The flu vaccine contains something that "looks like" the expected flu virus, but is inactive, or attenuated. What is the idea behind any of the various cancer vaccines" Is it to create an inactive prostate cancer cell or an attenuated one, by some means, that the immune system can practice on and learn to defeat?
Or, does anyone have the URL of a site that explains the structure of what gets infused with the Provenge treatment. The URL should indicate at least the type(s) of cells (dendritic, and whether of myeloid or lymphoid origin) and the presenting anti-gen(s) and whether these antigens are associated with MHC-I or MHC-II structures, or not. Additionally it should explain whether checkpoints are relevant either in their presence or their absence.
No Provenge is not an attenuated cancer cell vaccine. White blood cells are removed and then tagged with certain proteins that sensitives the immune system to recognize the prostate cancer as an invader. The tagged cells are re-infused, "educate" other white blood cells to also be sensitive to the cancer.
The FDA has a good site which describes the process and mode of action at:
Provenge is best given at the very earliest stage of castrate resistant prostate cancer while the disease burden is at a low level since it takes some time after it has been administered to become effective. It should be the first treatment given when you become castrate resistant to trade on its potential benefits (my opinion).
The active components of PROVENGE are autologous antigen presenting cells (APCs) and the protein called PAP-GM-CSF. APCs are activated during a defined culture period with a recombinant human protein, PAP-GM-CSF, consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM‑CSF), an immune cell activator.
Translating:
The patient's own cells are returned with an anti-gen presented on the surface consisting of the prostate specific acid phosphotase (PAP). GM-CSF is also involved in some unspecified way, possibly separate from the APC.
Is the PAP presented on an MHCII complex?
If the point is to present PAP as an antigen, why is not the PAP that is already freely circulating triggering a response in the B cells? Or is the PAP bound to the APC's membrane?
It is not clear.
Most vaccines work by presenting something that is somewhat like the thing that they are intended to protect against.
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Yes it is not dead or weak cancer cells that are introduced into the body. There are, one hopes, many such dead cancer cells in the body already as a result of any of the many effective treatments.
This might not be answering your question, but I believe that the linking of the PAP to the surface of the T cell sensitizes these cells to the cancer.
The actual mechanism of action is not understood, what we do know is that based on 2 different phase 3 clinical trials the men receiving Provenge had a statistical increased survival over those who did not receive the treatment.
No, I know it's vague and all. I am trying to relate what I hear about Provenge to the Kahn Academy series on the Human Immune System Physiology, which I think is pretty amazingly excellent.
The particular disconnect I have is if PAP on a T-Cell serves as a stimulus to the "immune system", and here I get lost a little. Need to watch the videos again. I think that activated T-cells turn into memory T-cells and effector T-cells, and the effector T-cells release cytokines, mostly, that do what...? What kills the cancer cell and how. No idea. Phagocytosis? By what. Or ...
PAP is a residue that already circulates in the blood, and so if it is a stimulus of some kind to the immune system, then some naive B-cell should bind to it, and actually consume the PAP - which I don't think happens. I think PAP is considered "self". My blood tests list PAP levels as part of routine screening (Alkaline Phosphatase - is that the same - maybe not.) Obviously I am missing something very central and basic, but ... I don't "get" it.
The Khan Academy videos are great however and I do recommend them to anyone who is interested.
Putting the PAP on the surface of the T-cell does not cause that T-cell to kill any cancer cell (I don't think). I am assuming that it is presented on an MHC-II factor, which is like a framework around a wanted poster, the person wanted dead or alive is PAP.
If the PAP is presented on a MHC-I factor, then that means that the cell is saying "I am sick" and "this stuff is part of what is killing me", so maybe that is the mechanism, and some other cell comes along and kills the Provengified cell, and ... what ...
I better stop now.
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Wait no. The PAP and the GM-CSF are stictched together in some way, and both? presented as an antigen? Seems kind of a long molecule to present as an antigen. Hmmm. I thought the antigens on the B cells each had a corresponding receptor on the T cells. Were for the same protein fragments. One-to-one. The logic around the elimination of auto-immune disease seemed to require that. Now I'm lost.
