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Author Topic: Calimmune: Safety Study of a Dual Anti-HIV Gene Transfer Construct to Treat HIV-  (Read 33081 times)

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Offline Hoyland

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Hi dico, sorry to hear that Prof Berkhout has not replied to you. I have no reason to contact him personally and so I really cannot assist any further. Here is his email address, in case you have been using a different one b.berkhout@amc.uva.nl

Offline dico

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I emailed him again :)

Do you know more about the way Prof Berkhout plans to eradicate hiv from the body  ? I know it is a gene therapy aiming to keep the HIV proviral silent inside cells. But I've never seen any scientific paper about this approach. And I am quite dubious about this way as we do not know where the HIV hides... I am sceptical.

Thank you.


Offline dico

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My email to Prof Berkhout :

Hi Prof. Berkhout,

I just wanted to know if you still plan to begin your clinical trial of hiv gene therapy ? I am a French hiv positive man interested by your research.

The American are conducting since last year a gene therapy thanks to Calimmune and Benitech technology. Unfortunately they don't plan to have a trial here in France. What about you ? How can we be more informed about your research ?

Thanks a lot.

Julian

Envoyé à partir de mon smartphone Sony Xperia™



Prof Berkhout answered :

Dear Julian,
Pre-clinical research is moving slowly forward, in part because of limited funding. Thus, we are there yet. Thank you for inquiring.
All the best,
Ben Berkhout


Unfortunately he gave no date for the clinical trial...

Offline dico

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Latest updated: (delay)

"We are still trying to fill cohort 1. We have a waiting list for all of the other cohorts that include chemo, but its been really hard trying to fill the non-chemo arm. We currently have a few guys lined up to screen for the last spot and hopefully one would qualify. Because of the delay, all of the other cohorts must be pushed back as well. We will not know if any of the three qualifies until the end of December/early Jan. If that is the case, we would not be expecting to start the next cohort, small dose of chemo, until probably Feb/March. You are still in the forefront!"

So JazJon did you hear some good news about the cohort 1?

Offline JazJon

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So JazJon did you hear some good news about the cohort 1?

Nothing yet but I was called back to participate a second time in the Gilead HIV Latency Study​​ again.  (3 hour apheresis)  I'll ask for an update on Calimmune.

Offline dico

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Nothing yet but I was called back to participate a second time in the Gilead HIV Latency Study​​ again.  (3 hour apheresis)  I'll ask for an update on Calimmune.

Thanks.

What is this study ? They take blood from you and that's all ? Fo what purpose ?

Offline JazJon

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Thanks.

What is this study ? They take blood from you and that's all ? Fo what purpose ?

http://www.questclinical.com/#!studies/cjg9
(Scroll down)

Offline dico

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Unfortunately, there were no news of the calimmune trial at CROI 2014.

Anybody here has new information ?

Offline JazJon

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Update.   Looks like I'm on stand by for cohort 3.  Here's a summary of what else I learned.

- San Francisco finally filled the last slot in cohort one and are starting to bring people in for cohort 2 (low dose chemo)

- They are currently 8 months behind schedule because of the unexpectedly high screen fail rate.  One of the reasons, or 'problems', with why it took so long to fill the first cohort is because the FDA did not allow them to screen more than one patient at a time!! Which is at least a 6 week process per patient!

-  They have recently changed the protocol to allow them to screen 4 patients at once, so hopefully that will help expedite cohort 2's screening.

Offline dico

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Great news.

There's a chance you can get ''cured'' with this medium busulfan dose. It would have been better if they'd give you an immunotoxin and a therapeutic vaccine with it but do not forget that it is only a phase I study.

I hope you'll begin this year. I have great hope for the cohort 3 people.

Imagine what a great combination would be this ddRNAi gene therapy coupled with an antibody vaccine (such as the VIP of David Baltimore encoding the PG09/PG16/PG121 antibodies) boosted with a Tcell vaccine (CMV vaccine of Louis Picker) and the dual TLR7 agonist/romidepsin therapy being investigated by Gilead.

