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Author Topic: PD-1 antibody experiments show great results.  (Read 15604 times)

0 Members and 1 Guest are viewing this topic.

Offline bimazek

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PD-1 antibody experiments show great results.
« on: September 17, 2007, 04:39:03 AM »
explosion of articles and research on PD-1 and CD8 in 2007 after the big discoveries on PD-1 and CD8 exhaustion in 2006

i did a search on google scholar all peer reviewed science for ...
PD-1 and CD8 HIV in 2007 only articles

dozens of amazing finds in many areas...

this one jumps out because it says that the exhaused cd8 cell because of PD-1 activation would be a major causative effect in shingles and all herpes major attacks in hiv guys...

CD8 T cells and latent herpes simplex virus type 1: keeping the peace in sensory ganglia
BS Sheridan, JE Knickelbein, RL Hendricks - Expert Opinion on Biological Therapy, 2007 - Expert Opinion
... do not express the inhibitory receptor PD-1 observed on exhausted memory CD8 + T
cells in the context of chronic LCMV infection in mice and HIV infection in ...


Treatment of chronic viral infection: tackling the problem from a new angle - all 3 versions »
CM Filippi, MG von Herrath - Future, 2007 - Future Medicine
... PD)-1 expression is associated with HCV-specific CD8 + T-cell ... block the IL-10 signaling
pathway and PD-1/PD-L1 ... in humans, such as HCV and possibly HIV or CMV. ...
Web Search
http://www.futuremedicine.com/doi/pdf/10.2217/17460794.2.2.119?cookieSet=1

IL-10 receptor blocker antibody repairs mouse and they gained weight in study, dev. anti-viral response

this is a major major article... every hiv researcher should read this... this is out of la jolla california...

they propose that anti-PD-1 would be a major anti viral success and treatments should be found asap for anti-pd-1 for hiv etc

they kind of look gay to me in the above pic.




this is PD-1 !!! artice says is great to block to treat cancer and hiv possibly
http://www.springerlink.com/content/63g3718nt0112023/

this article from denver is amazing.. it almost says that PD-1 is the key
... well  wow wow here...
read the first sentance ten times till u fully take it in.. 
then they say  "blockade of the PD-1 pathway restores HIV-specific CD4+ and CD8+ T cell function in HIV infection. "   that sounds frigken good to hear   restores restores HIV-specific CD4+ AND CD8+ T cell function
i am so excited...
http://www.jimmunol.org/cgi/content/abstract/179/3/1979
Functional impairment of HIV-specific CD4+ T cells during chronic HIV infection is closely linked to viral replication and thought to be due to CD8 T cell exhaustion. Programmed death 1 (PD-1) has been linked to T cell CD8 exhaustion and dysfunction in chronic viral infections, and blockade of the PD-1 pathway restores HIV-specific CD4+ and CD8+ T cell function in HIV infection. This study extends those findings by directly examining PD-1 expression on virus-specific CD4+ T cells. To investigate the role of PD-1 in HIV-associated CD4+ T cell dysfunction, we measured PD-1 expression on blood and lymph node T cells from HIV-infected subjects with chronic disease. PD-1 expression was significantly higher on IFN-{gamma}-producing HIV-specific CD4+ T cells compared with total or CMV-specific CD4+ T cells in untreated HIV-infected subjects (p = 0.0001 and p < 0.0001, respectively). PD-1 expression on HIV-specific CD4+ T cells from subjects receiving antiretroviral therapy was significantly reduced (p = 0.007), and there was a direct correlation between PD-1 expression on HIV-specific CD4+ T cells and plasma viral load

PD-1 expression on HIV-specific CD4+ T cells from subjects receiving antiretroviral therapy was significantly reduced

can someone with access get in to read the whole article... esp. conclusions
http://www.jimmunol.org/cgi/content/abstract/179/3/1979


The obvious question is why...


Human immunodeficiency virus (HIV)ndashspecific CD4+ T cell cytokine secretion is characteristically weak during HIV infection, in part because HIV-specific CD4+ T cells undergo massive apoptotic deletion. Glucocorticoid-induced tumor necrosis factor (TNF) receptor familyndashrelated (GITR) protein triggering enhances murine antigen-specific T cell cytokine secretion by protecting T cells from apoptosis.
http://www.journals.uchicago.edu/cgi-bin/resolve?id=doi:10.1086/518613&erFrom=7477301438149857204Guest


http://www.springerlink.com/content/v6q1x341jj442350/
one more

i dont have time to read the hundreds of PD-1 discoveries in 2007 got to go to bed

bimazek

Offline bimazek

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Re: PD-1 Research
« Reply #1 on: September 17, 2007, 04:40:50 AM »

Offline bimazek

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Re: PD-1 Research
« Reply #2 on: September 17, 2007, 04:47:08 AM »
june 2007
basically what this says is revolutionary... it says even after treatment with haart and low low zero viral load people the immune system DOES NOT bounce back WHY because PD-1 is still to high and must be treated
this is revolutionary, this means all the guys with 100 or 35 or 175 or low low t cells who are not reconstituting it is because of PD-1... this is earth shattering and means drastic actions must be taken IMMEDIATELY to try to save guys... there is only one company in world that has an anti-PD-1 antibody and they are trying it only on cancer patients  !!! we have dying hiv patients and this may save them... we need to take up letter writing.

We found raised levels of PD-L1 in aviraemic chronically infected HIV-1-positive patients, which may contribute to incomplete immune reconstitution after treatment with HAART.

June 2007, 21:10 > Expression of PD-L1, a marker of...
   
   Expression of PD-L1, a marker of disease status, is not reduced by HAART in aviraemic patients.

    Research Letters
    AIDS. 21(10):1379-1381, June 2007.
    Rosignoli, Guglielmo a; Cranage, Alison a; Burton, Catherine a; Nelson, Mark b; Steel, Alan b; Gazzard, Brian b; Gotch, Frances a; Imami, Nesrina a

    Abstract:
    Anergy and defective immune responses are characteristic of chronic HIV-1 infection. The programmed death 1 (PD-1)/PD-1 ligand (PD-L1) pathway appears to be involved in downregulating T-cell functionality. We found raised levels of PD-L1 in aviraemic chronically infected HIV-1-positive patients, which may contribute to incomplete immune reconstitution after treatment with HAART.


http://www.aidsonline.com/pt/re/aids/abstract.00002030-200706190-00025.htm;jsessionid=GnzV2YsB1jNvnDzR0ZlpzJJ2yJvHjgV2j1hT251hQj7mJSqWRTcM!-1754492629!181195629!8091!-1

Offline bimazek

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Re: PD-1 Research
« Reply #3 on: September 17, 2007, 04:48:33 AM »
http://bloodjournal.hematologylibrary.org/cgi/reprint/109/11/4593
this is a major article on pd-1 and hiv

with complex chart

Offline bimazek

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Re: PD-1 Research
« Reply #4 on: September 17, 2007, 04:51:29 AM »
Immunologic Memory - all 2 versions »
V IMMUNOLOGY - VIRAL IMMUNOLOGY, 2007 - liebertonline.com
... This was supported by Rafick-Pierre Sékaly (Uni- versity of Montreal, Montreal,
QC, Canada), who showed that PD-1 is upregulated on HIV-specific CD8 T cells ...
Web Search

Rafick-Pierre Sékaly (Uni- versity of Montreal

this guy in montreal is one of the top top researchers and he is working with harvard dr walker

tim can you get up there and meet him

this could save the guys whose immune system will not bounce back

it is a beautiful train ride from NYC to montreal

please please take a meeting


Offline bimazek

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Offline bimazek

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Re: PD-1 Research
« Reply #6 on: September 17, 2007, 05:01:50 AM »
Session 4: Initiation and potentiation of antiviral immunity
A Options, TOC Latest - Immunology, 2007 - ingentaconnect.com
... PD-1 expression which might con- tribute to this. The consequences for the T cell -
Death or Glory - will be discussed in the context of HIV and HCV. IS21 CD8 ..

