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Old 03-26-2011, 09:14 AM   #1
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Cool Ipilimumab - great advance likely (IMPaCT Conference, FDA approval)

After years of waiting for a slow trickle of new drugs and approaches to fight prostate cancer, we are now joyfully encountering several advances with more following behind. It's hard to keep up with all that is happening, but these are good things, so the more the merrier.

Ipilimumab, a monoclonal antibody as you can tell from the name, is the latest to become clinically available, as of yesterday's FDA approval for metastatic melanoma (brand name Yervoy®), and Phase III trials for advanced prostate cancer are nearing conclusion. This has the potential to be a magnificent advance in treatment! That FDA approval also means that the drug will now be available under "off-label" provisions, while the prostate cancer trials results are pending.

We survivor representatives attending the IMPaCT conference for the DoD's highly innovative Prostate Cancer Research Program (PCRP) (see recent thread on the conference) heard about ipilimumab from one of its leading researchers, Dr. Eugene D. Kwon of the Mayo Clinic in Minnestoa, who had been supported by grants under the PCRP. His plenary session presentation was entitled "Checkpoint Blockade for Prostate Cancer Immunotherapy". I'll give you my version first and then his keypoints.

The immune system, in the case of ipilimumab the T cells of the immune system, is like a defense that destroys incoming threats that are foreign and harmful to the body. The movie "Independence Day" is playing a lot on TV these days, and you can visualize the immune system defenders as those jets that take off to attack the invaders. However, before any attacking goes on, even before any launching of attackers, there is a system to identify friend or foe - you don't want to be attacking your own body (sometimes happens as in autoimmune disorders). Unfortunately, prostate cancer (and other cancers) hijack that identification system so that they look like innocent cells, and the T cell defenders do not get launched, or, if they have been launched, they can't lock on to the cancer cells as targets. It's as if the cancer cells have a defensive shield, like the defensive shield in "Indpendence Day." That shield hinges on CTLA-4 cells, which play a key role in preventing autoimmune responses.

Researchers realized that they might be able to lower the shield if they could turn off the CTLA-4 shields, allowing the T cells to recognize the cancer cell targets and destroy them. They came up with an antibody known as MDX-010, which was later given the name ipilimumab. (Pronounce ip ih lim' oo mab, with the oo like you but without the y - you get a gold star if you can say it three times fast and correctly; I'm still working on that.) Research has shown that ipilimumab is effective in neutralizing the CTLA-4 shields, thereby allowing the T cells to do their work.

However, the issue was whether the therapy could be targeted so that healthy and desirable cells would not also be attacked by our own T cell defense system. At least two approaches look promising, but Dr. Kwon has been involved in combining hormonal therapy with ipilimumab. In essence, hormonal therapy causes T cells to go to prostate cells, both healthy and cancerous. Ipilimumab lowers the shields so that the cells may be wiped out by the T cells.

Ipilimumab therapy for prostate cancer has already successfully completed Phase I and Phase II trials, and the outcome was a robust response to the therapy. Two Phase III trials for patients with castration resistant prostate cancer (meaning that hormonal therapy can no longer control the cancer) are now well underway. Ipilimumab may also work well for prostate cancer patients with much more favorable disease. In one of the trials involving patients preparing for RPs, there was a 70% to 100% response among 73 of 108 patients. It is thought that ipilimumab may enable some patients who have cancer that is too extensive for local therapy to downstage their cancer so that local therapy will work!

So, what's the rub? Some of the earlier work showed that multiple doses of ipilimumab for melanoma resulted in "autoimmune toxicity" - a number of undesirable side effects, but all were corrected with steroids while keeping the desirable immune system response. That said, some of those effects are potentially fatal. However, single dose ipilimumab appears to be "extremely tolerable", and also effective for prostate cancer. Those Phase III trial results should tell us what we need to know, and hopefully we will get the results soon; my impression was that we may get the results this year.

Here's another very encouraging point: combination therapy, especially with GM-CSF (already a player with the drugs Leukine® and Provenge®) "markedly improves the overall antitumoral effectiveness of CTLA-4 blockade." (Houston 2006, Urol Oncol).

The latter paper was published as
Urol Oncol. 2006 ; 24(5): 442–447. Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy
for the treatment of prostate cancer
R. Houston Thompson, M.D.a, James P. Allison, Ph.D.b, and Eugene D. Kwon, M.D.

The paper precedes some of the later findings, but it is available for free in complete form from PubMed (www.pubmed.gov, a site we can use on the board because it is Government sponsored), and the paper is very helpful in understanding the technology.

I'm thinking that years from now we are going to see the advent of ipilimumab as a grand slam home run!

Take care all,

Jim

Last edited by IADT3since2000; 03-26-2011 at 09:24 AM. Reason: Added brand name Yervoy® shortly after initial posting.

