R.  I have been doing a lot of reading  and I have kind of got hooked on this and I am trying to educate myself on this.  This guy named Wodarz did some mathematical model of tumor immunity and he came up with this ratio of cross presentation to direct presentation of antigen.  He said that as the ratio goes up, it appears that the efficacy goes up.  And being Provenge Centric I’ve taken this as maybe some support as to why Provenge has been efficacious, because they infuse so many activated dendritic cells into the patient.  Would this have any correlation as to what they have done at Dendreon or do you think I am going off track here?

L.  Pause…. I think I lost you.

R. What’s that?  You lost me? 

R.  What I said is, they are trying to get a lot of APC’s activated

L. Yah, Yah, Yah,

R.    And APC, the whole deal there is they are a cross presenting antigen. O.K?  When you have a lot of direct presentation by say tumor cells, the more of those you have and the less you have of the cross presentation the less affect the antigen vaccine would be.  

L.  Oh, I see.  I think it is an interesting hypothesis.  It has never been entirely clear to me what the direct presentation by a tumor is.   I think what is likely to be much more important is the activation state of the antigen presenting cells.  Most lymphocytes traveling throughout the body never make it to the tumor site.  But they do make it to the lymph nodes.  In the lymph nodes with the exception of tumor metastases in the lymph nodes, which clearly does happen and is an interesting event in it’s own right, with the exception of that, the vast majority of cells that will present tumor antigen to the tumor specific T-cell are in the lymph node, not in the tumor, and they are antigen presenting cells.  So, the models that I have looked at have suggested that they are much more the determiner of the outcome rather than if the tumor cell does express  or doesn’t express those tumor antigen molecules.  Part of the concept is the same, that is, what is the ratio of stimulatory to nonstimulatory events.  All I am saying that would differ from the model that you are proposing is that I think the nonstimulatory events can be antigen presenting cells that are not appropriately activated and the stimulatory events are the antigen presenting cells that are appropriately activated.  From there I think the models are pretty compatible. 

R.  How much of a factor do you think T-regs are?

L.  Huge

R.  How will they get around this?

L.  There are a lot of ideas that are being pursued.  Many of them have an effect but no one has hit a homerun with it yet, but they are a clearly a very important bottleneck in the system. 

R.  What Avenue has the most potential at this time?

L.  Well, we don’t have specific drugs so we are left with relatively selectively depleting them.  And there are monoclonal antibodies, there are cytotoxic drugs and then there are pharmacologic inhibitors that impact on the survival of those cells and their reduction.

L. Listen my friend, I am going to have to cut this short.  I can’t remember, can you remind me, are you an investor or a hobbyist.

R.  I am an investor that has become obsessed basically.   It looked to me that it had a hell of a lot of potential.  I looked at it about 5 years ago and had a huge position and then I got frustrated and I sold it and bought back about half of my position.  For me, it is called a proverbial shit load.  For a lot of investors it wouldn’t be a whole lot but for me it sure is.  I looked at the science behind it and I just found it fascinating.  I am a dentist but I have just taken this up and read as much as I could about this and came across guys like you and Zitvogel and Apetoh and all these other guys and whenever you PubMed this stuff it is huge.  I mean it is huge.  People have been looking at it for a long time.

L.  I’m not even that old of a guy and I have been working on this for 20 years.   If you add up all of the papers it’s a lot of work.

R.    From my perspective this will get the field jump started.

L.  Yah, I hope so.   And for your sake I hope you make some money off of this.

R.   Can I ask you one more question?

L.  Sure but then I have to go.

R.  What property that Provenge has accounts for its efficacy?  Is it the large number of APCs activated, the fact that they don’t have GM-CSF in the final product, the ex-vivo activation or is it a combination of all of these factors that accounted for the supposed efficacy.

L.  If I had to guess, I would suspect that Dendreon was very lucky that they did not try to make this a cleaner and purer product.   I think that part of the success comes from the fact that they are infusing dendritic  cells that have been loaded with antigen and appropriately activated, that they then on the next cycle they pull out T-cells that have been activated by that first infusion, that those T-cells promote further activation in the bag and then go back into the patient and is doing it again and again.  It is really a combination of active immuno-therapy and passive adoptive T-cell therapy and it is really that combination of those 2 together that contributes to that efficacy.  That is pure speculation on my part.   It’s testable.

That was it for our talk except for some small talk.  A subsequent question that I asked in an email follows:

Hy,

The press release I referred to is here: http://investor.dendreon.com/ReleaseDetail.cfm?ReleaseID=378034&Header=News

One last question if you don’t mind.  When the company says this,

"We are encouraged to see that CD54 upregulation in APCs is maintained after boosting in men with androgen-dependent prostate cancer," said David Urdal, chief scientific officer of Dendreon. "This pattern of CD54 upregulation suggests that the first dose 'primes' the immune system for subsequent 'memory' responses and is consistent with that observed in our studies of men with androgen-independent disease where the cumulative CD54 upregulation dose correlated with survival. We also are encouraged by these data which suggest that the immune response generated by PROVENGE is durable for a year or more after initial treatment and that it can be maintained following boosting."

Given that it’s really the activation of PAP specific T helper cells that they are measuring when they look at the increasing CD54 numbers, as you explained, then I guess it really isn’t overstating their case when they say that, “the first dose’primes’ the immune system for subsequent ‘memory’ responses.”

One response that I saw to this press release said that this is just “spin” by the company and they said this,

The current press release on the P-11 data does not indicate any memory responses at all.  No matter how anyone spins CD54 upregulation on DCs, such flow cytometry results simply indicate persistent DC activation which in the absence of interferon-gamma or IL-17 ELISPOT frequencies to PAP or other possible prostate spreading antigens are no a measure of any immunologic memory, period.  I don’t know any immunologist who would accept DC activation markers as a gratifying substitute for adaptive memory in the absence of readily available ELISPOT frequencies.  There are just too many non-specific and/or innate immune events that can upregulate CD54 in the absence of any adaptive T cell responses involving immune memory.

IMHO, by not providing ELISPOT frequencies like they have in the past, DNDN’s press release may be best appreciated if considered in the simple context of re-establishing analyst awareness to the inevitable expansion of the Provenge market to PC patients at the very earliest stages of diagnosis.  The P-11 trial is simply a prep run for the clinical events/trial that will ultimately expand the label to early onset patients.  It’s very effective to keep this concept bouncing around the top of the cortex during the drive to the 28^th and beyond, but let’s not mistake innate activity for adaptive memory measurements. 

But from what I gather from you the CD54 upregulation really is a measure of memory given that it’s really the PAP specific T helper cells that are being indirectly measured.

Dr. Levitsky’s response:

Dear Rufus,

I agree with your take on the CD54 data.  Usually the guys who post on the business sites are ex scientists who like to impress people in thinking that they know something.  It astounds me how quick people are to render an opinion, even when they’ve not seen the data and wouldn’t know what to do with it if they had.

All the best,

HY