Offline newt

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Re: PD-1 Research
« Reply #7 on: September 17, 2007, 06:49:15 AM »
Revolutionary is a strong word..

what the letter says is that PD-L1 (er, "programmed death ligand 1") is higher in "aviraemic chronically infected HIV-1-positive patients, which may contribute to incomplete immune reconstitution after treatment with HAART".

See also:

HIV 'switches off' immune cells (BBC)

How HIV 'exhausts' killer T cells (Eureka)

How HIV 'burns out' the human immune system (New Scientist)

Not a great fan of NS, but it does report the effect on PD-1 expression by CD8 cells well:

"Walker and his collaborators examined CD8 cells from 71 untreated HIV-positive patients in Durban, South Africa. They found that the more virus the patients had in their bodies, the more PD-1 they had on their CD8 cell surfaces.

"But when Walker massively suppressed the amount of virus circulating in their blood by giving the patients antiretroviral drugs, the amount of PD-1 on their CD8 cells went down too, suggesting that the two rise and fall in tandem.

"The same phenomenon was demonstrated in 19 North American individuals by a team led by Rafick-Pierre Sekaly at the Central Hospital of Montreal in Canada."

I'll come back in 5-10 years.

If anything, this adds (a little) weight to the growing body of evidence pointing in the direction of earlier rather than later treatment.

- matt

PS - the title of your thread is inaccurate, the immune system does bounce back with treatment in many, many respects
« Last Edit: September 17, 2007, 06:51:07 AM by newt »
"The object is to be a well patient, not a good patient"

Offline Tim Horn

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Re: PD-1 Research
« Reply #8 on: September 17, 2007, 07:42:34 AM »
Bim:

I've locked the other PD-1 thread started by you; it simply wasn't necessary to start a second thread regarding this subject -- this is spamming.

As Newt has been kind enough to address your questions(?) -- and God bless him for it -- I won't go into any detail here. However, I think you're making this into something much larger than it really is.

For starters, these studies show an ASSOCIATIVE, not a CAUSATIVE , relationship between levels of PD-1 and immune suppression.

Second, Bim, we don't need to take up letter writing. Fact of the matter is, researchers ARE looking at monoclonal antibodies targeting PD-1 as a potential therapy for HIV infection. We've seen data in mice and now we're seeing studies involving rhesus macaques. This, Bim, is the way all new agents are studied -- first in laboratories, then in animals, and eventually moving into human studies... if animal studies suggest that the new agent is reasonably effective and safe. For the record, there's ALWAYS an exciting patchwork of basic science papers supporting the exploration of virtually every drug we've seen enter human studies for the treatment of HIV -- many of which failed to pan out. 

Third, I should point out one of the important findings in one of the studies involving mice. While the monoclonal antibody helped to revive exhausted CD4 cell responses in the rodents with lymphocytic choriomeningitis virus (LCMV, a basic model of HIV infection in mice), it also triggered autoimmunity -- a dangerous situation in which the body's immune system starts attacking itself. And when there's such potentially dangerous "writing on the wall" in animal studies, we are reminded of the fact that many, many "potentially promising" HIV treatment approaches have the ability to do more harm than good... and that the drug discovery process is slow and cautionary for this reason alone.

I'm with Newt, Bim... why don't we talk about this five years from now, if and/or when this approach actually makes it into human HIV studies.

Tim Horn

Offline Customer

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  • Posts: 98
Re: PD-1 Research
« Reply #9 on: September 17, 2007, 12:08:36 PM »

This kind of news bring a lot of hope... it could be revolutionary, but than again, its too early to say.

Here is an image of PD-1: Programmed cell death protein 1 precursor (Protein PD-1) (hPD-1).
http://www.nysgrc.org/img/upload/T749-PD-1.jpg

Some info on PD-1

http://en.wikipedia.org/wiki/PD-1
http://en.wikipedia.org/wiki/Transmembrane_protein
http://en.wikipedia.org/wiki/Biological_membrane



A biological membrane or biomembrane is an enclosing or separating tissue which acts as a barrier within or around a cell. It is, almost invariably, a lipid bilayer, composed of a double layer of lipid-class molecules.

A transmembrane protein is a protein that spans the entire biological membrane.

PD-1 is a Type I transmembrane protein containing a single IgV domain and a transmembrane region followed by a cytoplasmic tail containing an immunoreceptor tyrosine-based inhibitory motif and immunoreceptor tyrosine-based switch motif2. 

PD-1 was originally isolated from apoptotic 2B4.11 T cells stimulated to undergo apoptosis by treatment with PMA. PD-1 is homologous to CTLA-4, CD28, and ICOS, but unlike these co-stimulatory molecules, does not dimerize.


Offline powerpuff

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Re: PD-1 Research
« Reply #10 on: September 17, 2007, 02:09:08 PM »
thats the pd1 i was researching too sounded promising

Offline Ann

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  • It just is, OK?
    • Num is sum qui mentiar tibi?
Re: PD-1 Research
« Reply #11 on: September 17, 2007, 03:05:19 PM »
powerpuff,

Again, I'll remind you of what Tim Horn has said to you:

http://forums.poz.com/index.php?topic=15584.msg197429#msg197429

I'm giving you a time out. To understand what this means, read the Welcome thread.

Ann
Condoms are a girl's best friend

Condom and Lube Info  



"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

Offline Miss Philicia

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  • Posts: 24,511
  • celebrity poster, faker & poser
Re: PD-1 Research
« Reply #12 on: September 17, 2007, 03:44:24 PM »
[
PS - the title of your thread is inaccurate, the immune system does bounce back with treatment in many, many respects[/font]

It would be nice if this particular poster took more care with such things -- I imagine a thread title like this can upset our "guest" members and assorted newly diagnosed folks.  It's certainly not the first infraction like this, unfortunately.  In fact there is a distinct trend and I'm amazed how it's allowed to go on... and on... and on.
"I’ve slept with enough men to know that I’m not gay"

Offline Tim Horn

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Re: PD-1 Research
« Reply #13 on: September 17, 2007, 04:26:06 PM »
In fact there is a distinct trend and I'm amazed how it's allowed to go on... and on... and on.

Philly:

I really don't understand what you mean by this. There's really no moderator penalty for starting or engaging in scientific conversations that are, perhaps, much deeper and more complex than one believes them to be. Matt stepped in to correct him and that's what really matters here. 

Tim 

Offline Miss Philicia

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  • celebrity poster, faker & poser
Re: PD-1 Research
« Reply #14 on: September 17, 2007, 05:52:11 PM »
Well Mr. Horn, if you feel like investing a day reading all of bimazek's past posts 98% of which are in the "Research News and Studies" section you'll probably see what I'm talking about.  I could be wildly off base on all of this, but I'm hardly the first person to make this observation.
"I’ve slept with enough men to know that I’m not gay"

Offline bimazek

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  • Posts: 781
Re: PD-1 Research
« Reply #15 on: September 18, 2007, 02:32:49 AM »

if you go to
advanced google scholar search

http://scholar.google.com/advanced_scholar_search?hl=en&lr=

and type in PD-1 and HIV and limit the search to each year of the last 12 years as i have done
you will see that 2007 is a big year of new papers as science rushes to publish on this..

in 2006 only 167 articles

in 2007 146 already

i did this year by year from the first articles about just PD-1 with out hiv and with hiv

the point is

this is a big issue

i have not had time in all 2007 to do any good research on this so i was surprised

the point of this specific new article and many other posts is

there is a protein or inhibitory signal that is keeping PD-1 high even when zero viral load with haart

there is only one fda approved at least for phase 2 trials for a anti-pd-1 monoclonal anti body and they are currently treating humans with it for melanoma i believe...

the company is looking to move into other area

what is interesting is the new discoveries

i am kind of tired... phillly ... the front page of this site has headlines ...

