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Author Topic: Calimmune: Safety Study of a Dual Anti-HIV Gene Transfer Construct to Treat HIV-  (Read 101745 times)

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Offline Tadeys

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This is an early phase research study looking at whether an experimental gene transfer, LVsh5/C46 (also known as Cal-1), is safe and if it can protect the immune system from the effects of HIV without the use of antiretroviral drugs.

Cal-1 is an experimental gene transfer agent designed to inhibit HIV infection through 2 active parts:

Removing a protein named CCR5 from bone marrow and white blood cells
Producing a protein named C46 on bone marrow and white blood cells
Detailed Description   
It is estimated that 33 million individuals are currently infected with HIV. HIV/AIDS is a disease that impairs immune function, primarily by decreasing CD4+ T lymphocytes. The progression can be contained by daily dosing with antiretroviral therapy (ART) but there are side effects that can be treatment limiting, and the development of HIV drug resistance can force the physician to modify the ART regimen. There are no effective vaccines currently available for HIV.

LVsh5/C46 (also known as Cal-1) is a dual therapeutic, self-inactivating lentiviral vector that encodes for both a short hairpin RNA against the HIV-1 co-receptor CCR5 (sh5) and a HIV-1 fusion inhibitor, C46 and inhibits two processes required for HIV-1 infection:

Binding of the virus to the cellular CCR5 co-receptor and
Fusion of the virus with the host cell
The rationale is that Cal-1 introduced into hematopoietic progenitor/stem cells (HSPC) and mature CD4+ T lymphocytes will protect these cells and their progeny cells from HIV-1 infection and its pathogenic sequelae. This may provide a continuous means of controlling HIV-1 after a single or infrequent dose(s), thereby decreasing or delaying (partially or completely) the need for antiretroviral drug therapy.

http://clinicaltrials.gov/ct2/show/record/NCT01734850

Offline Matts

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It seems they want to repeat the success of the "Berlin Patient" but without a transplantation.

http://www.calimmune.com/therapy.php
Dovato

Offline geobee

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I've been on the list at Quest Research in SF for this trial.  I've been following the Sangamo trials (also at Quest) and am going to wait and see what becomes of them first.

Offline geobee

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Just got an email from Quest -- they are now recruiting for the CalImmune trial.

Offline Matts

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Maybe You are "cured" soon. I would be scared if somebody botches on my lovely genes. But CalImmune works with Benitec, and they really have the money and experience with the small hairpin ddRNAi, I think it will be a succes. :)
Dovato

Offline JazJon

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I'm on the Calimmune list as well, I'll post what I can if I make it.  I'm excited to help move research forward.

Offline geobee

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Well I didn't qualify again for the Sangamo T-Cell trial.  My adenovirus titre went from 500 something to 100 something but it needs to be below 40.  So... nixed again for that trial.

But Quest called back today and I did qualify for the CalImmune trial and am considering it.  I'm pretty comfortable replacing some of my T-Cells -- but more apprehensive re: stem cells.

Offline JazJon

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Well I didn't qualify again for the Sangamo T-Cell trial.  My adenovirus titre went from 500 something to 100 something but it needs to be below 40.  So... nixed again for that trial.

But Quest called back today and I did qualify for the CalImmune trial and am considering it.  I'm pretty comfortable replacing some of my T-Cells -- but more apprehensive re: stem cells.

If we both get on board, we'll have to share and compare our experiences.   I was told you can either do Stem cell without chemotherapy, with "light" chemotherapy. or with "medium" chemotherapy.    I think the logic of doing chemo to reset your immune system is very logical, so I'm going for the chemo if I get to pick.   Our hair won't fall out or anything, it's not the intense long dosage they give cancer patients.   It won't happen until later that year probably from what I understood. 

Offline POZnLA

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If we both get on board, we'll have to share and compare our experiences.   I was told you can either do Stem cell without chemotherapy, with "light" chemotherapy. or with "medium" chemotherapy.    I think the logic of doing chemo to reset your immune system is very logical, so I'm going for the chemo if I get to pick.   Our hair won't fall out or anything, it's not the intense long dosage they give cancer patients.   It won't happen until later that year probably from what I understood.

I have an appointment for a consult, not screen yet, this coming Wed in LA at UCLA Center for Aids research. Wish me luck. I have been off meds since 3/15, due to drug reactions. They said that they expect to start screening this week, or the next.

Offline geobee

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After mulling it over, I'm leaning towards doing this trial.  I sent an email to my doc and will let you know what her opinion is.   If she's neutral or better I'm going to talk to Quest and schedule a short informational session with Dr. Jay.

Offline Matts

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I wish the 3 brave guinea pigs the best of luck. It has to be a difficult decision; getting Busulfan and an unapproved Gene product.
I think that we will know the results in a decade or so.

http://en.wikipedia.org/wiki/Busulfan
http://clinicaltrials.gov/ct2/show/NCT01734850
Dovato

Offline Hoyland

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While not using the same targets as the Calimmune trial the City of Hope has run and is running a ddRNAi trial for HIV. One of the lead investigators is Dr Rossi. Here is a video of him speaking about the use of ddRNAi in the treatment of HIV. This may help some who are considering the Calimmune trial. Good luck.

http://www.youtube.com/watch?v=9XqJyYrYgwU


Offline freewillie99

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I wish the 3 brave guinea pigs the best of luck. It has to be a difficult decision; getting Busulfan and an unapproved Gene product.
I think that we will know the results in a decade or so.

http://en.wikipedia.org/wiki/Busulfan
http://clinicaltrials.gov/ct2/show/NCT01734850

A decade?  More like inside a year.  Seriously, dude...where'd you pull that one out from  :o

Best of luck to all.
Beware Romanians bearing strange gifts

Offline jaace24

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Do you know when the study is supposed to start?  And how long it will be?

Offline POZnLA

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Do you know when the study is supposed to start?  And how long it will be?
The Study has selected 4 persons for the 1st of 3 Arms, and participants for the second Arm are being selected now. There is a talk given by Dr. Ronald Mitsuyasu at Plummer Park in West Hollywood this coming Thursday at 6:00 pm, rsvp required, contact UCLA HIV care and research center. Dr. Mitsuyasu is the principle investigator for this study, and an associate director at UCLA AIDS Institute.
Quest labs in San Francisco as well as UCLA are the 2 investigation sites.

Offline POZnLA

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Do you know when the study is supposed to start?  And how long it will be?
Oops, I forgot something. The study is for a period of 48 weeks, and though not a full year, for researchers, it is my understanding, that it is 12, 4 week periods, and they refer to it as a year long study.
The Study officially was listed as "recruiting" as of 4/15/13.

