R.    Easy enough to do.  It is easy enough for us to say, whether they will ever do it is another question.

R.    Dendreon just released this information on CD54, ICAM-1  upregulation and their P11 trial.  Did you have a chance to look at that?

L.    No.   Is P11 the name of the latest trial?

R.    The P11 is one they are doing in androgen dependent prostate cancer.

L.    O.K.  I didn’t see this I know the  study, actually at the risk of sounding modest, I think I explained to them the way that ICAM-1 is predictive.  But I did not see the press release. 

R.    How did you explain it to them?

L.    Oh my…Ha Ha Ha….

R.    Were they receptive to it? Did it take awhile to be convinced? Or…

L.    No, no, no, I think once I spelled it out, they were like, “Uh, ha”

R.    Alright, ha?

L.    Well, I will try to give you the short version.  The whole focus of the company had been on turning the cells and the apheresis product into dendritic cells.  Which of course it does to some extent, but a lot of what is in there are not only dendritic cells but a lot of other cells like T cells for example the product, O.K.  So, if you remember, they did 3 infusions based 2 weeks apart.  First when they take the blood out, they throw in the protein fused to GM-CSF and then they take a small sample of the material before they add it and another aloquot of the material after it has been incubated with the antigen and they do flow cytomotry and measure the level of CD54.  If it goes up, they call that the delta or difference or the up regulation of the CD54.  So they measure the numbers from the 1^st cycle, 2^nd cycle and the 3^rd cycle.  What they noticed was it went up very little, if at all with the 1^st cycle.  But, in some patients in the 2^nd cycle and particularly with the 3^rd cycle, it went up a lot.  And in other patients it didn’t.  They found that if they made a mathematical index for summing up or making the average of the increase in CD54 measurement across the 3 infusions, that they could separate, there was a good correlation between those subjects that had a high up-regulation and those that didn’t and that correlated very well with a beneficial survival.  So at face value, it didn’t make sense because CD54 is found on the antigen presenting cells, like the dendritic cells and they are not long living cells.  They live normally only a few days and then they die.  So it didn’t make sense in the 2^nd and 3^rd infusions that they were pulling out the cells that they had put in 2 weeks earlier.  It just didn’t make any sense.  So something else had to be responsible for the increasing CD54 in these cells.  So looking at the data and thinking about it, we knew there were a couple different things that cause CD54 to go up.  One of the things is when the antigen presenting cell is activated by a T cell.  So if an antigen presenting cell has captured the antigen and is presenting it to a T-cell that is specific for that antigen, the T-cell among other things will send a signal back to the antigen presenting cell helping to activate it.  As a result, CD54 goes up.

R.  Is that the T-helper cell?

L.  Yes

R .  O.k. that is the T-helper cell

L.  So in a long winded way of saying it, what I proposed to them, was that by measuring CD54 up-regulation in the product after peptide incubation, what they were really indirectly measuring was the frequency of antigen specific T-helper cell.  They are long living unlike the dendritic cells.  And you would expect them to not be very abundant in the 1^st product.  But, if you had successfully primed the patient there would be more abundant in the 2^nd product and even more in the 3^rd product.

R.  You know, I have never heard it explained that way.  That explains a lot. 

L.  Furthermore you would predict that a patient with a higher number of helper cells would do better.  And that is exactly what they showed.  That the patient that had the CD54 up-regulation , which I am just making the case reflects the frequency of Antigen specific helper cells.  They did better.  So there are many interesting implications to this, one of which is that their product is not strictly a vaccine, it is also a form of adoptive T-cell therapy.

R.   Yah. That is getting into Rosenberg territory.

L.   Well, that is a lot of people’s territory.  But he is certainly making the most noise about it.

R.   Ha, Ha, Ha.   Well I was just read between the lines.

L.    No, I mean. No, he is clearly, well, he has made good use of the tax payer’s money.   Absolutely.

R.  Uh HA.  And there is just some discussion or a study recently that someone has uncovered, that natural killer cells have memory.  Is that a sort of an ambiguous study?