HIV Damages Brain Despite Treatment
     
   High Risk of Peripheral Artery Disease in HIV

i dont think my highly scientific post are going to scare newbies, in fact i have been posting cause so many hiv-ers i met when i found out talked about a conspiracy of holding back treatment and a cure

which i know is completely impossible

the question is still out there, why is PD-1 high when viral load is low or zero, there is either a protein like gag or  some other protein that is produced by latent dendric cells or some surface change in T or B or dendric cell that is keeping PD-1 turned on and in the up reg state, telling cd8 to stop working

i am poz for two years still not on meds and many days completely fine, then there is a viral escape, or i dont get enough sleep and i am like pulled down fast, i have to take perfect care of everything and still my cd4s are slowly going away from 592 a year ago to 492 etc now and even lower

if the cocktail completely supresses the viral load then in large majority peoples immune system restores and redev.s much much better than science ever thought could happen

but in some indiv. this does not happen, and the PD-1 is... well i am tired of writing about it

actually i think dentric cell stimulated vaccines and such are much more promising and vaccines in general are so so close now

philly i wish you could forgive me for being against poppers and just be civil, i certainly never did anything to purposefully cause any one suffering or pain infact just the opposite

i post to give my self hope and others

to me the cocktail is still very scary and unknown

i have never put one of those pills in my mouth i will immediately if i get to 350 t cells as is recommended

i have lost countless lovers, boyfriends, best friends, mentors, etc to death by this disease

cant i be a little exhuberant now and then


Offline bimazek

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Re: PD-1 Research
« Reply #16 on: September 18, 2007, 02:39:47 AM »
one more quick thing, the reason i post alot about pd-1 is because when i found out i was poz one year ago about

it was a big news item so i happened to do alot of digging into it and i was writing for a gay paper and they said they would do a big article then they didnt have space cause money issues, so i had done all this research and called all these scientists and they were very excited, i am taking the guy under the guy in montreal that others say is one of the best virologist in world and talked to phd md at harvard under dr walker and these guys were very excited and expressed it too me

so i didnt have space, the gay paper didnt want to do big hiv research stories

so i got pulled in here

again i appologize if i offend anyone, i think of science as a great exciting game of search and weaving threads together, i can see how others can feel frightened by the uncertainty


Offline newt

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  • the one and original newt
Re: PD-1 Research
« Reply #17 on: September 18, 2007, 04:40:05 AM »
Perhaps the key recent paper on PD-1 was in Nature Medicine in 2006: Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction (link to abstract) + a series of related papers.

Title says it all really...this is not big news to me, just a clarification of one detail of something known for a long time, that somehow HIV hijacks the CD4+/CD8+ dynamics of the immune system.

I agree it is interesting basic science. Walker, the key Howard Hughes' researcher, has pointed out we don't really know the role of the PD-1 pathway right now, and his greatest hope is that it might soon become an additional diagnostic marker.

As for turning this into treatment, monoclonal antibody technology is fraught.  A monoclonal antibody study was stopped (dramatically, with much press hoo haa) in the UK this year because most of the participants got a severe (life-threatening) auto-immune reaction.  This is, unfortunately, a typical feature of experimental monoclonal antibody therapies at present. 

There were many, many more scholarly articles on CCR5 co-receptors (perhaps topic du jour) & resistance than PD-1 published in the last 5 years, many more.

- matt
"The object is to be a well patient, not a good patient"

Offline messer

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Re: PD-1 Research
« Reply #18 on: September 18, 2007, 10:45:21 AM »
Another interesting article was published in the Journal of Virology, titled" Elevated Expression Levels of Inhibitory Receptor Programmed Death 1 on Simian Immunodefiency Virus Specific CD-8 T-Cells during Chronic Infection but Not after Vaccination".   
The research was done Emory University using a DNA/MVA vaccine.   The researchers submitted the article in January and it was published March 21, 2007.   

   






Offline Customer

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  • Posts: 98
Re: PD-1 Research
« Reply #19 on: September 18, 2007, 11:56:16 AM »
Bimazek, atleast i found this thread interesting. But let's not start a new thread for each comment.
 
http://www.jem.org/cgi/content/full/jem;203/10/2223 (Published online 25 September 2006)

Concluding remarks
The reports by Petrovas et al. (23), Day et al. (24), and Trautmann et al. (25) suggest that blocking PD-1–PD-L interactions may be a therapeutic strategy for HIV infection that could allow the reactivation of anti-HIV T cell responses. Because this pathway has an important role in regulating the balance between T cell activation and tolerance, it will be important to identify the optimal timing and frequency of therapy to minimize the risk of immunopathology or autoimmunity. The effects of blocking only PD-1, PD-L1, or PD-L2 or a combination thereof will need to be evaluated for efficacy and safety. It might also be beneficial to combine PD-1 blockade with antiviral therapy or therapeutic vaccination. In particular, since the therapeutic effects of interferons may be limited by the induction of PD-1 ligands, there may be synergistic benefits of PD-1 blockade in conjunction with interferon therapy. Further studies are needed to investigate to what extent, and for how long, PD-1–PD-L blockade can restore different effector functions, particularly cytolysis.


http://brasilmilhaodollarwebsite.com/tinc?key=MODXjUCj&id=1

this is the best news of all because it can take a decade to create a new drug and another decade to approve it, there is already a anti-PD-1 monclonal antibody molecule that has been approved for another use that will fit in the keyhole and turn the CD8 cell back on!  Researchers are hoping to start larger HIV trials in Montreal and in Boston at Harvard's Massachusetts General Hospital by Christmas.  One company in New Jersey has MDX-1106 the anti-PD-1 antibody already in existence.

The biotech company Medarex does research and drug development in New Jersey and has developed a fully human anti-PD-1 monoclonal antibody for the treatment of cancer. Medarex President and CEO Dr. Donald L. Drakeman believes that MDX-1106 (the anti-PD-1 antibody) is part of an emerging new group of immunopotentiators -- antibodies that target immune regulatory pathways, such as CTLA-4, PD-1 etc. that are designed to boost a patient's immune response to eliminate cancer and chronic [viral] infections.  Shockingly, Medarex has no plans and is not presently planning on doing any trails for this new immunopotentiator on HIV patients only on cancer patients. Currently, MDX-1106 the anti-PD1 is in Phase I Cancer trails.   


« Last Edit: September 18, 2007, 02:06:58 PM by Customer »

Offline hahaha

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Re: PD-1 Research
« Reply #20 on: September 19, 2007, 12:48:29 AM »

 such as CTLA-4, PD-1 etc. that are designed to boost a patient's immune response to eliminate cancer and chronic [viral] infections.  Shockingly, Medarex has no plans and is not presently planning on doing any trails for this new immunopotentiator on HIV patients only on cancer patients. Currently, MDX-1106 the anti-PD1 is in Phase I Cancer trails.   


It is quite a "Shocking", isn't it? 

Cancer patient's market obviously is bigger than the HIVer. 
And no one write to Medarex for the protest? 
Aug 9, 2006 Get infected in Japan #$%^*
Oct 2006 CD4 239
Nov 2006 CD4 299 VL 60,000
Dec 1, Sustiva, Ziagan and 3TC
Jan 07, CD4 400

Offline Tim Horn

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Re: PD-1 Research
« Reply #21 on: September 19, 2007, 09:11:46 AM »
haha:

Instead of first sounding the protest alarm -- and I do think this is premature, basing it entirely on a lay media report -- I suggest that you do some homework first. Call Madarex and ask to speak with Nils Londberg, PhD, the company's scientific director, to discuss this.

The fact is, Medarex is a relatively small biotech firm. It may simply be lacking in resources to explore this antibody-based therapy for the much larger, potentially much more lucrative HIV market. Like other biotechs, Medarex may simply be waiting for a larger pharmaceutical company to purchase the rights to the drug and explore it further. And that's just one possibility.