Offline Matts

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Ok, then we will know in 1 year if it works or not?
Am I right in thinking, that You get only one shot of  LVsh5/C46 (with or without Busulfan) and the CCCR5 receptor in the bone marrow is destroyed forever?
The body produces only CCR5 free cells from then on (theoretically)?
I know the  LVsh5/C46 destroys also 2 other HIV genes; Is this also forever or only for the time of treatment?
Dovato

Offline Hoyland

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The theory is that the full treatment will be a single session (or very few sessions) and that the gene therapy component of the drug will turn off the gene that produces the CCR5 receptor. This will not happen for every white blood cell in the body immediately but the new, modified cells will reproduce and eventually replace all the ones with the receptor.

Once made, this modification is intended to last forever and not just for the period of the treatment.

This is only a Pl/ll safety study and so dosing will likely be low or lower than that anticipated for a full recovery from HIV. However, as mentioned in the video which I posted previously, a patient who was treated with the same gene silencing technology (different target) continues to see an increase in modified cells after a very low initial transfection of new cells years after the initial treatment. Participants in this Calimmune trial could, therefore, expect to see similar continued improvement.

Offline POZnLA

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Ok, then we will know in 1 year if it works or not?
Am I right in thinking, that You get only one shot of  LVsh5/C46 (with or without Busulfan) and the CCCR5 receptor in the bone marrow is destroyed forever?
The body produces only CCR5 free cells from then on (theoretically)?
I know the  LVsh5/C46 destroys also 2 other HIV genes; Is this also forever or only for the time of treatment?
I am no expert, but as a candidate and potential participant in the study, this is my understanding. CD4 cells and CD34 cells (bone marrow cells) are removed, genetically modified to be CCR5 free, as well as to produce CR46(a 2nd barrier to HIV). The modified cells are grown (allowed to multiply) so that there are many of them (billions, as opposed to millions used in other studies), then reintroduced. After reintroduction the modified cells will reside along side the unmodified cells. It is hoped that the genetically modified cells will become predominant as HIV eliminates the cells that are not modified. In the 1st Arm of the study no chemotherapy is used, in the 2nd Arm one does is used (Busulfan), and in the 3rd and last arm, 2 doses of chemotherapy are used. The purpose of the Chemotherapy is to "make room" for the newly introduced modified cells. In some of the previous gene therapy studies the newly introduced cells resisted the HIV virus, but were eventually thinned out and unable to control HIV in those study participants.
If some one else knows more or I am in error, please add your response.

Offline Hoyland

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POZnLA, your understanding is correct.

The other study that you refer to is probably the first trial conducted at CoH. This was done a few years ago when the transfection process was not very efficient. That study did prove that there was no toxicity associated with the treatment and since then levels of transfection have improved.

Dr Anderson at UC Davis is working on a similar treatment but I believe that he is yet to source funding for a trial.  Prof Berkhout in the Netherlands is also working with ddRNAi but has taken a somewhat different approach. His team my be in the clinic next year. There is also a team in Russia using ddRNAi technology to find a treatment for HIV but I am not sure of their progress.

Offline Matts

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Ok thank You. I think its for sure, if there will be a cure it will be a "CCCR 5 thing". I wrote a mail to Dr.Hütter, and I hope he will answer.
Today another vaccine trial has totally failed (HVTN 505). So long everything  has failed within the last decades. It's about time for a success after 30 years. :)
Anyway, I think the CalImmune trial is not dangerous for the guinea pigs, its already tested in humans.
So long I take my Selzentry that blocks the CCR5 receptor; but it would be better to disrupt CCR5 definetely in the bone marrow, than taking pills everyday :).
If there will be no cure, then there will be even better drugs. GSK1265744 is very promising; a nano drug that will be administered once a month.

The future is bright. :)
« Last Edit: April 25, 2013, 05:12:29 pm by Matts »
Dovato

Offline buginme2

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". I wrote a mail to Dr.Hütter, and I hope he will answer.


What did you say in our letter? Was it like fan mail or was their a specific request?
Don't be fancy, just get dancey

Offline Hoyland

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Does anyone know when the first patients will dosed?

Offline JazJon

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Does anyone know when the first patients will dosed?

I originally was interested in volunteering for gene therapy when I was first diagnosed early 2012.  Since nothing was available I went ahead with a trial med that blocks ccr5
http://www.aidsmeds.com/archive/cenicriviroc_2656.shtml

I just ended the 12 month trial and switched over to complara for now. 
(It worked great, no sides, undetectable)

I have a follow up appointment later this week to make sure I'm still undetectable on Complara (should be fine)

Since I was told they want me for the Calimmune study at my last appointment I should know more this month on timelines. 

I'm actually doing a short study in a few weeks (one time thing) where they Harvest a ton of my white blood cells.  This is for research that involves finding/waking the hidden reservoirs.  (Not related to Calimmune)

But yeah I'm confident enough to go for the double Busulfan immune system format c: so the custom Firmware update of my new immune system takes root.   Best case scenario I can then give people hope by reporting I'm still undetectable month after month while completely off meds. (And do the happy dance)

I think I'm a great Canadiate.  When I discovered I was poz in march 2012 I was still testing neg for antibodies.   I dove into the cenicriviroc trial meds study and became undetecable in weeks.   I should have very little reserves in my body from what I understand. 

Offline Dr.Strangelove

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I remember reading an article about Dr. Gero Hütter recently. He is not working on HIV any more. Also, he never really was a HIV researcher but a hematologist. It was more of a happenstance that one of this leukemia patients was HIV positive. So, I doubt that he is still in the 'cure business'.

The approach for the Calimmune trial sound pretty promising. But it's still early on.

Offline Matts

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Yes he is only a simple hematologist in Heidelberg. I think he gave only his good name for CalImmune for a decent amount of money. :) Don't know what to think about the trial, there is not much information.  Let's see what will happen.
Dovato

Offline Hoyland

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Quote
there is not much information

This is the abstract of a paper that Calimmune will be presenting in two weeks time at the ASGCT conference. I hope this helps.