Romas Geleziunas of Gilead has made a speach in CROI 2014: they think an activating agent such as an improved romidepsin with a TLR7 agonist taken with intensified ART (Stribild+maraviroc) could lead to a cure. He told the audiance that these drugs could be taken for one to three months, then a prime antibody vaccine boosted with a T cell vaccine could keep the HIV under control for a lifetime.

Offline dico

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I received an email : the first patient of the cohort 2 will begin his theray within 2 weeks.

They have enrolled all of the cohort 2 and people are queueing to be part of the cohort 3.

Offline Seanl

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Is anyone on this forum part of the first cohort for callimune?
Id love to IM you and pick your brains...

Offline dico

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I would also be interested to know how was the whole process? Do you know your VL and CD4?
.thanks

Offline Cosmicdancer

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Do you know how many people are in each cohort?  The link I saw to the clinical trial didn't say.
Summer, 2007 - &$#@?
November, 2007 - Tested poz, 300,000 vl, 560 cd4
Feb, 2008 - 57,000 vl, 520 cd4, started Atripla
June, 2008 - undetectable, 612 cd4
January, 2009 - undetectable, 670 cd4
May, 2009 - undetectable, 593 cd4
Sept, 2009 - 83 vl, 763 cd4, 34%
Dec, 2009 - undetectable, 889 cd4, 32%
April, 2010 - undetectable, 860 cd4, 31%
October, 2010 - undetectable, 800 cd4, 38%
April, 2011 - undetectable, t-cell test not done
October, 2011 - undetectable
April, 2012 - undetectable, 850 cd4, 39%
November, 2012 - undetectable, 901 cd4, 41%
April, 2013 - undetectable, 846 cd4, 36%
October, 2013 - undetectable
May, 2014 - undetectable, 784 cd4, 48%

Offline dico

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It s a very small trial. Only 4 in each cohort

Offline Hoyland

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Calimmune's collaborator, UCLA, published some new pre-clinical data. UCLA has tracked the long term viability of CCR5 shrna modified HSPCs (blood stem cells) in non-human primates. This is important work as it models the Cal-1 treatment for HIV that Calimmume is currently trialling in patients.

The study showed that about half of the clones contributed to long term (3-10 years)  repopulation. While this is extremely exciting in terms of Cal-1 potential as a long term cure for HIV, it still remains to be seen if sufficient HSPC's can be transfected in the first place in order to provide patients with a viable population to overcome the HIV.

http://www.sciencedirect.com/science/article/pii/S1934590913005614

Dr Chen, a co-author, is on Calimmune's Scientific Advisory Board.

Offline Hoyland

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As mentioned previously, Calimmune is going to expand its clinical trial to Australia. They are now advertising for a Clinical Trial Manager in Australia. In the absence of any official news, this is probably the best indication that the current trial is going well and that the safety profile is meeting expectations.

http://www.seek.com.au/job/26477101

I expect that the company will have to report back to the CIRM soon, as CIRM is funding the current trial. It is unclear how the company will fund the expansion of the trial.

Offline dico

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So is there anybody here who is included in the 2nd cohort ?

Offline Hoyland

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The American Society for Gene and Cell Therapy has released some new publications in readiness for presentation at the annual meeting. The following may be of some interest.

Lentiviral Vector Mediated Gene Therapies Provide Stable Protection Against HIV Infection: The Use of Short-Hairpin RNA to CCR5 and Membrane Anchored C Peptide Entry Inhibitors

From Calimmune

Conclusions:

These results demonstrate the potential for gene-containing lentiviral vectors to treat HIV infection; there is both stability of the insert and absence of negative effects. These results indicate that both of the examined therapeutic genes protect against HIV infection. They show, more importantly, that the combination of these genes in a single construct provides greater protection than either therapeutic alone, indicating an additive effect of the genes. This finding shows great promise for the use of combination gene therapies in the treatment of HIV infection.