I think some oncologists are now arguing that Provenge should be administered even BEFORE a patient becomes castrate resistant. The idea is that while the Lupron (or whatever) is holding the tumor population to a very low level, the immune system may, conceivably, wipe it out completely, or at least beat it half to death. It's the same argument for giving ADT + chemo at the same time.
My inexpert view of this is that it makes sense, and I know there are case reports that show benefit, but I don't know if there have been any clinical trial reports.
The immune treatments currently work better with lower PSA and lower tumor burden. The castrate resistant state is defined as beginning at nadir, which is the lowest PSA blood level. However nadir is usually determined (oops) months later, after two successive rises to the PSA.
So they could better identify nadir, and move up treatment to there, or somewhat earlier.
Most people would say not to overlap Provenge with chemo.
As I understand it, most chemotherapies damage the bone marrow where immune cells are generated, hence chemotherapy and immunotherapy have been thought to be incompatible.
Interestingly, when I searched clinicaltrials.gov for "chemotherapy and immunotherapy" I saw three trials in China combining "precision cell immunotherapy" (whatever that is) and chemotherapy.
My inexpert view is that immunotherapy has an expanding future. Jimmy Carter was treated with a kind of immunotherapy (not at all like Provenge) for his metastatic melanoma and appears to be in complete remission with no detectable sign of cancer. Amazing! With a previously incurable type of cancer! In a 91 year old man!
I was briefly in a Provenge clinical trial for relatively early stage men, about a decade ago. (I was removed because the Dendreon monitor found an error made by the hospital where I was participating.) I didn't see published findings, & eventually asked someone. I was advised that the trial did not prove that better results were obtained. Perhaps you'll want to put your hands on this & let us know whether that's an accurate version of the report. Thank you.
Shows overall survival benefit of 4 months between the two arms, and survival benefit of one year between those who took the drug vs those who did not. The standard-of-care arm was allowed to cross over to Provenge on progression.
This may not have been Neal's trial. As I read it, 100% of the men in the trial had had previous ADT and already become castration resistant. 18% also had previous chemotherapy.
Neal:I was hoping that early stage Provenge would do better. However, if your (almost) trial involved Provenge without ADT, I'm not sure that its failure to do better than later stage treatment means that early stage Provenge + ADT wouldn't work better. The idea here is that the immune system would be attacking a much smaller number of tumor cells and those cells would be much weakened by ADT. Other combination therapies in other cancers have also demonstrated that it's more difficult for cancer to evolve defenses against multiple different treatments at once than it is to evolve defenses against just one.
I know at least one fellow with early stage metastatic prostate cancer who participated in a trial of simultaneous ADT (Lupron) and chemotherapy (docetaxel). His last treatment (a Lupron injection) was in 2010 and in 2012 he began testosterone supplementation. At last report in August 2016, he still has an undetectable PSA. I know of other people in his trial who have experienced disease progression, so he might be a one off, but I think there is evidence from multiple trials that combination therapy is producing longer remissions than ADT followed by chemo after ADT failure. I'm thinking that the same might also be true of ADT + Provenge rather than ADT followed by Provenge after ADT failure.
Standard of care for newly diagnosed metastatic prostate cancer is simultaneous docetaxel and ADT, ever since the CHAARTED trial. (corrected from IMPACT trial 09/2017)
But you say that that after Lupron, he went on to Testosterone supplementation. Very interesting. Is this technique written up someplace? IE - was it a published trial?
Yes, sequential vs simultaneous is a conference topic.
I didn't realize that the standard of care had changed. I suspect that it hasn't yet changed here in the U.S., but I could well be wrong. Our medical system here is advanced in some ways but rather chaotic in that not all doctors follow the same guidelines or switch to new approaches as soon as new guidelines are published.
As far as I know, the guy who had the testosterone supplementation was not part of a trial, but rather arranged this with his oncologist. (I could be wrong about that too.) He has posted about his experience from time to time in the newsgroup alt.support.cancer.prostate. You can see the group on the web at:
To see his postings, look for "Gourd Dancer". See, for example, his posting on September 5.