[48] Engineering Resistance to HIV-1 Infection with a Dual Therapeutic Lentiviral Vector

Bryan P. Burke, Maureen P. Boyd, Michelle L. Millington, Helen Impey, Jane Zhang, Maria V. Carroll, Joanna Camba-Colon, Naomi Keech, Frederic Delebecque, Orit Wolstein, Annett Howe, Rachel Koldej, Tamara Nicolson, Bernard R. Levin, Valerie Rezek, Dimitrios N. Vatakis, Scott G. Kitchen, Louis R. Breton, Jeffrey S. Bartlett, Geoff P. Symonds. Calimmune, Inc., Los Angeles, CA; Division of Hematology-Oncology and UCLA CFAR, The David Geffen School of Medicine, University of California, Los Angeles, CA

We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) capable of generating cellular resistance to multiple strains of both R5- and X4-tropic HIV-1. LVsh5/C46 (Cal-1) has two separate mechanisms of action for inhibiting HIV-1 infection: (1) down-regulation of CCR5 expression via RNAi; and (2) inhibition of HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This combinatorial approach allowed for two points of inhibition for R5-tropic HIV-1 reducing the potential of escape mutations, and was also active against X4-tropic HIV-1. Cal-1 is being clinically developed for use in cell-mediated gene therapeutic applications for treatment of HIV-1 infected patients, for engineering HIV-resistant CD34+ hematopoietic stem/progenitor cells (HSPC) and CD4+ T-cells. Here we report Cal-1 pre-clinical safety and efficacy data for inhibition of HIV-1 infection in vitro and in vivo. Peripheral blood mononuclear cells (PBMCS) and CD4+ T-cell lines treated with Cal-1 were resistant to both clinical isolates and laboratory strains of HIV-1 that were R5-tropic, X4-tropic, or dual-tropic. In addition, Cal-1 modified PBMCs displayed greater protection from HIV-1 infection compared to PBMCs modified with either transgene alone. The ability of Cal-1 modified CD34+ HSPC to confer protection from HIV-1 infection in vivo was determined using the humanized Bone Marrow, Liver, Thymus (BLT) mouse model. Following intravenous challenge with R5-tropic HIV-1, Cal-1 transduced human CD34+ HSPC treated animals demonstrated recovery and maintenance of CD4+ T-cells and significantly reduced viral load compared to control animals that received non-modified human CD34+ HSPC. Four of six animals treated with Cal-1 modified cells had undetectable viremia at terminal analysis, whereas HIV was readily detected in all control animals. Cal-1 modification supported normal hematopoietic development and function without evidence of toxicity. Cal-1 treatment of PBMCs did not induce apoptosis, proliferation, or inflammatory responses; and CD34+ HSPCs treated with Cal-1 displayed normal differentiation, low potential for immortalization in vitro, and oligo-/polyclonal hematopoietic repopulation in vivo. As such, the preliminary safety profile and current efficacy data for Cal-1 strongly support the use of this vector and therapeutic paradigm for clinical treatment of HIV-1 infection.

Offline JazJon

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We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) capable of generating cellular resistance to multiple strains of both R5- and X4-tropic HIV-1.

Peripheral blood mononuclear cells (PBMCS) and CD4+ T-cell lines treated with Cal-1 were resistant to both clinical isolates and laboratory strains of HIV-1 that were R5-tropic, X4-tropic, or dual-tropic.

Four of six animals treated with Cal-1 modified cells had undetectable viremia at terminal analysis, whereas HIV was readily detected in all control animals. Cal-1 modification supported normal hematopoietic development and function without evidence of toxicity.

Very interesting, especially the humanized animal reactions to it so far.   I'm really excited to volunteer the more I learn about Callimune.  I'm more than ready to help move medical science forward.  As with anything new, the first run has the potential for yet another failure.  Having said that,  I'm still feeling more confident 2013 could be a true breakthrough year with cure or "functional" cure news.  I think we are all growing restless with the "cure" news popping up each year that soon fades into the what happened to it category. 

I didn't realize this was hitting both R5-tropic & X4-tropic HIV. (I thought it was a dual approach to R5 only)   Any friends I talk to about CCR5 cures usually remind me about the XCR4 re-exposure threat out there.   I'm really impressed that they are able to move forward with the dual approach. 
« Last Edit: April 30, 2013, 10:42:09 pm by JazJon »

Offline JazJon

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Here's an update.   I assumed groups 1, 2 & 3 were happening at the same time but I was mistaken.

-Group 1 (no-chemo) is screening right now, and treatment is then weeks away.
-Group 2 (low-chemo) is screening at the end of 2013, and treatment early  2014
-Group 3 (medium-chemo) is screening mid/end 2014 and treatment 2015

I'm on the list.   Based on the results of Group 1, I'll have to decide if I want to do Group 2 sooner, or wait an extra year for Group 3.  I'm looking forward to seeing how the Group 1 responds, and happy at least a few people are trying out the actual treatment process before I will. (assuming I qualify etc)

It's too early to tell if low vs med chemo pre-conditioning will be all that important.   If Group 1 has outstanding results, I'd drive into Group 2 no questions.  If Group 1 only has ok'ish results, then I might wait the extra year for Group 3.    I'm happy to be in ANY Group to be honest, & just typing up my thoughts.   

I'm glad I formed a good relationship with Quest early on to at least be on the list.
(and looking forward to that call in a few months)  I'm apparently their healthiest patient :)

Here's the other interesting thing.  Calimmune only have 12 slots total SHARED between LA and SF.   Apparently it's almost a first come first serve thing based on screening etc.  That's 4 slots per group, and it's hard to say who will get more LA or SF.   So again having said that, I'd be happy to be in ANY group with such a small number of spots potentially available.

P.S. Group 1 is full obviously, so if you haven't already signed up, it will be a long shot at this point.    Let's hope this actually works and turns into a Phase I/II/III trial by 2016!
« Last Edit: May 01, 2013, 06:25:23 pm by JazJon »

Offline POZnLA

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Here's an update.   I assumed groups 1, 2 & 3 were happening at the same time but I was mistaken.

-Group 1 (no-chemo) is screening right now, and treatment is then weeks away.
-Group 2 (low-chemo) is screening at the end of 2013, and treatment early  2014
-Group 3 (medium-chemo) is screening mid/end 2014 and treatment 2015

Thanks for update JazJon, I received similar info here in LA, from UCLA, They said that the 3 groups were consecutive, not concurrent with a review for safety after each group gets into the study, at what point that review occurs I am unsure. The study recruiting opened 4/15/13 and the study has a estimated primary completion date of June 2015, that's according to the listing on clinicaltrials.gov. Based on that and some dates I was given for screening and the apheresis. I was assuming that it was going faster then that. Maybe not.