 
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Old 03-26-2011, 02:47 PM   #2
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Re: Ipilimumab - great advance likely (IMPaCT Conference, FDA approval)

Jim,
That is indeed exciting news! I loved your comparison to "Independence Day"! There was one point I wasn't clear on that perhaps you can explain. You said:

Quote:
However, the issue was whether the therapy could be targeted so that healthy and desirable cells would not also be attacked by our own T cell defense system. At least two approaches look promising, but Dr. Kwon has been involved in combining hormonal therapy with ipilimumab. In essence, hormonal therapy causes T cells to go to prostate cells, both healthy and cancerous. Ipilimumab lowers the shields so that the cells may be wiped out by the T cells.
If hormone therapy causes T cells to be attracted to both healthy and cancerous cells, wouldn't that increase the risk of an autoimmune response?

My other question, especially if ipilimumab is eventually used for early stage disease, is how does it penetrate the notoriously dense an somewhat impermeable prostate? I know that radiation and infection can increase the porosity of the prostate. (Some of the novel cures in lab studies involve attaching cancer-killing drugs to known prostate-infecting microbes.) How can they get the ipilimumab to where it's most needed?

Was there any indication of the cost of treatment? I'll bet it costs almost as much as my anticipated lottery winnings.

- Allen

 
Old 03-26-2011, 04:25 PM   #3
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Re: Ipilimumab - great advance likely (IMPaCT Conference, FDA approval)

Hi Allen,

I'll insert what I know and thoughts in green.


Quote:
Originally Posted by Tall Allen View Post
Jim,
That is indeed exciting news! I loved your comparison to "Independence Day"! There was one point I wasn't clear on that perhaps you can explain. You said: "However, the issue was whether the therapy could be targeted so that healthy and desirable cells would not also be attacked by our own T cell defense system. At least two approaches look promising, but Dr. Kwon has been involved in combining hormonal therapy with ipilimumab. In essence, hormonal therapy causes T cells to go to prostate cells, both healthy and cancerous. Ipilimumab lowers the shields so that the cells may be wiped out by the T cells."

If hormone therapy causes T cells to be attracted to both healthy and cancerous cells, wouldn't that increase the risk of an autoimmune response?
My impression is that ipilimumab would attack both cancerous and healthy prostate cells. For someone like me, who has never had radical therapy, either surgery or radiation, that could cause loss of prostate function that I now have. However, for someone who has had an RP, essentially there would be nothing left to lose. I suppose that an RT veteran would be somewhere in between, but much closer to my end of the scale than an RP veteran. I don't feel expert in this area, though I have some basis for this view.

Quote:
My other question, especially if ipilimumab is eventually used for early stage disease, is how does it penetrate the notoriously dense an somewhat impermeable prostate? I know that radiation and infection can increase the porosity of the prostate. (Some of the novel cures in lab studies involve attaching cancer-killing drugs to known prostate-infecting microbes.) How can they get the ipilimumab to where it's most needed?
Good question! As a monoclonal antibody, I would think it could go where other antibodies are able to go. My impression is that ipilimumab could penetrate the prostate, but, again, my knowledge here is a bit shaky.


Quote:
Was there any indication of the cost of treatment? I'll bet it costs almost as much as my anticipated lottery winnings.

- Allen
I'm wondering about that too. Provenge® costs $93,000 plus associated hospital costs, but ipilimumab involves just pills that do not require the sophisticated processing of blood from the patient. Also, it looks like this drug may have very wide application to many cancers, as it involves making T cells more effective, so the developer may feel that its development cost can be spread over a wide base, permitting a lower cost. However, I'm just speculating, and the costs may be high. The thalidomide I sometimes take is also just a pill, but the makers charge my insurer thousands of dollars for a one month supply; Revlimid®, a drug similar to thalidomide but newer, is extremely expensive, and it too is "just a pill". I hope that one of us will be able to come up with some cost information.

Take care,

Jim

 
Old 03-26-2011, 05:29 PM   #4
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Re: Ipilimumab - great advance likely (IMPaCT Conference, FDA approval)

Hi Allen,

I'm sad to say that you were not far off in your cost estimate. It turns out the drug is not a pill but is given by infusion. You wrote:


Quote:
Originally Posted by Tall Allen View Post
...Was there any indication of the cost of treatment? I'll bet it costs almost as much as my anticipated lottery winnings.

- Allen
A reporter for the Washington Post, Rob Stein, who often covers prostate cancer, wrote: Bristol-Myers said it would charge $120,000 for a complete course of treatment, four infusions given over thee months."

Ouch!

Jim

Last edited by IADT3since2000; 03-26-2011 at 05:31 PM. Reason: Just color of text.

