L.    The reason that my own bias is the way it is done now and is not necessarily in the best interest of the patient is very nicely illustrated by the whole Dendreon story, which I hope some science writer will someday write up because it is a really fascinating story. Isn’t it?

L.    Yah, Yah, it’s a heck of a story isn’t it?

L.   From many, many different angles.   The reason I think that this is so enlightening in terms of  public policy is that it was quite clear at the time of the FDA hearing (Advisory Panel), that there were 2 kinds of mistakes that could have been made and the FDA had to choose which one they were willing to make.  Right?  They could make the mistake of approving a drug or therapy on insufficient data, only to be shown 2 years later that it was really nonefficacious.  Right?  And the risks of doing that would have been, I guess the cost of the health care system in that 2 years and I guess the embarrassment and I don’t think it should be viewed as an embarrassment,  but I guess they would view it as an embarrassment  of having to pull a previously approved drug off of the market.  My own sense of that is, we are learning all the time and if something tomorrow looks bad that today looks good, you pull it off the market.  There is no shame in that.  The other kind of mistake that they could have chosen to risk is to say, “nope the data isn’t good enough, we are not going to approve it, so keep studying it and bring it back when you have better data”.   Of course that risk there is to the patient, because, individuals that would have benefited from that therapy aren’t going to be able to get it.  And if you want to be harsh about it, that given the number of men that have had prostate cancer, and I have never run the numbers, but you could, and given the number of those that have Hormone Refractory Metastatic  Disease which is also a big number,  And of those based on the Dendreon results if you apply the stats to that denominator, there are people out there, not a small number,  that are dead now that might not be otherwise.

R.    I definitely side on that.  I am def. biased as you can tell

L.    I am too and I confess that fully.  There are counter arguments that can be made too, that the companies can do compassionate use if somebody really wants the compound etc. etc.  but I think that becomes untenable on the scale of what is the problem of prostate cancer.

 R.    On top of that, you got a small biotech that is struggling to survive and it is a cost factor for them.  But you can’t be Mother Theresa. 

R.    You, know, I am a big fan of this guy named Ian York, he is out of Michigan State University.  He is an immunologist there.  And uh, he was discussing a paper by, Apetoh, he has done a lot of work with Zitvogel and Kroemer

L.    Oh yes, I know the group

R.    They have done a lot of work on Chemo-immunotherapy and TLR4 activation by high mobility group box 1.

L.    Yes, I know this very well.

R.    He made a quote after this one study and it deals with PAMPS (pathogen-associated molecular pattern) and The Danger Model.  He made it clear and I just want to read it to you…

http://www.iayork.com/MysteryRays/2007/09/10/taking-advantage-of-the-dirty-little-secrets/

In fact, the fundamental observation was well established when cells are damaged, they do release factors that enhance adaptive immune responses that prove very difficult to purify the specific factors responsible for this.  But in 2003 she identified one such factor as uric acid.  I am not going to talk about that now.  It was while I was in the Rock lab so it was just two benches away from me during a very exciting period.  To know that Yan also identifies other fractions in cell life saved with similar activity.  And Bla, bla, bla, it goes on and on about HMGB1 and TRL4 and then the conclusion of this, it is not the whole story, it makes a case for calreticulin playing a part as well, for example.  But, if this is true, this is the key part, this is not only very cool but a little unsettling.  It kind of makes Chemotherapy sound like cargo colt medicine or witch doctory, trying to cause cell death, even though that is only peripheral to the true therapeutic  effect of primary adaptive immune system. 

R.    What is your feeling on this and what sort of developments do you see in the future, where chemotherapy, say metronomic Cytoxan therapy, or like in the Dendreon case, docetaxel  where Petrylak saw a strong synergistic effect.  Seems that I saw some presentation by Max Cheever, talking about this very topic and using not only various chemotherapies but I guess you can call it adjuvants to increase the affect of cancer vaccines and immunotherapy.  Where do you see this going?