Offline JazJon

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Well things are always changing it seems, so maybe what I wrote is just the conservative estimated schedule.   I wouldn't be surprised if Group 2 ends up happening sooner rather than later if Group 1 goes better/smoother than expected.  The wait begins.  I hope the Group 1 data is shared right away, or a Group 1 person chimes in on here. (or if anyone else hears an update they can share)

Offline Dr.Strangelove

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There was a poster by the Calimmune people presented at CROI this year.
I think it hasn't been posted yet in this thread. Here is the abstract:

http://www.retroconference.org/2013b/Abstracts/47457.htm

Looking good
« Last Edit: May 03, 2013, 12:20:13 am by Dr.Strangelove »

Offline JazJon

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There was a poster by the Calimmune people presented at CROI this year.
I think it hasn't been posted yet in this thread. Here is the abstract:

http://www.retroconference.org/2013b/Abstracts/47457.htm

Looking good


Interesting, I only wish I had the medical training to understand every nuance of that page.   I get the gist of it though.

They said:
"Conclusions: These data provide proof of principle that shRNA targeting HIV-1 promoter is able to suppress HIV-1 replication"

I know they have to  be careful which words they pick, but I'm hoping "suppress" is to the point of the virus being eliminated over time.    Do we know if these humanized mice will be monitored long term? (assuming the humanized mice live very long to begin with)    I wonder what length of time a mouse would need to remain undetectable to be considered a functional cure and finally a cure cure.  (again assuming they live for very long to begin with)      Google said a wild mouse only lives less than a year!

Interesting stuff,  I'm looking forward to finding out how real humans respond long term. 
(assuming the short term goes as well, one step at a time)

Offline JazJon

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I just had an interesting discovery.    Anyone that volunteers for a clinical trial that has you STOP your ART (such as Calimmune) might actually be doing TWO experiments.  Check this out.

Topic: Early HIV drugs 'functionally cure about one in 10'
http://forums.poz.com/index.php?topic=47816.0

Here's where I possibly come in:

Here's a copy and paste:
_______________________________________________

http://forums.poz.com/index.php?topic=47816.msg587206#msg587206

Post-treatment controllers tended to have very high viral loads soon after infection, while elite controllers are more likely to keep virus levels down, even at the start, the researchers said. The immune systems of the post-treatment controllers also tended to differ in certain ways from those of elite controllers.

Maybe I'll end up as a post controller?   I actually have a potential situation where I'll be able to find out in several months.  (I'll post my results if/when it happens)

Details.........
I was diagnosed early 2012.   I had a pretty bad flu for 3 weeks so I got tested.  They told me I had a VL of 2 million, but still tested negative for antibodies.  (they have a dual HIV test at the clinic I went to)  So that means I caught it about as early as it gets.

I did research and I jumped into a clinical trial of a new CC5 blocking med:
http://www.aidsmeds.com/archive/cenicriviroc_2656.shtml  (with Truvada)
(when I started, I felt normal, and VL was pretty low naturally)
I became undetectable in several weeks. (and zero side effects)

I just completed the cenicriviroc trial and switched to complera a month ago. (again zero side effects)

The next trial I'm on the top of the list to participate in Arm 2 or 3 of the Calimmune Gene transfer trial.
http://forums.poz.com/index.php?topic=46455.0

Here's the interesting part.........

I need to STOP taking my meds several weeks before I get treated via Calimmune.    I never imagined that I might remain undetectable after I stop ART.  I'll have been on ART nearly 2 years by the time they would want me.   The fact I was on the CCR5 blocking cenicriviroc for so long and started so early gives me a decent chance at least.   I was told I was the healthiest patient in every program they have across the board too.   So pending my qualification for Calimmune, and they call me,  I'll consider it a double experiment!

I'm pretty sure I was told the Calimmune trial requires you to actually have a detectable VL before they'll treat you.    What if I remain UD month after month?  I would imagine they want test groups to be detectable so they can rule out the potential Post-treatment controller anomalies

________________________________________________
« Last Edit: May 03, 2013, 03:37:41 am by JazJon »

Offline JazJon

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There was another "cure" post today that got me thinking.    Here's the one I'm referring to.

http://www.africareview.com/Special-Reports/After-Berlin-Man--two-reported-cured-of-HIV-in-Kenya/-/979182/1843388/-/3saq6o/-/index.html

Topic: Two reported cured of HIV in Kenya?
http://forums.poz.com/index.php?topic=48486.0

First off, it's hard to say if this is even legit, but what the article talks about still generated questions.

Quote
“I have demonstrated the HIV cure in two people by stopping rapid multiplication of CD4 progenitor cells in the bone marrow, where the HIV virus hides (to avoid) elimination by the immune system and thus achieved the first complete cure without bone marrow transplantation,” Dr Barasa said.

His treatment, he says, is based on the world’s first known cure of HIV, that of Timothy Ray Brown, 47, who was diagnosed with HIV in 1995 and put on ARVs, but in 2006 developed leukaemia (blood cancer) and, for this reason, was given a bone marrow transplant with a rare gene mutation that provides natural resistance to HIV.

His doctor, Gero Hutter, said this resistance seemed to have been transferred to Brown, but Dr Barasa says this was not the case, arguing that the removal of Brown’s bone marrow did it

“Removing the bone marrow, where the CD4 cells replicate, denied the virus the capacity to replicate and consequently the patient was free of HIV,” says Dr Barasa. Since the new bone marrow was resistant to the virus, the already existing bugs in circulation and from the secondary reservoirs — which include the brain, glands, intestines, and skin — could not create new hideouts, hence the ultimate eradication of the virus.

So again, assuming this story is even legit, I wonder if what his Theory on what REALLY happened with Timothy Brown (Berlin Patient) is true?  If you read about the new claimed cure worked, He's basically saying you only need to use Methotrexate to reset someones immune system deep enough to flush out the HIV reserves.   A full Stem Cell transplant isn't' required.

Quote
Medical doctors using antiretrovirals are able to bring down a patient’s viral load to undetectable levels, but once the patient stops the medication, the viral load goes up again.

“This means there is a reservoir in the body where the virus is hiding and where the ARVs are not able to reach. The hideout is in some parts of the bone marrow. Get rid of this reservoir and, theoretically, you are home and dry,” Dr Barasa says, adding that he has achieved this using a method that comprises the use of a cancer drug (methotraxate) in combination with other agents. Two patients who have undergone the therapy, Dr Barasa adds, have shown no signs of the virus for the past six months.

Methotrexate is used to treat cancer but is indicated to have very serious side effects and should not be used without advice from a competent physician.