You can't "protest" without all of the available information.

Tim Horn 

Offline Customer

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Re: PD-1 Research
« Reply #22 on: September 19, 2007, 10:46:58 AM »

http://www.eurekalert.org/pub_releases/2006-08/hhmi-hh081706.php
"Walker said that scientists know little about the evolutionary purpose of a pathway that would deactivate such an important component of the immune system in the face of a viral attack. "It may be that in the heat of a battle that it sees it's not winning, the body makes an adjustment to try to co-exist," he said. "But we really do not know at this point." "

This excerpt raised a quiestion. Do we even know that it is  the HIV who is actively switching T-cells of? What if it is the body own autoimmune system? Does the virus have to tools to switch off T-cells?


Offline hahaha

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Re: PD-1 Research
« Reply #23 on: September 19, 2007, 01:36:47 PM »
haha:

Instead of first sounding the protest alarm -- and I do think this is premature, basing it entirely on a lay media report -- I suggest that you do some homework first. Call Madarex and ask to speak with Nils Londberg, PhD, the company's scientific director, to discuss this.

The fact is, Medarex is a relatively small biotech firm. It may simply be lacking in resources to explore this antibody-based therapy for the much larger, potentially much more lucrative HIV market. Like other biotechs, Medarex may simply be waiting for a larger pharmaceutical company to purchase the rights to the drug and explore it further. And that's just one possibility.

You can't "protest" without all of the available information.

Tim Horn 

Dear Tim,
May be you are right.   I am just a self-centered bitch without inquiring further information and jump to the conclusion....... Maybe it is because I am an HIVer, so deep down I am depressed and desperate and afraid to die........
Aug 9, 2006 Get infected in Japan #$%^*
Oct 2006 CD4 239
Nov 2006 CD4 299 VL 60,000
Dec 1, Sustiva, Ziagan and 3TC
Jan 07, CD4 400

Offline bimazek

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The road to recovery: translating PD-1 biology into clinical benefit. 2006
« Reply #24 on: September 26, 2007, 05:57:41 PM »
Milker or another PhD type. I Was wondering if you could get the full text of this article i just found.  I dont have access until they release it for free.

 Trends Immunol. 2007 Feb;28(2):48-50. Epub 2006 Dec 22.Click here to read Links
    The road to recovery: translating PD-1 biology into clinical benefit.
    Riley JL, June CH.

    Abramson Family Research Cancer Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

    Negative immune regulation can result in the poor control of virus replication in chronic infections but is probably important to prevent tissue damage from chronic immune activation. Three recent studies have shown that programmed cell death (PD)-1 expression on T cells correlates with viral load in HIV infection, and that interrupting PD-1 signaling using an antagonistic antibody rejuvenates T-cell effector functions in vitro. These findings have important implications for potential therapies for chronic infection and, perhaps, for improved tumor immunity. Here, we discuss impending issues in the translation to clinical studies in light of recent adverse events with costimulatory antibody therapy.

Offline Customer

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Re: PD-1 Research
« Reply #25 on: September 27, 2007, 12:18:02 PM »

The trial with TNG1412 antibody was not well planned. Ofcourse, when handling new substance, they should have started with small doses and long dosing intervalls.


http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2006/04/tgn1412_a_cauti.html

In a nutshell, TGN1412 is a monoclonal antibody (essentially a modified version of an antibody derived from a mouse) that was designed to specifically target a molecule called CD28 that is expressed on many T cells. Triggering CD28 activates T cells, meaning they begin a program of multiple divisions (generating many new T cells) and release potent immune system proteins called cytokines.

the most severely affected individual is likely to lose fingers and toes due to damage akin to that seen in frostbite. I... Hopefully some lessons will be learnt from this trial; most glaringly, the almost simultaneous dosing of the participants with an antibody with potentially potent T cell activating properties was a terrible idea. A pause of just an hour or two would have made a huge difference. The company that makes TGN1412, TeGenero, has stated that no causes for concern emerged in animal studies, but this does not address the fact that they could have sought input from more immunologists with experience researching CD28. Many such immunologists, unaware of the trial at the time it was getting underway, have expressed shock that the study was not conducted more carefully given what is known about the molecule.

Offline milker

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Re: PD-1 Research
« Reply #26 on: September 27, 2007, 04:11:33 PM »
Tim can you please have some real science types tell us what all this means...
in terms of finding small molecules vs. monoclonal antibodies for anti-PD-1
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6W7H-4MMP2JJ-1&_user=10&_coverDate=02%2F28%2F2007&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a737418fbd34e6476337c8a3829f36d3
antagonistic antibodies are those that block a specific cell response, as opposed to agonistic antibodies that trigger a specific cell response. So if a monoclonal antibody is generated to block PD-1 response, it will be called antagonistic.

Milker.
mid-dec: stupid ass
mid-jan: seroconversion
mid-feb: poz
mar 07: cd4 432 (35%) vl 54000
may 07: cd4 399 (28%) vl 27760
jul 07: cd4 403 (26%) vl 99241
oct 07: cd4 353 (24%) vl 29993
jan 08: cd4 332 (26%) vl 33308
mar 08: cd4 392 (23%) vl 75548
jun 08: cd4 325 (27%) vl 45880
oct 08: cd4 197 (20%) vl 154000 <== aids diagnosis
nov 2 08 start Atripla
nov 30 08: cd4 478 (23%) vl 1880 !!!!!!!!!!!!!!!!!!!!!!!!!!
feb 19 09: cd4 398 (24%) vl 430 getting there!
apr 23 09: cd4 604 (29%) vl 50 woohoo :D :D
jul 30 09: cd4 512 (29%) vl undetectable :D :D
may 27 10: cd4 655 (32%) vl undetectable :D :D

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Offline Miss Philicia

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Re: PD-1 Research
« Reply #27 on: September 27, 2007, 05:21:49 PM »
Why are there so many PD-1 threads?  I'm getting confused.
"I’ve slept with enough men to know that I’m not gay"

Offline milker

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Re: PD-1 Research
« Reply #28 on: September 27, 2007, 06:55:31 PM »
Interleukin-10 is found on monocytes, and Type 2 helper cells, and inhibits cytotoxic reaction. Blocking IL-10 is yet another concern for autoimmune imbalance and cell exhaustion. Furthermore we don't know what effect IL-10 blockage would have on monocytes. PD-1 and PD-Ligands are new discoveries, and PD-1 blockade in the human body would not be a piece of cake. Also, PD-1 is a costimulation that happens after CD28 and CTLA-4 stimulations. Some costimulations have been thought has beein backups, so blockade of one could trigger other stimulations that are not well known. And although PD-1 is expressed on most CD4s, it's not always expressed on CD8s. Figure b of this picture http://www.nature.com/nature/journal/v443/n7109/fig_tab/nature05115_F1.html shows about 25% of CD8 expressing PD-1.

Bim, research is what it is: research, and programmed cell death and apoptosis (which are related but not equal) are not very well understood yet. I'm not sure that posting every article that relates to PD-1 will help our members. Or at least, please comment on them in a way that triggers discussion. wow wow and omg it's a breakthru does not help. I'm sure Tim knows who to contact if he thinks that he needs more information about a study.

Milker.
mid-dec: stupid ass
mid-jan: seroconversion
mid-feb: poz
mar 07: cd4 432 (35%) vl 54000
may 07: cd4 399 (28%) vl 27760
jul 07: cd4 403 (26%) vl 99241
oct 07: cd4 353 (24%) vl 29993
jan 08: cd4 332 (26%) vl 33308
mar 08: cd4 392 (23%) vl 75548
jun 08: cd4 325 (27%) vl 45880
oct 08: cd4 197 (20%) vl 154000 <== aids diagnosis
nov 2 08 start Atripla
nov 30 08: cd4 478 (23%) vl 1880 !!!!!!!!!!!!!!!!!!!!!!!!!!
feb 19 09: cd4 398 (24%) vl 430 getting there!
apr 23 09: cd4 604 (29%) vl 50 woohoo :D :D
jul 30 09: cd4 512 (29%) vl undetectable :D :D
may 27 10: cd4 655 (32%) vl undetectable :D :D

Now accepting applications from blowjob ninjas™

Offline Tim Horn

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Re: PD-1 Research
« Reply #29 on: September 27, 2007, 07:20:12 PM »
I have merged all of the PD-1 threads in the Research News forum into a single thread. Let's keep this discussion in one thread... and on point, if possible.