L.   No, No, it is actually a very interesting study.  I’m not sure that it is relevant to this.

R.  Well, I was just thinking is that perhaps natural killer cells, NKT cells, and other cells that you have mentioned are in that mix getting exposed to the cassette.  Perhaps, that might activate natural killer cells. Or am I off base?

L.  No, they may possibly do that.  I don’t know if it has been all that carefully looked at.  Let’s look at it this way.  There are going to be a lot of ifs in what I am about to say.  If the FDA approves Provenge and if Dendreon starts to make some money and if they keep their word to the encouragement that people like myself have given them and continue to study the biology of the treatment that they are developing.  I think it would be in their best interest to do that.   I think they should take a significant amount of the money they make from this and really study the hell out of it. 

R.  Well, I guess they are trying it with NeoAct trial and giving it before prostatectomy and for scheduled prostatectomy and they take the prostate tissue out and find out what the hell happened to it.

L.    Yes

R.  Along those lines.  What do you think Dendreon should do next?  Should they expand into antigen dependent  prostate cancer, should they look into boosters, should they combine (Gold said this at a conference) their vaccine ASI with incomplete  Freund’s  adjuvant or with montanide ISA-51, I guess it’s  just oil.  Isn’t it?  Is it some kind of oil to make the antigen release slowly?

L.    Yes, I don’t know how that would be relevant to this.

R.  Yah, he said that and I thought, ‘what the hell is he talking about?’ , You aren’t putting the antigen into somebody and having it released over a slow period of time.  Yah, I didn’t follow that myself.  So where do you think they are going with this?  Try to maximize the efficacy of this?

L.  I think there are a number of different directions that they could go and I would gladly categorize them into taking the platform that they have already developed and testing it in slightly different clinical settings, such as early stage disease or neoadjuvant or all the things that you are talking about.  To modifying the therapy that would potentially make it work better based on better preclinical models, to trying it indifferent diseases.

R.    How do you think they can modify it to boost the effect.  

L.  I think there are a lot of very reasonable 1^st and 2^nd level maneuvers they could do.  Again, they do have preclinical models.  I don’t remember the details of them.  I think they were working with mice and rat prostate tumors.  It wouldn’t be difficult and it wouldn’t take long to make a list of the top 10 things you would want to look at and run it through their models and see which ones look good and then do pilot trials with them.

R.  Well, why do you think the Dendreon approach was successful versus the GVAX ‘ s problem?

L.  Well, I think that will be a subject of considerable debate that will be greatly aided by having the data out there for people to look at in detail.  At this point of ignorance, I am willing to bet you that a major parameter was that  GVAX went up against Taxotere and Provenge went up against the placebo.

R.  O.K.  it is hypothesized that these ASI’s  work  against micrometastases and not necessarily reduce tumor volume.  With all these cancers, you could have a group of cells about  1/125 of a cubic centimeter and that is enough to start to metastasize.  That size is below something that you could detect.  They seem to grow until they are about 2-3mm in size and then start generating their own blood supply.  Then you have this problem where say someone has a primary removed and then all of the sudden things take off.  My understanding is because the angiogenic factors don’t last as long as the antiangiogenic  factors in the blood stream so the main tumor is inhibiting the micromets when you take out the main tumor the micrometastasize take off because they are not inhibited anymore.  Do you see this as their main utility for going after early lesions that really can’t be detected?

L.  Well I think the relationship between tumor burden and the nature and magnitude of the immune response is a fascinating topic.  I don’t know, it is my belief, based on a lot of animal work and reading clinical literature that the likelihood of success is going to be great in the setting of minimal residual disease or microscopic disease.  But, I don’t know that the reciprocal is also true.  I don’t know that a vaccine couldn’t work in the setting of a more extensive tumor and in the melanoma literature, there are these anecdotes , or renal cell for that matter where people have had a chest x-ray full of cannonballs and have them go away.  So, I don’t know if it is an absolute but I think that if you took across the spectrum of lots and lots of cancer, the likelihood is greater that it would work in microscopic disease.