“Although the drug is available in local pharmacies on prescription, it must never be used without clear instruction from your doctors,” says Dr Barasa.

How does Methotrexate compare to Busulfan for pre-conditioning?

So again if the Methotrexate did somehow work, I'm assuming you wouldn't be immune from getting re-infected with HIV again.   At least with Calimmune you hopefully permanently block CCR5 and CSCR4 entries and gain partial/full immunity after the potential "cure"

2013 is very interesting so far.

Offline buginme2

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I just had an interesting discovery.    Anyone that volunteers for a clinical trial that has you STOP your ART (such as Calimmune) might actually be doing TWO experiments.  Check this out.

Topic: Early HIV drugs 'functionally cure about one in 10'
http://forums.poz.com/index.php?topic=47816.0

Here's where I possibly come in:

Here's a copy and paste:
_______________________________________________

http://forums.poz.com/index.php?topic=47816.msg587206#msg587206

Maybe I'll end up as a post controller?   I actually have a potential situation where I'll be able to find out in several months.  (I'll post my results if/when it happens)

Details.........
I was diagnosed early 2012.   I had a pretty bad flu for 3 weeks so I got tested.  They told me I had a VL of 2 million, but still tested negative for antibodies.  (they have a dual HIV test at the clinic I went to)  So that means I caught it about as early as it gets.

I did research and I jumped into a clinical trial of a new CC5 blocking med:
http://www.aidsmeds.com/archive/cenicriviroc_2656.shtml  (with Truvada)
(when I started, I felt normal, and VL was pretty low naturally)
I became undetectable in several weeks. (and zero side effects)

I just completed the cenicriviroc trial and switched to complera a month ago. (again zero side effects)

The next trial I'm on the top of the list to participate in Arm 2 or 3 of the Calimmune Gene transfer trial.
http://forums.poz.com/index.php?topic=46455.0

Here's the interesting part.........

I need to STOP taking my meds several weeks before I get treated via Calimmune.    I never imagined that I might remain undetectable after I stop ART.  I'll have been on ART nearly 2 years by the time they would want me.   The fact I was on the CCR5 blocking cenicriviroc for so long and started so early gives me a decent chance at least.   I was told I was the healthiest patient in every program they have across the board too.   So pending my qualification for Calimmune, and they call me,  I'll consider it a double experiment!

I'm pretty sure I was told the Calimmune trial requires you to actually have a detectable VL before they'll treat you.    What if I remain UD month after month?  I would imagine they want test groups to be detectable so they can rule out the potential Post-treatment controller anomalies

________________________________________________

Regarding methotrexate, the NIH states methotrexate may cause serious side effects including death.  You should only take methotrexate to treat life threatening cancer or certain other conditions that cannot be treated with other medications.

Bulsulfan, while not as dire as methotrexate can cause a severe decrease in blood cells in your bone marrow and has been shown to increase the risk that you will develop other cancers.  It is considered a class 1 carcinogen.
Don't be fancy, just get dancey

Offline buginme2

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It's highly doubtful the fda would allow a study to use methotrexate to treat hiv.  Kenya must not have as strict a regulatory system to protect patients.
Don't be fancy, just get dancey

Offline POZnLA

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I just had an interesting discovery.    Anyone that volunteers for a clinical trial that has you STOP your ART (such as Calimmune) might actually be doing TWO experiments.  .......  .................  ..............  .................................................  .................  ........................
I need to STOP taking my meds several weeks before I get treated via Calimmune.    I never imagined that I might remain undetectable after I stop ART.  I'll have been on ART nearly 2 years by the time they would want me.   The fact I was on the CCR5 blocking cenicriviroc for so long and started so early gives me a decent chance at least.   I was told I was the healthiest patient in every program they have across the board too.   So pending my qualification for Calimmune, and they call me,  I'll consider it a double experiment!

I'm pretty sure I was told the Calimmune trial requires you to actually have a detectable VL before they'll treat you.    What if I remain UD month after month?  I would imagine they want test groups to be detectable so they can rule out the potential Post-treatment controller anomalies


The Calimmune study does not have you stop your ART, what they do is look for persons that have already stopped at least 6 weeks prior to thier 1st screening.

copy and paste from the study posting of inclusion requirements
__________________________________________________________

* Not taking antiretroviral therapy for ≥ 6 weeks prior to Screening 1, for one or more of the following reasons:

i) Concerns over short-term or long-term toxicities associated with antiretroviral agents, or ii) Treatment fatigue from the daily regimen of life-long therapy
____________________________________________________________

Now if you wanted to be in the study, you may first stop because you have these concerns. I stopped my ART meds at the recommendation of my Dr. because of severe allergic reactions to my meds,  I am scheduled for screening and study procedures this summer.

Offline JazJon

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I almost forgot about that important part.  It's true, they can't ethically ask you to stop taking your meds.    It's assumed you will and want to stop taking meds for "other" reasons before hand.    (such as the one you listed)

"i) Concerns over short-term or long-term toxicities associated with antiretroviral agents, or ii) Treatment fatigue from the daily regimen of life-long therapy"
((works for me))

Offline SFGMOMO

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I hope the Group 1 data is shared right away, or a Group 1 person chimes in on here. (or if anyone else hears an update they can share)

I very much appreciate the info being shared here -- the folks at Quest tell me I'm the first participant in Group 1 in San Francisco, so hopefully I'll have something worthwhile to contribute soon.  So far I've completed all the screenings, and the first apheresis was this week.  I agree it's an exciting study, and am looking forward to learning about the results.

Offline JazJon

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I very much appreciate the info being shared here -- the folks at Quest tell me I'm the first participant in Group 1 in San Francisco, so hopefully I'll have something worthwhile to contribute soon.  So far I've completed all the screenings, and the first apheresis was this week.  I agree it's an exciting study, and am looking forward to learning about the results.

Excellent!
Welcome to the forums.
We're looking forward to hearing how it goes.
Did the medicine you took pre-apheresis to release stem cells cause much discomfort?
I heard it might make your bones ache a bit. 
How long was apheresis? 1,2,3 hours?
« Last Edit: May 10, 2013, 03:02:24 pm by JazJon »

Offline SFGMOMO

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Excellent!
Welcome to the forums.
We're looking forward to hearing how it goes.
Did the medicine you took pre-apheresis to release stem cells cause much discomfort?
I heard it might make your bones ache a bit. 
How long was apheresis? 1,2,3 hours?
The first apheresis (about 3 hours, and other than a couple of painful initial jabs, not all that bad) was just for T-cells, rather than stem cells, so no prep med (Neupogen) necessary -- that's for apheresis #2 (end of next week).    That one's supposed to be longer (5-6 hours), but having been through it once, I'm not as apprehensive as I was about this week's (okay, so I admit I almost fainted, but that lidocaine needle hurt like hell!).

