A four part interview with  Hy Levitsky M.D., professor of oncology and tumor immunology at Johns Hopkins Medical School and co-inventor GVAX anti-cancer vaccine, is posted on Dendreon Investor Village website.

Interview conducted by rufustoehee, a dentist and Dendreon investor, published 4/22/2009.

By way of introduction, Dr Levitsky’s bio is posted alphabetically downpage among those of other speakers at Cancer Immunology & Immunotherapy 2008: From Discovery to Development to Drug.

EXCERPTS FROM INTERVIEW

Conversation with Dr. Levitsky Part 1
“. . . . how this impacts on the field of tumor immunology, I feel it will very much depend on the nature of the data they present, assuming for the sake of discussion, that this is an unequivocal and unambiguous win, then I think it will have a very significant impact. Number one, I think that unless there are aspects to this that have not been made public, I think the FDA would in this instance need to move it forward in the approval process and I think that how it ultimately gets integrated into clinical practice will be a fascinating thing to watch.

“. . . . It is important to acknowledge that tumor response is a surrogate endpoint. It is a surrogate endpoint for perhaps 2 other endpoints that might be more meaningful. One is overall survival which is the gold standard and the other perhaps is the quality of life. No one can argue that those two things have sort of the paramount importance where as to an objective 50% or greater reduction in the mean diameter of all measurable tumor masses is an interesting yard stick, but it is only a yard stick.”

“. . . . issues of the drug approval process and how the rules are set is an extraordinary challenge, and I have strong opinions about this as a scientist and as a physician that cares for patients. I will comment on my own beliefs in just a moment. It is important to recognize that whoever sets this policy has to do so with the recognition that is really the interface between science, medicine and the business world. And that wherever the bar is set it cannot be arbitrary.

“It can’t be, ‘we will do it one way because that is how we feel today and we will do it another way because that is how we feel tomorrow.’ It has to be reasonably unambiguous so that the investment community and other people that choose to place their bets, in the business sense of the word, know exactly what they can anticipate. I’m conceding that there are challenges to doing it.

“Having made that concession, I feel the way it has been done is not in the best interest of patients. I also think that just as science and our knowledge of biology evolves, we should also take fresh looks at the way we test and ultimately approve drugs for cancer. I am saying two contradictory things, you have to have consistency and you also have to evolve.”

EXCERPTS from

Conversation With Dr. Levitsky Part 2

“. . . .  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 two 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.”

“. . . . 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.”

EXCERPTS from

Conversation With Dr. Levitsky Part 3

“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 1st cycle, 2nd cycle and the 3rd cycle.

“What they noticed was it went up very little, if at all with the 1st cycle. But, in some patients in the 2nd cycle and particularly with the 3rd 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.

“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 2nd and 3rd 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.

“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 1st product. But, if you had successfully primed the patient there would be more abundant in the 2nd product and even more in the 3rd product.

“. . . . 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.

“. . . . 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.”

EXCERPT from Conversation With Dr. Levitsky Part 4

“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.”

CURRICULUM VITAE OF HYAM LEVITSKY, M.D. (posted by rufustoehee)