There's another guy in that group named Ed Friedman. I think he's a math professor in the U.S., but with a deep interest in medical oncology for prostate cancer and the use of testosterone therapy. He made a posting on September 21 where he cites a new article on testosterone therapy and prostate cancer in the October 2016 issue of the Journal of Urology. Ed has other postings going some years back about this topic, and I think he's published in some of the academic journals.
Thanks Alan. The theory made total sense to me, and 2 out of 3 participants were getting Provenge, so I was extremely disappointed when I was removed before my first infusion. Provenge was only approved for late stage at the time, following Eric Small's study showing a 4 1/2 month survival benefit, if I remember the number correctly.
Provenge did show longer survival for men who received it against placebo, thus it was approved by the FDA. FYI- The FDA made Dendreon go back and perform a second phase 3 trial which also demonstrated that the treatment did provide a survival advantage.
You said that the trial was for relatively early men. Are you referring to castrate sensitive or castrate resistant men? The two positive trials were for men who were castrate resistant.
I searched clinicaltrials.gov. Using the advanced search with intervention=sipuleucel-T and condition=Prostate cancer, I got 37 hits. Of those, there were several that appeared to be testing early stage use of Provenge, however I couldn't tell which one might have been yours. If you want to take a look, here is the first page of the search results:
If you look at any of the trials, you can see start and end dates which might help you locate your trial and also a list of participating institutions, so you can see if you visited one of them.
Near the top of each clinical trial page there are several tabs, one of which will say "Study results", or "No study results". Unfortunately, not all completed trials have results, but some do.
Thank you very much, Alan, for scouting this out for me. I have records with dates, & I went to Alta Bates in Berkeley, so it should be easy to find with what you provided.
No, there have not been any clinical trials using Provenge in castrate sensitive men. So, we do not have any data and it is very unlikely that any insurance coverage would be extended for a man who is castrate sensitive. I do not know the actual current cost of Provenge, but I believe that it is about $130,000 for the three infusions.
It will take Dendreon to run the necessary trials to move it to an earlier stage. My assumption is that if this happens it will be years off since they were bought out of bankruptcy and I do not know if they are yet profitable. I am told that their sales numbers have been increasing, so let us hope that we will eventually see the necessary trials.
I did find one study sponsored by Dendreon that tested hormone sensitive men. The study recently completed but no results have been posted yet. Here is the record for it:
I guess that we will just have to wait and see if there are results released. We can not count on positive results because the number of mutations is going to be different in castrate resistant and castrate sensitive prostate cancer. All we can do is keep our fingers crossed
This sounds right (PROTECT at Alta Bates), but if they enrolled in 2008, that sounds too late. I'll let you know when I look in my records.
Neal
Most vaccines inject a free floating anti-gen (protein) that the body's b-cells react to.
Provenge is not a free floating anti-gen, it is a cell. A T-cell. A T-cell that presents a piece of its victims dead body. Since the patient's T-cells are not doing this, some are taken outside the body and made to look like they are.
So, not like an attenuated cancer cell, no.
Another attempt at thhe difference between CAR-T and Provenge.
CAR-T is an activated T cell. It is supposed to look just like a T cell that your body would make, if it made T cells against the specific antigen, which they don't.
Provenge is not an activated T cell. I don't know what it is exactly, but the hope is to make the body think that PAP is a foreign antigen, which it isn't. PAP is a naturally occcurring protein, apparently related to prostate cells only, and I think involved in the creation of bone mets. How they (Dendrion) planned to trick the body into thinking that a natural protein was a foreign protein, I have no idea, and I think that they also have no idea, but "it seems to work", and "the data is the data".
This sounds sketchy.
Here is a pdf that presents the Provenge data, and is skeptical of the results of the trials. I think it is worth (my) reading.
Briefly, the people in the placebo arm were harmed, and that is why Provenge was better than placebo. The placebo arm had all their white cells extracted, and 2/3 kept out for Frovenge if asked for later on, and the 1/3 that were re-infused were dead by then. This happened 3 times.
In the provenge arm, the benefit was due to the GM-CSF, not the incubation in PAP, which they allege was pointless.
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Starting Provenge in January
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Port in chest for Provenge?