Thanks for the welcome -- looking forward to staying in touch!

Offline Hoyland

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Quote
Thanks for the welcome -- looking forward to staying in touch!

I wish you well SFGMOMO. You could be chronicling a history making event in the annals of HIV treatment. Good luck.

Offline freewillie99

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The first apheresis (about 3 hours, and other than a couple of painful initial jabs, not all that bad) was just for T-cells, rather than stem cells, so no prep med (Neupogen) necessary -- that's for apheresis #2 (end of next week).    That one's supposed to be longer (5-6 hours), but having been through it once, I'm not as apprehensive as I was about this week's (okay, so I admit I almost fainted, but that lidocaine needle hurt like hell!).

Thanks for the welcome -- looking forward to staying in touch!

Best of luck to you as well, SFGMOMO.  Hopefully since Calimmune isn't a publicly traded company you'll be able to get away with posting updates as you move through the process.

Signed,

A Charter Member of the Club for Junior Scientists
Beware Romanians bearing strange gifts

Offline Tadeys

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Can anybody tell me the diference between Calimmune and Benitec? Are they both working on HIV?  Benitec licences their RNAi technology to Calimune? Thank you.

Offline Hoyland

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Quote
Can anybody tell me the diference between Calimmune and Benitec? Are they both working on HIV?  Benitec licences their RNAi technology to Calimune?

Benitec is an Australian company that has exclusive rights to a technology call DNA Directed RNA Interference or ddRNAi which was developed by the Commonwealth Government Scientific Research Organisation, CSIRO. This technology is a way of turning off genes which make unwanted proteins and because it works at the DNA level in the cell the effect can be passed on through cell division thus providing a lasting "turning off" effect. This technique can be used to treat many types of diseases including HIV, HCV. HBV and various cancers.

3/4 years ago Benitec did a Pl trial in conjunction with the City of Hope for the application of the technology against HIV. This proved that the treatment was safe, however, the level of engraftment (the number of modified patient cells affected by the treatment and re-introduced to the patients) was low and so more work was required to increase the efficiency of the treatment. CoH is still conducting this work and there is a Pll program that they are working on for patients with HIV and Non-Hodgkin Lymphoma.

That said, one of the five patients treated in the Pl trial continues to have increased numbers of modified cells in their body and in theory eventually could be permanently free of the disease without any further intervention.

Benitec is no longer funding this research but one of its scientific advisors, Dr John Rossi, is still very much involved.

Calimmume has connections to Australia. They have a lab at the Uni New South Wales which is also used by Johnson and Johnson. Benitec are also using the labs at the UNSW to develop their Non-Small Cell Lung Cancer treatment. As Calimmune were working with ddRNAi as a possible treatment for HIV, albeit that their genetic constructs are different to that used by Benitec/CoH, they decided to licence ddRNAi from Benitec for the treatment of HIV.

So HIV is no longer Benitec's primary focus for the application of ddRNAi; it has left that to Calimmune, its licencee, which does have a cure for HIV as its primary goal.

UC Davis also has a ddRNAi HIV program that has been recommended for a clinical trail. This program is being run by Dr Joseph Anderson but the last I heard they have yet to secure funding. This program is very similar in its approach and targets as the CoH research.

Next year a team in Europe will start a clinical trial using ddRNAi to treat HIV. They will apply the technology in a different way to Calimmune but still with the hope of providing a single (or very limited) treatment for a complete cure from HIV.

I hope this answers your question Tadeys.

Offline POZnLA

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Benitec is an Australian company that has exclusive rights to a technology call DNA Directed RNA Interference or ddRNAi which was developed by the Commonwealth Government Scientific Research Organisation, CSIRO. ............................................... . . .         ................ ................   .......  .............. .  . . . .  .  ...................

Next year a team in Europe will start a clinical trial using ddRNAi to treat HIV. They will apply the technology in a different way to Calimmune but still with the hope of providing a single (or very limited) treatment for a complete cure from HIV.

I hope this answers your question Tadeys.

Thank you very much, a great explanation, and It is appreciated that you took the time to explain.

Offline POZnLA

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I very much appreciate the info being shared here -- the folks at Quest tell me I'm the first participant in Group 1 in San Francisco, so hopefully I'll have something worthwhile to contribute soon.  So far I've completed all the screenings, and the first apheresis was this week.  I agree it's an exciting study, and am looking forward to learning about the results.

SFGMOMO, Thanks for joining and posting. And most of all thanks for being the lead on this study.

If I understand correctly, I am the 4th, or last subject of the 1st Cohort. I was originally to be the 1st of the 2nd Cohort, I think some one dropped out and I was moved forward.

I am scheduled for my first of 2 screenings here in LA at UCLA Center for Clinical AIDS Research this coming June 10th, 2nd Screening June 26th. Assuming all goes well with the screenings 1st apheresis is July 5th, and then 5 days of Neupogen before the 2nd apheresis on July 19th.

Each study subject is done one at a time because the lab can only modify and grow one subject at a time. After the 1st cohort is finished there is a safety review before the 2nd cohort begins, again as I understand it.

Offline Tadeys

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Thank you Hoyland  ;)

It's good to know that there are other gene therapy trials under way.  Dr John Rossi says in an interview--on Youtube--, that a breakthrough using this technology will be just explosive. I agree. But not just for HIV, but for many, many, diseases.

Cheers

Offline Hoyland

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Sangamo has just released its data on the use of Zinc Fingered Nuclease against HIV. This was presented to the ASGCT and while some positives can be taken from the results, reading between the lines, I suspect that they are disappointed with the degree of engraftment. This was the same problem that CoH/Benitec encountered and one that CoH is still working on.

This makes the Calimmune trial even more important because CoH have spent the last three years on improving engraftment for their version of ddRNAi and if Sangamo are forced to do the same for ZFN that will be a major setback.

Hopefully, Calimmune has cracked that problem and Cal-1 will prove to not only be safe but efficacious too.