Tim Horn

Offline J220

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PD-1 antibody experiments show great results.
« Reply #30 on: December 10, 2008, 11:28:40 PM »
From http://www.sciencedaily.com/releases/2008/12/081210131034.htm .

Blocking Immune Inhibitor Improves Response To HIV-like Virus, Prolongs Survival In Monkeys

ScienceDaily (Dec. 10, 2008) — By blocking PD-1 (programmed death-1), an immune receptor molecule known to inhibit the immune response to chronic viral infections, scientists have safely and significantly reduced the plasma viral load and also prolonged survival of rhesus macaque monkeys severely infected with simian immunodeficiency virus (SIV), the nonhuman primate version of human immunodeficiency virus (HIV). The therapeutic strategy worked by boosting the function of anti-viral killer cells (CD8 T cells) and improving antibody response to the virus.

Scientists at the Yerkes National Primate Research Center of Emory University, the Emory Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School and the University of Pennsylvania Medical School conducted the research, which were recently published in the journal Nature.

"Our findings raise the possibility that PD-1 blocking antibody treatment not only could improve the anti-viral T cell response to chronic HIV infections, but it also could generate an effective antibody response against the mutated virus of the infected host," says Rama Amara, PhD, principal investigator of the study.

"It also is important to note that this therapy was effective without anti-retroviral drugs and in monkeys with severe AIDS. It is critical to induce protective immune responses targeting the mutated virus for developing a successful immune therapy to control HIV infection," Amara continues.

In the current study, which builds on findings from previous studies with mice, the researchers tested the potential of blocking PD-1 to control HIV infection using a macaque monkey model of SIV. They injected nine SIV-infected monkeys with an antibody to human PD-1 four times over 10 days. Gordon Freeman, PhD, of the Dana-Farber Cancer Institute and Harvard Medical School, provided the antibody.

Of the nine animals, five were infected for three months and four were infected for about 21 months at the time of antibody treatment. Another five SIV-infected monkeys received a control antibody at the same dose and schedule. The researchers then tested the function of the anti-SIV killer cells, antibody responses to the virus and plasma viral load.

Results showed that the improved anti-viral immune responses were associated with a reduction in plasma viral load and prolonged the survival of the infected animals. All nine animals receiving the PD-1 antibody survived more than seven months following initiation of treatment (the current time of the study), while four of the five animals receiving the control antibody died within four months following initiation of treatment.

The antibody treatment appeared to be safe and well tolerated. Within seven days of treatment, the number of anti-SIV killer T cells increased significantly and had improved function. This improvement was noted both in the blood and the gut, which is a major repository of SIV and HIV. The PD-1 antibody treatment also increased the proliferation of memory B cells and the level of antibody against SIV, a finding that had not been reported in earlier mouse studies.

"These findings are important not only because they highlight a potential therapy for HIV, but also because of the insights they offer for other challenging chronic infectious diseases such as hepatitis C virus and tuberculosis," says Emory Vaccine Center Director Rafi Ahmed, PhD, who is a Georgia Research Alliance Eminent Scholar. "Through the Grand Challenges in Global Health initiative, which also funded the current study, we soon will begin testing the effectiveness of the PD-1 blockade against HCV in nonhuman primates."

Several years ago, Ahmed and his colleagues discovered that the immune receptor PD-1 essentially functions as a molecular switch to turn off an effective immune response by overwhelming T cells in their fight against chronic viral infections. By injecting an antibody that binds to PD-1 into mice infected with chronic lymphocytic choriomeningitis virus (LCMV), they were able to switch the immune response back on and control the virus. Dr. Ahmed is a co-principal investigator of the current study.

Other studies have since shown that anti-viral CD8 T cells express high levels of PD-1 during many human chronic infections, including HIV, hepatitis C virus and tuberculosis. However, until now the safety and effectiveness of blocking PD-1 in an appropriate animal model for these human viral infections had not been shown.

The current research team plans to continue testing the antibody therapy in combination with anti-retroviral drugs to try and improve its effectiveness. They also will explore the benefits of prolonged treatment (up to three months as opposed to 10 days in the current study). In addition, they are studying the effectiveness of antibodies against PD-1 ligands (target molecules), a strategy that was part of the earlier mouse research.

The National Institutes of Health (NIH), the Bill & Melinda Gates Foundation, the Foundation for the NIH through the Grand Challenges Global Health Initiative, the Yerkes National Primate Research Center and the Emory Center for AIDS Research supported the current research.

First authors of the paper are Vijayakumar Velu and Kehmia Titanji of the Yerkes National Primate Research Center and the Emory Vaccine Center.
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Offline bimazek

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Re: PD-1 Research
« Reply #31 on: December 11, 2008, 02:23:11 AM »
i hate to say i told you so.... but i was right... 

"Our findings raise the possibility that PD-1 blocking antibody treatment not only could improve the anti-viral T cell response to chronic HIV infections, but it also could generate an effective antibody response against the mutated virus of the infected host," says Rama Amara, PhD, principal investigator of the study.    http://www.sciencedaily.com/releases/2008/12/081210131034.htm

"It also is important to note that this therapy was effective without anti-retroviral drugs and in monkeys with severe AIDS. It is critical to induce protective immune responses targeting the mutated virus for developing a successful immune therapy to control HIV infection," Amara continues.
In the current study, which builds on findings from previous studies with mice, the researchers tested the potential of blocking PD-1 to control HIV infection using a macaque monkey model of SIV. They injected nine SIV-infected monkeys with an antibody to human PD-1 four times over 10 days. Gordon Freeman, PhD, of the Dana-Farber Cancer Institute and Harvard Medical School, provided the antibody.
Of the nine animals, five were infected for three months and four were infected for about 21 months at the time of antibody treatment. Another five SIV-infected monkeys received a control antibody at the same dose and schedule. The researchers then tested the function of the anti-SIV killer cells, antibody responses to the virus and plasma viral load.
Results showed that the improved anti-viral immune responses were associated with a reduction in plasma viral load and prolonged the survival of the infected animals. All nine animals receiving the PD-1 antibody survived more than seven months following initiation of treatment (the current time of the study), while four of the five animals receiving the control antibody died within four months following initiation of treatment.
The antibody treatment appeared to be safe and well tolerated. Within seven days of treatment, the number of anti-SIV killer T cells increased significantly and had improved function. This improvement was noted both in the blood and the gut, which is a major repository of SIV and HIV. The PD-1 antibody treatment also increased the proliferation of memory B cells and the level of antibody against SIV, a finding that had not been reported in earlier mouse studies.
"These findings are important not only because they highlight a potential therapy for HIV, but also because of the insights they offer for other challenging chronic infectious diseases such as hepatitis C virus and tuberculosis," says Emory Vaccine Center Director Rafi Ahmed, PhD, who is a Georgia Research Alliance Eminent Scholar. "Through the Grand Challenges in Global Health initiative, which also funded the current study, we soon will begin testing the effectiveness of the PD-1 blockade against HCV in nonhuman primates."
Several years ago, Ahmed and his colleagues discovered that the immune receptor PD-1 essentially functions as a molecular switch to turn off an effective immune response by overwhelming T cells in their fight against chronic viral infections. By injecting an antibody that binds to PD-1 into mice infected with chronic lymphocytic choriomeningitis virus (LCMV), they were able to switch the immune response back on and control the virus. Dr. Ahmed is a co-principal investigator of the current study.
Other studies have since shown that anti-viral CD8 T cells express high levels of PD-1 during many human chronic infections, including HIV, hepatitis C virus and tuberculosis. However, until now the safety and effectiveness of blocking PD-1 in an appropriate animal model for these human viral infections had not been shown.

