magnitude of an immune response that we could stimulate.

So it not we did a traditional gene therapy scheme the more the better. It's just you have to have enough.

PARTICIPANT: The last thing I wanted to ask you is if you know what proteins these transcripts may encode for? Are you looking at that?

DR. VIEWEG: Well, I think we looked at GFP, which is traditionally an overexpression. But we also looked actually, and I think this was recently published actually, we looked in the case of telemorase for functional telemorase protein as based on real time trap assays, which shows that actually we can achieve the expression of functional protein on the cell surface of these DC. But these are complicated assays, and by no means can be done on an individual basis for every patient.

DR. SANDA: Well, I would like to thank all of the presenters.

I'd like to just make one final comment, which is I think we, as urologists, have the unique opportunity in prostate cancer and other cancers as well quite frankly, in terms of moving some of these biological therapies and alternative treatments forward.

I think that when, for example, a study is ready for phase III, that would imply that it is in fact ready for hormone naive patients in the prostate cancer setting, at least. And I think that we ought to push hard on the FDA to have that be more meaningful in terms of potential licenses and so forth.

Thanks again to the presenters. They were wonderful presentations, and we will move on to the next session.

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