Offline Tadeys

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I remember reading on this forum a couple of months ago how scientist have discovered that they could DIRECTLY engraft cells with zinc fingers--- meaning, pour zinc fingers over cells. The cells studied endocytized the zinc fingers. This lead to a higher engrafment percentage then using the freaking adenovirus vector. But don't know if Callimine's technology can allow that "pouring"; besides, Calimunne is trying to delete a gene---like Sangamo-- AND insert an anti HIV gene....so, I think they need a the damn vector.

 There is Proof-of-principle that these anti HIV techniques CAN work...scientist just have to tweak them. Some newer anti HIV gene therapy technologies--still preclinical--seem light years ahead of the technology Sangamo, CoH, or Callimune have.

Offline geobee

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Carlos Barbas et al are doing "naked" ZFNs at the Scripps Institute in San Diego.  No vector.

http://www.genengnews.com/gen-news-highlights/naked-zfns-point-to-more-efficient-safer-gene-therapy/81246989/

Offline Hoyland

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For those interested Calimmune's CEO and CSO will be giving a talk on Thursday at noon explaining their work with stem cells and HIV. The talk will be webcast.

http://www.cirm.ca.gov/agendas/05202013/spotlight-hiv-immunity-pathway-clinical-trial?utm_source=twitterfeed&utm_medium=twitter

Offline JazJon

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For those interested Calimmune's CEO and CSO will be giving a talk on Thursday at noon explaining their work with stem cells and HIV. The talk will be webcast.

http://www.cirm.ca.gov/agendas/05202013/spotlight-hiv-immunity-pathway-clinical-trial?utm_source=twitterfeed&utm_medium=twitter

Interesting, I hope we can listen to it later in the day if we miss the live stream.

Offline JazJon

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For those interested Calimmune's CEO and CSO will be giving a talk on Thursday at noon explaining their work with stem cells and HIV. The talk will be webcast.

http://www.cirm.ca.gov/agendas/05202013/spotlight-hiv-immunity-pathway-clinical-trial?utm_source=twitterfeed&utm_medium=twitter

I missed it, I don't see any replay streaming options.   Did anyone catch it?  Did they share any interesting new information?

Offline Jmarksto

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I missed it, I don't see any replay streaming options.   Did anyone catch it?  Did they share any interesting new information?

Jaz; it is scheduled for Thursday (if I read Hoyl's post correctly), and it is still Wednesday so I don't think you have missed it.
03/15/12 Negative
06/15/12 Positive
07/11/12 CD4 790          VL 4,000
08/06/12 CD4 816/38%   VL 49,300
08/20/12 Started Complera
11/06/12 CD4   819/41% VL 38
02/11/13 CD4   935/41% VL UD
06/06/13 CD4   816/41% VL UD
10/28/13 CD4 1131/45% VL 25
02/25/14 CD4   792/37% VL UD
07/09/14 CD4 1004/39% VL UD
11/03/14 CD4   711/34% VL UD
03/13/15 CD4   833/36% VL UD
04/??/15 Truvada & Tivicay
06/01/15 CD4 1100/50% VL UD
10/16/15 CD4   826/43% VL UD
??/??/2017 Descov & Tivicay
2017 VL UD, CD4 stable around 850
2018 VL UD, CD4 stable around 850

Offline JazJon

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Jaz; it is scheduled for Thursday (if I read Hoyl's post correctly), and it is still Wednesday so I don't think you have missed it.

Oh whoops! lol

Offline Tadeys

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Can't see the presentation vía my f$&/@ing iPad. Can somebody comment on the presentation. Thanks. :)

Offline JazJon

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Well if they said anything interesting, it must have been in the beginning.   

I missed the first 30 minutes.   When I finally joined in, I only heard them voting down funding some unrelated bone stimulation thing.  (and then they broke for lunch)   

I tried again much later and all I heard was several good bye speeches to someone moving on.

So yeah someone will have to fill us in if anything interesting was talked about related to the Calimmune Study specifically.

Offline Hoyland

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The technology conspired against me and I too missed the presentation. However, the CIRM is shortly going to post a video online and so those that want to see the whole thing will be able to do so.

Offline Hoyland

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Hi SFGMOMO,

Based on your last post you should have had your second apheresis by now and possibly your treatment. How are things progressing, or have you had to sign a non-disclosure agreement and so are not in a position to tell us?

Offline JazJon

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"HIV Trial to Create New Immune Systems"
Tue, 2013-06-18

http://www.biosciencetechnology.com/articles/2013/06/hiv-trial-create-new-immune-systems#.UcI60PnbPL-

"Some preliminary results have been highly encouraging"


Offline Hoyland

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Looks like those on the trial will start dosing in July. Good luck to you all. :)

Offline Hoyland

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First Patient Treated in Clinical Trial Testing an Innovative Stem Cell Treatment for HIV/AIDS

San Francisco, CA – Calimmune has treated the first patient in a clinical trial involving the use of an innovative gene-based stem cell therapy to help protect individuals infected with HIV from the effects of the AIDS virus.

The Phase I/II clinical trial - which California’s stem cell agency, the California Institute for Regenerative Medicine (CIRM) is helping fund - focuses on a protein called CCR5 that plays a critical role in enabling HIV to infect cells. Blocking CCR5 may provide the cells a protective shield against HIV, which in turn would help retain immune system functionality

In this study 12 HIV-positive individuals will be infused with their own blood stem cells that carry a gene that has been modified to block production of CCR5. The hope is that those stem cells will then create a new blood system that is resistant to HIV. To guard against the virus forming resistance, the team has used a second mechanism to prevent the virus from fusing with the patient’s cells.

“This study is an early but important step in an emerging area of scientific exploration, representing the culmination of more than a decade of research and development,” says Calimmune Chief Executive Officer Louis Breton.  “We are optimistic that what we learn from this study may bring us closer to the day when a one-time or infrequent treatment could lessen, delay or provide an alternative to a lifetime of antiretroviral therapy.”

The goal of the trial – which is being conducted in San Francisco and Los Angeles - is to assess the safety of the therapy, to determine the ease of use and feasibility of the approach for HIV/AIDS patients and to evaluate what, if any, side effects there may be.

“CIRM funding of this Phase l/ll trial is an important milestone for us,” says Alan Trounson, PhD, President of the stem cell agency. “One of our goals is to support research that moves the most promising science out of the lab and into clinical trials in people. To be able to do that with a disease as devastating as HIV/AIDS highlights the importance of our funding and the potential impact it could have on the health of people around the world.”