 
Old 03-27-2011, 04:32 AM   #5
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Re: Ipilimumab - great advance likely (IMPaCT Conference, FDA approval)

Here's another thought about the likely cost of ipilimumab, first with an excerpt from my last post here:

Quote:
Originally Posted by IADT3since2000 View Post
A reporter for the Washington Post, Rob Stein, who often covers prostate cancer, wrote: Bristol-Myers said it would charge $120,000 for a complete course of treatment, four infusions given over thee months."

Ouch!

Jim
The reporter is likely basing that on the approval for metastatic melanoma. I'm thinking, based on what I've heard and read, that just one infusion would be used for prostate cancer. That would probably bring the cost down to $30,000 - still very expensive, but more in reach for our copays and the health care system. However, I hope we will hear something solid in the next few months.

Take care,

Jim

 
Old 03-28-2011, 04:45 AM   #6
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Re: Ipilimumab - great advance likely (IMPaCT Conference, FDA approval)

I'm glad to see that Mayo is pursuing some of these advanced treatments. When I was looking for an oncologist for possible administration of triple hormone therapy, I researched their site, and could not find any mention. I called and was told I would have to make an appointment to discuss their treatment approaches, so I never found out if they were open to that type of therapy. My impression, however, was that they were not.

The local oncologist I was referred to stubbornly refused to consider triple hormone therapy. Interestingly, when I resisted his antiquated suggestions, he advised that I should see his pal Dr. Kwon. I looked him up (since I couldn't call and get information) and he did not appear any more open to triple hormone therapy than my oncologist, so I instead went to Dr. Scholz.

I would have liked to go to Mayo, as it is less than two hours away from my house, and a pretty drive at that. But, like PCa, their defenses appear to be impenetrable to discovery by mere patients.

Thanks for letting us know about this new development.

Tom

 
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Old 03-28-2011, 07:27 AM   #7
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Re: Ipilimumab - great advance likely (IMPaCT Conference, FDA approval)

RESISTANCE TO TRIPLE ADT

Hi Tom,

Thanks for writing about your experiences with the Mayo Clinic and your local oncologist. In the just previous post, you wrote in part:


Quote:
Originally Posted by Gleason9 View Post
...

The local oncologist I was referred to stubbornly refused to consider triple hormone therapy. Interestingly, when I resisted his antiquated suggestions, he advised that I should see his pal Dr. Kwon. I looked him up (since I couldn't call and get information) and he did not appear any more open to triple hormone therapy than my oncologist, so I instead went to Dr. Scholz.

I would have liked to go to Mayo, as it is less than two hours away from my house, and a pretty drive at that. But, like PCa, their defenses appear to be impenetrable to discovery by mere patients.

...
Been there! Done that too!

I raise the topic of intermittent triple androgen deprivation therapy (IADT3) with doctors treating prostate cancer whenever I get the chance, including at conferences I attend as a survivor representative (no enrolled medical education). That has included FDA meetings of its Oncologic Drugs Advisory Committee, annual meetings of the American Association for Cancer Research, two IMPaCT conferences highlighting results from prostate cancer research managed by the Department of Defense for Congress, research proposal review sessions for the DoD sponsored research, the conferences in the series known as the National Conferences on Prostate Cancer, and our own education and support group sessions when we have doctors come to speak.

I tend to get two reactions in most of these settings. One is interest, and often surprise at how well I have done myself. The other is stubborn resistance, often with some emotion, and a reluctance or unwillingness even to hear about the therapy. That appears similar to what you encountered. In sharp contrast, many of the experts at the National Conferences on Prostate Cancer, which are often moderated and organized by leading medical oncologists who specialize in prostate cancer, are often quite interested and receptive, even if they do not use IADT3 themselves. The key organizers of these conferences are all experts in IADT3 and use it regularly, though tailoring hormonal therapy to the particular patient's needs.

What I've found is that those doctors who have used ADT3 with a number of patients have come to like it a lot and go on to use it frequently. Those who have never used it are the ones most adamant in saying it will do no good. I'm not pleased with that unthinking and ignorant reaction , but some in that stubborn group are talented and thinking doctors when they are using other approaches.

Take care,

Jim

 
Old 03-30-2011, 10:50 AM   #8
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Re: Ipilimumab - great advance likely (IMPaCT Conference, FDA approval)

I've just been reading about another monoclonal antibody that may be useful. XGEVA (Denosumab) was originally developed as an anti-osteoporosis drug, but also slows down the appearance of bone mets in advanced PC. In the '147 clinical trial, recently completed, XGEVA increased the bone metastasis-free survival by 4.2 months and prolonged the time to first occurrence. This was among men with hormone-refractory disease and rapidly rising PSA. FDA approved it for prevention of bone mets from any solid tumor in November 2010. Amgen is seeking FDA approval for the specific PC use as well.

 
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