http://www.abstracts2view.com/asgct/view.php?nu=ASGCT14L1_702

Optimized Lentiviral Vectors for HIV Gene Therapy: Multiplexed Expression of Small RNAs and Inclusion of MGMTP140K Drug Resistance Gene

From CoH

Gene therapy with hematopoietic stem and progenitor cells (HSPCs) is a promising approach to engineering immunity to HIV and may lead to a functional cure for AIDS. In support of this approach, we created lentiviral vectors that utilized the MCM7 platform to express a diverse set of small anti-viral RNAs and a drug resistance gene (MGMTP140K). Multiple strategies for simultaneous expression of up to five RNA transgenes were tested. The placement and orientation of each transgene and its promoter were important determinants for optimal gene expression. RNA expression from the MCM7 platform with a U1 promoter was sufficient to provide protection from R5 tropic HIV in macrophages and resulted in reduced hematopoietic toxicity compared to constructs expressing RNA from independent Pol III promoters. Surprisingly, the addition of an HIV entry inhibitor and a nucleolar-localizing transcriptional inhibitor (TAR) did not enhance antiviral potency over constructs that targeted only viral RNA transcripts. We also demonstrated selective enrichment of gene modified HSPCs during in vitro expansion in the presence of BCNU. The use of these less toxic, potent anti-HIV vectors expressing a drug selection marker is likely to enhance the in vivo efficacy of our stem cell gene therapy approach to treating HIV/AIDS.

http://www.abstracts2view.com/asgct/view.php?nu=ASGCT14L1_57

http://www.abstracts2view.com/asgct/view.php?nu=ASGCT14L1_680

Offline tryingtostay

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What's the catch?  Does the virus remain in the body and the immune system just not react to it thus leaving people who've been infected with HIV still potentially able to transmit?

Offline buginme2

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What's the catch?  Does the virus remain in the body and the immune system just not react to it thus leaving people who've been infected with HIV still potentially able to transmit?

No.

1. This is a very early clinical trial.  It's not anything yet but they are trying to genetically alter immune cells to make them resistant to hiv.  HIV as with all other viruses cannot reproduce on its own, it needs a cell to do that.  If the cell is immune then HIV can't reproduce in it.  It does not "kill" the virus.

2.  There are NO hiv drugs that "kill" the virus.  They all either 1. prevent hiv from replicating within the Immune cell or 2. Prevent hiv from attaching itself or entering the cell in one way or another.

That's why HIV at this point in time cannot be cured.  All we can do is prevent it from replicating.   

Offline Hoyland

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Quote
No.

1. This is a very early clinical trial.  It's not anything yet but they are trying to genetically alter immune cells to make them resistant to hiv.  HIV as with all other viruses cannot reproduce on its own, it needs a cell to do that.  If the cell is immune then HIV can't reproduce in it.  It does not "kill" the virus.

2.  There are NO hiv drugs that "kill" the virus.  They all either 1. prevent hiv from replicating within the Immune cell or 2. Prevent hiv from attaching itself or entering the cell in one way or another.

That's why HIV at this point in time cannot be cured.  All we can do is prevent it from replicating.   

This is true, however, through these genetic modes of action HIV can be turned into a benign virus. In other words, the virus may still exist but it won't have any effect on treated humans. The trick will be to turn this work into a vaccine so that a greater population is exposed to it. The current mode of genetic treatment delivery will not lend itself to this and so a lot more work needs to be done in this area. However, the potential with these gene therapy treatments is that an infected patient may only need one treatment (no meds) to achieve a functional cure, after which, that patient will no longer be susceptible to HIV infection. 

This may not "kill" the virus but it does represent a considerable step forward in the treatment of the disease.


Offline tryingtostay

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This will be an amazing accomplishment if this works.  I am excited and these types of researches give me hope. 

So if this works it will be like a Chicken Pox vaccine, or functional cure, correct? Basically you are immune to it but you may still have it in your system, correct?