Offline datdude

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Hopes raised on HIV immune boost
« Reply #32 on: December 11, 2008, 02:24:48 AM »
Scientists believe successful tests in monkeys could prove a step towards a new type of drug to combat HIV.

The journal Nature reports infected animals survived almost twice as long after a single treatment to raise immune response to the virus.

An independent expert said multiple doses were possible, and might eliminate the virus.

Current antiretroviral drugs must be taken for life, giving HIV the opportunity to build up resistance.

  It's possible that multiple doses could eliminate the virus, although the present experiment has not shown that

Professor Thomas Lehner
King's College London

Although millions of people without HIV cannot currently receive them, modern antiretroviral drugs have transformed the life expectancy of people with the infection.

However, scientists are constantly looking for alternative ways to keep the virus in check.

One option is being tested in the US on macaque monkeys infected with "simian immunodeficiency virus" - their equivalent of HIV.

One of the features of HIV is its ability to shut down or impede the body's own methods for clearing viral infections.

In particular, it manages to activate a signalling system in the body's immune cells - which then actually holds back the body's immune response.

The latest treatment works by blocking that signalling system, which has the effect of boosting the function of "killer" immune cells.

The blocking antibody was injected once into nine animals who had developed AIDS after SIV infection, all of whom lived on average almost twice as long as other monkeys who did not receive the treatment.

The treated monkeys had clear signs of more active immune systems and reduction of the amount of virus circulating in their blood, both signs that they were tackling the disease more efficiently.

While the virus was not fully controlled in any of the monkeys, the scientists said that more than one dose was possible, and that it could be used in combination with antiretroviral drugs.

Long wait

Dr Rama Amara, who led the research, said: "It is important to note that this therapy was effective without antiretroviral drugs and in monkeys with severe AIDS.

"It is critical to induce protective immune responses targeting the mutated virus for developing a successful immune therapy to control HIV infection."

Another of the researchers said that the treatment also offered potential against other chronic infectious diseases such as hepatitis C and TB.

Professor Thomas Lehner, an immunologist from King's College London, said that the findings were "very interesting", and that the drug showed potential for human treatment.

He said: "It's possible that multiple doses could eliminate the virus, although the present experiment has not shown that.

"It's my understanding that some groups are already working to test this in humans, and although the safety of the drug is a concern, I see no reason why that should be a problem.

"It's most likely that we will see it used alongside antiretroviral therapy."

Dr Ade Fakoya, from the International HIV/AIDS Alliance, said that the research was "an important avenue" to pursue, particularly as it had managed to extend the lifespan of the monkeys.

However, he said: "There's a long process of many years before this basic research is translated into actual research with the HIV virus in humans and then identifying a way to be able to actively block this on a large enough scale for it to be another useful tool in HIV treatments."

http://news.bbc.co.uk/1/hi/health/7775342.stm

Offline freewillie99

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Re: Hopes raised on HIV immune boost
« Reply #33 on: December 11, 2008, 08:27:35 AM »
Sheesh...now we have three new PD-1 threads about the exact same thing:

"Hope Raised on HIV Immune Boost"

"PD-1 Research"

"PD-1 Antibody experiments show great promise"

Can we get a consolidator here, please?
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Offline veritas

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Re: Hopes raised on HIV immune boost
« Reply #34 on: December 11, 2008, 08:48:15 AM »

Free,

I agree that all the diff threads is confusing. Of course I appreciate the research, but it would be less confusing and redundant if posts on the same research would go to the original thread.

veritas

Offline freewillie99

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Re: Hopes raised on HIV immune boost
« Reply #35 on: December 11, 2008, 10:49:44 AM »
Thought I might add to today's PD-1 cavalcade:

Cut from the TAG (Treatment Action Group) website:

"The salutary outcome in anti-PD-1 recipients was associated with increases in the magnitude and functionality of SIV-specific CD8 T cell responses, and the researchers also found that B cell and antibody responses were enhanced, a result not predicted by the mouse studies. Of note, granzyme B and perforin expression by SIV-specific CD8 T cells increased significantly (a very recent study of human elite controllers identified production of these proteins by CD8 T cells as a key correlate of viral load control)".

Hmmm..." granzyme B and perforin expression by SIV-specific CD8 T cells increased significantly"??  Seems I read about this super CD8 granzyme B and perforin expression in Zephyr's recent posting below, "LTNP: New Discovery Defines a Mechanism of Control - NIH/NIAID".  Interesting connection.


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Offline freewillie99

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Re: Hopes raised on HIV immune boost
« Reply #36 on: December 11, 2008, 11:18:05 AM »
One more.  Wow:

http://www.nature.com/news/2008/081210/full/news.2008.1295.html

Published online 10 December 2008 | Nature

Antibody fights AIDS-like disease in monkeys
Approach being considered for HIV prevention in humans.

An antibody treatment has rejuvenated the immune systems of macaques infected with a virus called SIV, allowing the monkeys to fend off the symptoms of an AIDS-like disease for months. SIV is studied as a model for HIV infection in humans, and the therapy could be tested in clinical trials of HIV-infected patients as soon as next year, pending approval by regulators.

The antibody targets a protein called 'programmed death-1' (PD-1), one of several proteins that damp down immune responses during long-term infection by viruses like HIV and hepatitis C. Researchers have recently turned to PD-1 as a possible new therapy for HIV infection, in hopes that shutting down PD-1 signalling would reawaken important immune cells called killer T cells that can attack virus-infected cells (see Light shed on battle against HIV).

Although early results were promising, those experiments were performed in cell cultures and mice – neither of which has a clean record when it comes to predicting how a drug will perform in primates and humans.

"Everybody was still sceptical about it," says Rama Amara, an HIV researcher at the Yerkes National Primate Research Center at Emory University in Atlanta, Georgia. "Even I didn't anticipate it would be this effective in primates."

Amara and his colleagues now report in Nature that blocking PD-1 reduced levels of SIV in the blood of infected macaques1. SIV-infected monkeys who did not receive the treatment succumbed to an AIDS-like disease within five months of the start of the experiment; the nine monkeys who were treated with antibody against PD-1 showed no symptoms over the same time.

In the pipeline

The New Jersey-based antibody company Medarex is already developing PD-1 antibodies for use against cancer and the hepatitis C virus in humans, and early clinical trials are under way. Meanwhile, Amara says that he has communicated with another US company, which he declined to name, that hopes to apply for regulatory approval to begin tests in HIV patients next year.

It is, however, possible that blocking PD-1 could result in overactive T cells that target the body's own cells, causing an unwanted autoimmune response. "It's a big concern in the field how much reactivity you will induce in these cells," says immunologist John Wherry of the Wistar Institute in Philadelphia, Pennsylvania.

So far, however, studies in mice have given no evidence that blocking PD-1 causes autoimmunity, he notes, and the short-term treatment used in Amara's study did not produce adverse side effects.

Amara and his colleagues are now testing the effects on monkeys of longer-term treatment with the antibody. In the published study, macaques were given the antibody four times over ten days; the team is now testing treatment regimes lasting two and three months.

Wherry and his colleagues have also looked at the role of PD-1 in reducing T-cell responses. In a paper published recently in Nature Immunology2, Wherry's lab reported that inhibiting both PD-1 and another protein called LAG-3 boosted T-cell activity more than blocking either protein alone. But so far those experiments have only been carried out in mice. "There are clearly several other pathways that operate in conjunction with PD-1," he says. "Moving forward, we'd like to see examination of these other pathways in SIV and HIV infection as well."
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Offline HALOO

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Re: Hopes raised on HIV immune boost
« Reply #37 on: December 11, 2008, 03:39:00 PM »
PD-1 and Tim-3 were co-expressed by exhausted T cells

http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/11/identifying-and-reviving-tired-t-cells-via-tim3.html

This will definitely take a lot of time to find drug/vacccine that can block this PD-1 and Tim-3 express without any harmful affect(autoimmuse) but this thoery sound promising.