L.    Well, you said a lot

R.    That was a big ass question

L.    Maybe you should boil it down.  I think you are saying that drugs that we are using to treat cancer, not only act on the cell but on the immune system as well.  They act on the immune system directly, that is those drugs modulate immune responses and they act on the immune system indirectly by killing tumor cells in the way that you described it may be particularly alarming to the immune system.  So what are the implications of this?  I may be an immuno-therapist, but I trained as an oncologist and I know that these drugs, at least in 2009, are still very useful and achieve clinically meaning benefits to patients if used under the right conditions and if that is the landscape that we are integrating immunotherapy, so you know, whether or not the vaccine needs to be given together or in sequence with the chemo. We need to try to modulate how the cancer cells die with a given agent, such that maybe it kills more tumor cells directly, but also kills them in a way that is more favorable to adaptive immunity.  These are all reasonable ideas that smart people are now testing. 

R.    O.k., o.k.  What do you think about the Schlom, Gulley and Hodge, they did this study in mice on the effects of docetaxel on the immune system.

L.    There has been stuff on this for years

R.    Their conclusion was that it had no affect on T-regs, but it did lead to the antigen spreading effect.  And if you take the research by Apetoh and Zitvogel,  it seems to be this release of this high mobility group box 1, whatever the hell that is, and it’s affect on TLR4.  Do you see these toll-like receptors as an avenue with a lot of potential for potentiating immune-therapies?  I have read these Max Cheever, The Slides and he is talking about modified LPS or MPL as a TRL4 agonist that is approved in Europe.  But I guess the only thing that we got approved as an adjuvant in the United States is alum.  Do you feel a lot of potential there?

L.    Well, I think that stated more broadly, the whole development of vaccine adjuvant is an enormous opportunity, where a lot of toll –like receptors and analogist signal receptors, not just TRL4.  That are not redundant, that is to say that one doesn’t take the place of another but they act either synergistically or additively in some cases.  They are being as aggressively pursued as the vaccine itself.   And they should be.  I can tell you as a consultant to companies that have developed some very innovative ways to deliver antigens to antigen presenting cells, they are all too aware of the requirement to also activate those antigen presenting cells with things like adjuvants.   So, it is a huge area.

R.    It seems to be a major hurdle.  It was discussed at this FDA/ NCI workshop in 2007, before the advisory committee meeting , where I watched that thing and saw, Rosenberg berate some guy that was presenting this data, but, anyway, that is besides the point.  Um, the use of adjuvants in combination with whatever, a vaccine or not, it looks as though, if you wanted to do that, you would have to run the two in a trial together.  Is there any way to expedite that process?  Do you see that as a problem with the FDA?

L.    Well the whole question of combination studies is a challenge.  I think that the usual paradigm is that if they are two investigational agents there needs to be a small run of each one alone just in the sense of dose and toxicity.

R.    O.k.

L.    But at that point there is really no reason they can’t be put together

R.    And that at this point in time, you can do that?

L.    The major obstacle to those is not so much the FDA, but rather the companies.

R.    Oh.  The companies

L.    If the companies don’t own both pieces, they are very reticent until they have already shown that their compound doesn’t work by itself.  They are reticent to test it together with somebody else’s compound. And that is complicated also by the fact that by the way the FDA handles its investigational new drug files, is all adverse events are recorded in toxicities or deaths for example, a side effect, bad fevers or what have you.  They are recorded in an enormous file of each drug.  The companies fear that if they are testing 2 drugs together, they will get dinged for the toxicity of the other guy’s drugs.  And if they are still under the fantasy that they may get it approved as a single agent, they are not going to take that risk.  It is unfortunate.  I think that interesting enough, that problem could be fixed in a regulatory fashion.  The FDA could say that if you have a drug that you are pursuing as a single agent, but you also want to test it in other setting as a combination, that we will handle the toxicity of the combined trials distinctly.