What in your opinion do you think is the best approach towards either a vaccine, functional cure, or treatment?  I am routing for the "Kick & Kill" approach of Romidepson from Bionor.  I seems the least complicated and least hazardous.  The little bit I understand about Calimmune is that it's similar to the Berlin Paitent's treatment ???  please correct me here again if I am wrong. 


Offline buginme2

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So if this works it will be like a Chicken Pox vaccine, or functional cure, correct? Basically you are immune to it but you may still have it in your system, correct?

What in your opinion do you think is the best approach towards either a vaccine, functional cure, or treatment?  I am routing for the "Kick & Kill" approach of Romidepson from Bionor.  I seems the least complicated and least hazardous.  The little bit I understand about Calimmune is that it's similar to the Berlin Paitent's treatment ???  please correct me here again if I am wrong.

No.  Not really.  This approach they withdraw your blood.  They alter your own immune cells then inject them back into your body.  The hope is they will reproduce and you will have a group of immune cells resistant to hiv.  hiv will kill all the other immune cells in your body leaving the resistant ones. 

Its not a vaccine. 

This research is very very early in development.  Its still at the basic research phase.  Even if this work its still 10-20 years from the clinic.  And that is a BIG IF.


I dont really have a favorite research area.  In my opinion many of the "cure" research ideas are not very appealing.  They all involve either gene therapy, radiation, stem cell transplants, or high doses of cancer drugs.  None of which I would be jumping for joy over.

Offline Hoyland

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Calimmune's mode of action is to modify the blood stem cells which turn into the immune system's T Cells. These cells (in theory) will continually divide and thus extend and increase the resistance to HIV. Here is a description straight from Calimmune's website:


Quote
Dr. David Baltimore, Nobel Laureate and now President Emeritus of the California Institute of Technology, suggested in a Nature journal article over a decade ago, that gene therapy could provide a possible treatment for HIV/AIDS if the genes that block HIV production could be transferred into blood stem cells (precursors to T cells).  HIV-resistant T cells could then be produced by these individuals to maintain the immune/blood system, allowing the body to fight off infections and cancers, increasing one's quality of life, reducing the need for antiretrovirals and thereby eliminating the mortality associated with HIV/AIDS.

Since then, Dr. Baltimore, and his esteemed colleagues have pioneered a blood stem cell therapy that blocks the expression of CCR5, used by HIV to enter T cells.

Because of the rapid ability of HIV to develop resistance to monotherapy, the Calimmune team has included additional proprietary technologies to prevent HIV entry.

The treatment is aimed at controlling and preventing HIV from progressing to AIDS.  Armed with proof-of-concept, and safety/efficacy data, Calimmune continues to enhance the technology and is now in conversations with the FDA to take the first generation therapy of this innovative approach to the clinic.

If successful, the one-time treatment can not only help HIV infected individuals, but it would also be a benefit to uninfected people.  With reductions in viremia in infected individuals, this translates into a reduction in the community burden of HIV infection and that, in turn, has the ability to reduce the overall rate of new infections worldwide.

CoH have looked at this approach but it would seem that they favour disrupting the viral RNA as the virus tries to replicate, thus rendering it impotent.

Both treatments are designed to provide a lifetime of immunity to those treated. However, until the method of harvesting and treating blood cells is made simpler, only health centres that have apheresis facilities will be able to treat patients.

If either of the two trials currently in Pl clinical trials (Calimmune and CoH) proves to be safe and efficacious, I believe that those involved will seek Breakthrough Therapy status from the FDA. This would fast track the treatment in to the general clinical setting but it will do little to solve the problem in 3rd world countries.

Offline tryingtostay

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How fast does this therapy take to become effective?  One hooks up to an apheresis machine and in a day the "transfusion" is complete?  What other methods are they seeing to make this simpler?

Offline Hoyland

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Quote
How fast does this therapy take to become effective?  One hooks up to an apheresis machine and in a day the "transfusion" is complete?  What other methods are they seeing to make this simpler?