Offline Peter Staley

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Re: Hopes raised on HIV immune boost
« Reply #38 on: December 15, 2008, 02:18:15 PM »
Sheesh...now we have three new PD-1 threads about the exact same thing:

"Hope Raised on HIV Immune Boost"

"PD-1 Research"

"PD-1 Antibody experiments show great promise"

Can we get a consolidator here, please?

I merged them all under the thread titled "PD-1 Antibody experiments show great promise"

Offline messer

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Re: PD-1 Research
« Reply #39 on: December 16, 2008, 11:44:03 AM »
Another interesting article was published in the Journal of Virology, titled" Elevated Expression Levels of Inhibitory Receptor Programmed Death 1 on Simian Immunodefiency Virus Specific CD-8 T-Cells during Chronic Infection but Not after Vaccination".   
The research was done Emory University using a DNA/MVA vaccine.   The researchers submitted the article in January and it was published March 21, 2007.   

The article refers to a DNA/MVA vaccine from Emory which I think is also known as the Geovax vaccine planned for therapeutic trials in 2009.     If so, then this vaccine appears that it will reduce the elevations of  Pd-1 after a vaccination of the DNA/MVA vaccine, or so the paper states.      The people at GeoVax have said a successful vaccine may be closer than we think.   I hope they're right.



Offline bimazek

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Re: Hopes raised on HIV immune boost
« Reply #40 on: December 22, 2008, 08:56:14 PM »
PD-1 and Tim-3 were co-expressed by exhausted T cells

http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2008/11/identifying-and-reviving-tired-t-cells-via-tim3.html

This will definitely take a lot of time to find drug/vacccine that can block this PD-1 and Tim-3 express without any harmful affect(autoimmuse) but this thoery sound promising.

forget about auto immune problems--- we all have those now with hiv in us and with the meds in us, did you ever wake up all creaky and your joints kind of stiffer than normal and making sounds in morning that is because the meds are auto immune damaging i think and such

30 years ago the idea was that science had discovered monoclonal antibodies and when one was designed for every specific disease and every specific condition most all diseases would be cured, of course what has happened in last 30 years is the RISE of corp. finance and the take over of the world by corp. capitalism and finance at the COST of research and what is new and best, and toxic drugs are much more money makers for the mfg and for wall street.  finally now we have a fully human monoclonal antibody for pd-1 this exists today, the idea 30 years ago when the idea of monoclonal antibodies was thought us was , and you gotta look up all these terms in wikipedia

http://en.wikipedia.org/wiki/Monoclonal_antibodies

that they would not have ANY side effects what so ever because they were fully human genetically engineered to attack specific diseases.

lets put it this way, if the mouse version and the rat version and the chimp version which is all fully genetically engineered for each of those species does not do any harm and the animal is thriving in the cage without any arthritis

should we not be ready to use on those 15 humans in USA who are dying EACH DAY from hiv
perhaps half cannot be saved because the damage to the body is too great the damage to the immune system is too great from last 25 years or 20 years or 15 years

but isnt there compassionate use??
why are we not picketing in front of the one office in the world that has this

anti pd-1 fully human anti body???????????????????

do we have to wait to each of us slowly gets damaged from the assortment of meds , one after another that will / may eventually fail or develop resistance????

is this not worth a try????

there seems to be a critical mass of research and there needs to be a meeting of dr.s and researchers for compassionate use to save those who over next 5 years will die

i think that monoclonal antibodies would have been a billion times bigger if the "FINANCE sector" which is just a giant thieving machine to take money from everyone in the world would not have grown up around science,

it could be just as cheap to produce fully human monoclonal antibodies as toxic drugs if BY LAW they were demanded!!!!!

economies of scale and all that...
http://en.wikipedia.org/wiki/Monoclonal_antibodies

Monoclonal antibodies (mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell. Given (almost) any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the generic name ends in -mab (see "Nomenclature of monoclonal antibodies").



Offline leit

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Re: PD-1 antibody experiments show great results.
« Reply #41 on: December 23, 2008, 03:01:06 AM »

"bimazek":

- nodoby knows HIV-disease pathogenesis for certain
- the most recent hypothesis attributes HIV-disease progression to chronic immune activation and inflammation
- in this perspective, PD-1 could even be a body defence mechanism in front of an invincible enemy (HIV)
- even blocking PD-1, and so unleashing the immune system, it couldn't win the war against HIV, because it isn't able to recognize, and consequently destroy, the reservoirs.

On this point, you may read Guido Silvestri's talk at the last IAC (page 54, in particular).

On the other hand, I totally agree with you on unacceptable time between discoveries and trials: They have only been hindering virus replication for 12 years, while the facts prove that it's not enough (HIV-disease has only become longer and clinically different, but not less serious).


Offline bimazek

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Re: PD-1 antibody experiments show great results.
« Reply #42 on: December 29, 2008, 09:30:31 PM »
this is the only company in world that i know of that has patent for this anti-PD-1 and anti-CD70 antibody
and it has been shown to be seemingly safe in humans for cancer treatment,

do we need to start activism and call this company and ask for immediate compassionate use trails to start for those failing all classes of meds based on the recent monkey successes outlined above

i think we can make it win win, can someone call them up and say we want to do protests in front of thier headquarters in NEW JERSEY and can we try to set up a win win situation where they can announce on TV cameras that they commit to immediate compassionate use trails to start for those failing all classes of meds based on the recent monkey successes outlined above
for HIV poz guys and gals failing all meds

perhaps thiere are some poz guys who they treated who also had the cancer that this is in approval for

the reason they might want to do cancer first is because market is bigger

what is possible here

do we need to take to streets, call tv stations, set up meetings with thier CEO or senior people

can someone please call them, and get a time line

if we do not activate activism it may string out longer

were not anti bodies suppose to be LOW or NO side effects treatments for disease???
are we all not tired enough of all these toxic meds that have huge side effects
(see side effects and lipo and mental entire sections to this forum for example)

can someone who knows the science and can evaluate this better see if this is a promising path that should have activism going on??

can we make it win win where we are asking for thier meds on TV and they agree to accelerate testing for compassionate use and start asap  esp. for those who have the same cancer that this anti pd1 treats

for example....

we need to demand immediate trials of this for poz guys who have prostate cancer and or who have melanoma cancer and who are poz  RIGHT

can someone call them and get some info

can someone in new jersey organize a meeting or a protest??

Medarex, Inc. (Nasdaq: MEDX) announced that the following clinical and preclinical abstracts for ipilimumab in melanoma, prostate cancer and other cancers, as well as for anti-PD-1 and anti-CD70 antibody candidates for cancer treatment, are expected to be the subject of presentations at the Annual Meeting of the American Society of Clinical Oncology, being held May 30-June 3, 2008 in Chicago:

Survival, Response, Safety and Biomarker Data of Ipilimumab in Melanoma

-- "Antitumor response and new lesions in advanced melanoma patients on ipilimumab treatment" (Abstract #3020, Developmental Therapeutics: Immunotherapy Session) -- Poster presentation and discussion from 2:00 p.m. to 6:00 p.m. local time on Friday, May 30, 2008.

-- "Long-term survival of patients with advanced melanoma who received ipilimumab administered at 10mg/kg every 3 weeks for 4 doses (induction dosing)" (Abstract #3018, Developmental Therapeutics: Immunotherapy Session) - Poster presentation and discussion from 2:00 p.m. to 6:00 p.m. local time on Friday, May 30, 2008.

-- "Potential immune biomarkers of gastrointestinal toxicities and efficacy in patients with advanced melanoma treated with ipilimumab with or without prophylactic budesonide" (Abstract #3022, Developmental Therapeutics: Immunotherapy Session) -- Poster presentation and discussion from 2:00 p.m. to 6:00 p.m. local time on Friday, May 30, 2008.

-- "Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody" (Abstract #3008, Developmental Therapeutics: Immunotherapy Session) -- Oral presentation beginning at 4:30 p.m. local time one Saturday, May 31, 2008.

-- "Effect of prior treatment status on the efficacy and safety of ipilimumab monotherapy in treatment-naive and previously treated patients with advanced melanoma" (Abstract #9055, Melanoma Session) -- Poster presentation from 2:00 p.m. to 6:00 p.m. local time on Saturday, May 31, 2008.

-- "An analysis of the effectiveness of specific guidelines for the management of ipilimumab-mediated diarrhea/colitis: prevention of gastrointestinal perforation and/or colectomy" (Abstract #9063, Melanoma Session) - Poster presentation from 2:00 p.m. to 6:00 p.m. local time on Saturday, May 31, 2008.

-- "Model-based evaluation of ipilimumab dosage regimen in patients with advanced melanoma" (Abstract #9073, Melanoma Session) -- Poster presentation from 2:00 p.m. to 6:00 p.m. local time on Saturday, May 31, 2008.

-- "Safety and efficacy of ipilimumab with or without prophylactic budesonide in treatment-naive and previously treated patients with advanced melanoma" (Abstract #9010, Melanoma Session) -- Oral presentation beginning at 10:15 a.m. local time on Sunday, June 1, 2008.

-- "Efficacy and safety of ipilimumab induction and maintenance dosing in patients with advanced melanoma who progressed on one or more prior therapies" (Abstract #9021, Melanoma Session) -- Poster presentation and discussion from 2:00 p.m. to 6:00 p.m. local time on Sunday, June 1, 2008.

-- "Disease control and long-term survival in chemotherapy-naive patients with advanced melanoma treated with ipilimumab (MDX-010) with or without dacarbazine" (Abstract #9022, Melanoma Session) -- Poster presentation and discussion from 2:00 p.m. to 6:00 p.m. local time on Sunday, June 1, 2008.

-- "Dose effect of ipilimumab in patients with advanced melanoma: results from a phase 2, randomized, dose-ranging study" (Abstract #9025, Melanoma Session) -- Poster presentation and discussion from 2:00 p.m. to 6:00 p.m. local time on Sunday, June 1, 2008.

-- "Prolonged survival in objective responders to ipilimumab therapy" (Abstract #20004) -- Publication only.

Response and Safety Data of Ipilimumab in Prostate

-- "Phase 1 trial of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration resistant prostate cancer (mCRPC)" (Abstract #5004, New Targeted Strategies for Patients with Prostate Cancer Session) -- Oral presentation beginning at 11:30 a.m. local time on Monday, June 2, 2008.

-- "Expanded phase 1 combination trial of GVAX immunotherapy for prostate cancer and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHRPC)" (Abstract #5146, Genitourinary Cancer Session) -- Poster presentation from 8:00 a.m. to 12:00 p.m. local time on Saturday, May 31, 2008.

Clinical and Preclinical Data of Additional Immunotherapy and Antibody-Drug Conjugate Programs

-- "Safety and activity of MDX-1106 (ONO-4538), an anti-PD-1 monoclonal antibody, in patients with selected refractory or relapse malignancies" (Abstract #3006, Developmental Therapeutics: Immunotherapy Session) -- Oral presentation beginning at 4:00 p.m. local time on Saturday, May 31, 2008.

-- "Antitumor activity of anti-CTLA-4 monoclonal antibody (mAb) in combination with ixabepilone in preclinical tumor models" (Abstract #3048, Developmental Therapeutics: Immunotherapy Session) -- Poster presentation from 2:00 p.m. to 6:00 p.m. local time on Sunday, June 1, 2008.

-- "Effect of a fully human anti-CD70 antibody on apoptosis and dephosphorylation of MAPK proteins in chronic lymphocytic leukemia" (Abstract #3073, Developmental Therapeutics: Immunotherapy Session) -- Poster presentation from 2:00 p.m. to 6:00 p.m. local time on Sunday, June 1, 2008.

More information about the ASCO Annual Meeting may be found at http://www.asco.org.

About Medarex

Medarex is a biopharmaceutical company focused on the discovery, development and potential commercialization of fully human antibody-based therapeutics to treat life-threatening and debilitating diseases, including cancer, inflammation, autoimmune disorders and infectious diseases. Medarex applies its UltiMAb(R) technology and product development and clinical manufacturing experience to generate, support and potentially commercialize a broad range of fully human antibody product candidates for itself and its partners. More than 40 of these therapeutic product candidates derived from Medarex technology are in human clinical testing or have had INDs submitted for such trials, with seven of the most advanced product candidates currently in Phase 3 clinical trials or the subject of regulatory applications for marketing authorization. Medarex is committed to building value by developing a diverse pipeline of antibody products to address the world's unmet healthcare needs. For more information about Medarex, visit its website at http://www.medarex.com.


Safety and activity of MDX-1106 (ONO-4538), an anti-PD-1 ...
Safety and activity of MDX-1106 (ONO-4538), an anti-PD-1 monoclonal antibody, in patients with selected refractory or relapsed malignancies. ...
www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID.

2008 (May 20 suppl; abstr 3006)
Author(s):
J. R. Brahmer, S. Topalian, I. Wollner, J. D. Powderly, J. Picus, C. Drake, J. Covino, A. Korman, D. Pardoll, I. Lowy
Abstract:
Background: Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. Objectives of this first in human phase I trial of MDX-1106 (ONO-4538), a fully human IgG4 anti-PD-1 blocking antibody, are to evaluate safety and maximum tolerated dose (MTD). Other objectives include evaluation of pharmacokinetics (PK) and immunological effects. Methods: Patients (pts) had treatment refractory metastatic non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), colon cancer (CC), melanoma (MEL), or prostate cancer (HRPC), and no history of autoimmune disease. Sequential cohorts of 6 pts received a single IV dose of MDX-1106 at 0.3, 1, 3, or 10 mg/kg. Disease status was evaluated at wk 8 by RECIST criteria. Pts with SD or lesional responses could receive additional MDX-1106 at wks 12 and 16, at the original dose. Results: 24 pts, 6 at each dose level (9 CC, 5 NSCLC, 6 MEL, 4 HRPC), were enrolled through 11/07. 23 pts have been assessed for tumor response at 8 wks. All doses were well tolerated and no MDX-1106 related SAEs occurred. Two pts (treated at 3 and 10 mg/kg) developed arthritic symptoms requiring treatment, and 2 pts had an asymptomatic TSH elevation. Objective tumor responses (CR or PR) were not observed within 8 wks. Three pts had significant lesional regressions (1 NSCLC pt at 1 mg/kg, 2 MEL pts at 10 mg/kg). Five pts with SD or lesional regressions received retreatment. Biopsy of a regressing MEL lymph node metastasis showed a moderately increased CD8+ T cell infiltrate post treatment. PK and immunological evaluations are underway. Conclusions: The targeted maximum dose of 10 mg/kg of MDX-1106 was achieved without observing dose-limiting toxicities, and lesional tumor regressions were observed in 3 of 23 pts evaluated. An expansion cohort at 10 mg/kg is enrolling 15 additional pts. Therapy with MDX-1106 to enhance endogenous antitumor immunity, either alone or in combination with other therapeutic modalities, warrants further study.


http://www.google.com/search?hl=en&rlz=1C1GGLS_en-USUS294US306&q=anti+pd-1+monoclonal+medarex&btnG=Search

http://www.medicalnewstoday.com/articles/105744.php

http://www.google.com/search?rlz=1C1GGLS_en-USUS294US306&sourceid=chrome&ie=UTF-8&q=anti+pd-1+monoclonal

 


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