How fast? This is one of the questions the current trial is trying to determine and so we will have to wait for results from the trial before the answer to this question is known.

Here is a video made by one of the first Calimmune patients.

http://www.youtube.com/watch?feature=player_embedded&v=ymRJLICsMbQ

As to what else Calimmune is doing, this is a commercial matter and Calimmune is keeping this very much to itself.


Offline tryingtostay

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I'm sorry, I meant when a person sits down with this machine how long does it take to cycle in the new blood stem cells, but it's cool I was just curious.  It would seem like a long process and as mentioned it's not a simple thing to do. 

Offline Matts

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I didnt know how advanced Benitec's ddRNAi is; I think that one should take it seriously :) The TT-034 'one-shot-HCV-cure' trial  starts now and could be approved by FDA already in 2016 as 'breakthrough therapy'; if the trial is successful. I think that a Major Company could make an offer for Benitec or CalImmune within the next years.

http://online.wsj.com/article/PR-CO-20140529-906886.html
http://www.tacerebio.com/tt-034.htm
« Last Edit: June 04, 2014, 03:12:35 AM by Matts »
tivicay/kivexa

Offline tryingtostay

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This is sorta relative to the topic.

If the gene therapy for CCR5 & C46 work against the process of HIV-1 infecting immune cells which leaves the rest of the immune fighting cells to be killed off doesn't this still leave out a few loose ends?  For example isn't the inflammation un-addressed while the non modified immune cells are being killed off?  And for those people who this will work for what does this mean for non progressors who's immune cells are not or slowly effected which can be bad and good???
« Last Edit: June 04, 2014, 11:07:17 AM by tryingtostay »

Offline Matts

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I think that we have 2 or 3 AidsMeds guinea pigs for Cal-1, just wait what they tell to all of us in 2015 or 2016 :)

The last presentation of CalImmune tells literally nothing new, not worth to post it. I think that it is a big field experiment and we have to wait.
tivicay/kivexa

Offline dico

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When Will the the cohort 3 (high busulfan) begin treatment?

Offline dico

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Offline Hoyland

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Dico, those readers who are participating in this trial may know the answer to your question but they are probably subject to a non-disclosure agreement, which prevents them from answering or reporting on the progress of the trial.

Offline Hoyland

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Mathematical analysis and computer simulation supports Calimmune's approach to treating HIV. This modelling suggests that even a 20% modified cell transfection rate of  could be a therapeutic.

Quote
In conclusion we have demonstrated that gene therapy employing entry/fusion inhibitors can achieve substantial clinical impact in terms of long-term preservation of total CD4+T cells counts and forestalment of AIDS. Importantly, this was observed even if only a subset of total cells received the gene construct, indicating that full immune system ablation is not necessary (prior to delivery of the gene therapy) in order to achieve substantial clinical impact. We determined that therapy delivery to CD34+ HSC generally resulted in better outcomes than therapy delivery to CD4+T cells. Maximal impact in our modelling was observed if the uninfected G+ CD4+T cells, in addition to having reduced likelihood of productive infection, exhibited lower levels of bystander apoptosis over G- CD4+T cells. Under this scenario therapy delivery to either CD4+T cells or to CD34+ HSC resulted in substantial preservation of total CD4+T cell counts. The present mathematical modelling demonstrates that gene therapy employing entry/fusion inhibitors represents a promising and potent anti-HIV modality, and that further clinical investigation of these gene therapeutics is more than justified.

http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1003681?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+ploscompbiol%2FNewArticles+(PLOS+Computational+Biology+-+New+Articles)

 

Offline dico

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Thanks for sharing Hoyland.

Hope they will combine that with a vaccine as gene therapy alone is not enough.

Offline Hoyland

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Offline tryingtostay

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That's great to hear and I'm hopeful it will stop the progression of the HIV virus into AIDS.  I wonder what it could do for controllers?  Could it possibly give the immune system a break?  Hmm, wonders

 


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