Jeff Sheehy, the Patient Advocate member of our governing Board for HIV/AIDS, and a longtime community activist, says regardless of the results the trial is important:

"This trial will hopefully offer several important insights into the safety and feasibility of genetically modifying blood forming stem cells in an HIV patient as a potential therapy.  We are very early in this research, and with this Phase I trial's goal of establishing safety and the risks involved, I applaud the courage and altruism demonstrated by the patients who are willing to participate in this study."

According to the Centers for Disease Control and Infection (CDC) more than 1.2 million people in the US are living with HIV. This number is growing because new and more effective medications are keeping people alive longer with the infection. However, these medications – which have to be taken every day - are expensive and, over time, have side effects.
For more information about this trial, visit www.clinicaltrials.gov

About CIRM: CIRM was established in November 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The statewide ballot measure, which provided $3 billion in funding for stem cell research at California universities and research institutions, was overwhelmingly approved by voters, and called for the establishment of an entity to make grants and provide loans for stem cell research, research facilities, and other vital research.

About Calimmune
Calimmune is a clinical-stage HIV gene medicines company focused on developing innovative cell-based therapies for HIV.  The company’s stem cell technology was discovered in the labs of Nobel Laureate, Dr. David Baltimore (Caltech) and Dr. Irvin Chen (UCLA AIDS Institute).  Calimmune is also developing a rich product candidate pipeline to address the needs of different types of individuals at different states of HIV infection and with different levels of treatment experience.

Offline 1in1000000

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Can someone explain  with more details how protein (C46) inhibits HIV?
It is on the surface of the cell or inside?
« Last Edit: July 10, 2013, 08:03:45 pm by 1in1000000 »

Offline Matts

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...."As mentioned above, only a fraction of cells will acquire mutations at both alleles of CCR5 following genetic targeting. By combining this gene therapy approach with pharmacological approaches, antagonism of HIV entry may be further enhanced. For example, peptides such as C46 and T20/enfuvirtide act as dominant negatives to block membrane fusion.CCR5 binding small molecules, such as INCB9471, Vicriviroc, Aplaviroc and, most notably, Maraviroc, block association with env and are predicted to phenocopy CCR5 genetic disruption...."

http://www.nature.com/gt/journal/v20/n7/full/gt201298a.html


"Calimmune’s ddRNAi-based HIV candidate LVsh5/C46 for example down-regulates the cellular receptor for viral entry, CCR5, such that HIV particles cannot enter cells and integrate into their genomes in the first place.  As an ddRNAi gene therapy approach, LVsh5/C46 further takes advantage of the fact that you can express a therapeutic protein along with the RNAi trigger, thus uniquely combining mechanisms of actions in a single drug...."

http://rnaitherapeutics.blogspot.de/2012/12/viruses-beware-this-time-rnai.html

Dovato

Offline Hoyland

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This latest profile of Calimmune may be of interest to some who could not seem themselves as qualifying for the treatment currently being trial by the company. See the sentence in bold:

Quote
Calimmune is a clinical-stage HIV gene medicines company focused on developing innovative cell-based therapies for HIV. The company’s stem cell technology was discovered in the labs of Nobel Laureate Dr. David Baltimore (Caltech) and Dr. Irvin Chen (UCLA AIDS Institute). Calimmune is also developing a rich product candidate pipeline to address the needs of different types of individuals at different states of HIV infection and with different levels of treatment experience.

Offline Hoyland

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Video of Calimmune presentation to CIRM.

http://www.youtube.com/watch?v=d5GSJeaAgP0

Offline freewillie99

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Video of Calimmune presentation to CIRM.

http://www.youtube.com/watch?v=d5GSJeaAgP0

Good video, as is the second featuring Dr. Geoff Symonds, Calimmune's Chief Scientific Officer.  The quiet confidence both bring to their presentations (vs. more typical corporate bravado and hyperbole) gives me hope.  Also liked the comments of the HIV doc at around the 8:00 mark in the second part.   Very good and got me a little choked up.  Of course, there are still so many questions: efficacy, distribution, cost, etc, but the science and their assembled team are fantastic.  Best of luck. 
« Last Edit: July 19, 2013, 09:45:08 am by freewillie99 »
Beware Romanians bearing strange gifts

Offline geobee

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Here's the second video -- Dr. Symond's talk after Louis Breton's talk.

http://www.youtube.com/watch?v=dVtCl4Vmt6k

Offline Hoyland

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The first cohort should have been dosed by now and so some preliminary data should be available in about another 4 months.

Has anyone heard any anecdotal comments about the study?


Offline JazJon

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I just checked in asking to confirm that I'm still on the list for 2013/2014

I was told that as soon as the last person in this cohort gets their infusion they will give me a call to start my treatment interruption for screening. 
(Probably sometime in November)

I'm still ready to do this and standing by.

Offline JazJon

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Video of Calimmune presentation to CIRM.

HIV/AIDS Stem Cell Clinical Trial: Louis Breton, CEO, Calimmune
http://www.youtube.com/watch?v=d5GSJeaAgP0

Here's the second video -- Dr. Symond's talk after Louis Breton's talk.

HIV/AIDS Stem Cell Clinical Trial: Geoff Symonds, Chief Scientific Officer, Calimmune
http://www.youtube.com/watch?v=dVtCl4Vmt6k

I forgot to say thanks for posting those videos, great updates!

Offline GoForIt

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I forgot to say thanks for posting those videos, great updates!

Thanks for re-posting these...I just watched them and my general feeling is hopeful and optimistic.  I think it takes very brave people to be apart of these trials and wish you, JazJon, all the luck in the world with this. 

I know I will be anxiously waiting to hear more.  Thanks again all who are contributing to keeping everyone informed on these medical advances in the pipeline.
08/09/2013  Diagnosed WB positive
08/20/2013  CD4-506(28%)  VL-10,800
09/12/2013  CD4-391(28%)  VL-14,900
09/17/2013  Start ART (Truvada + Tivicay)
10/11/2013  CD4-377(26%)  VL-UD
12/20/2013  CD4-590(??%)  VL-UD
03/18/2014  CD4-660(29%)  VL-UD
07/22/2014  CD4-613(29%)  VL-UD
08/01/2014   Start Phase 3 TAF (Truvada 2.0) Clinical Trial (TAF + Tivicay)
10/09/2014  CD4-498(29.5%) VL-UD
11/06/2014  CD4-600(30.2%) VL-UD
01/30/2015  CD4-529(31.3%) VL-UD
07/25/2015  CD4-742(36.5%) VL-UD
10/06/2015  CD4-765(28.9%) VL-UD
01/05/2016  CD4-907(33.1%) VL-UD
03/24/2016  CD4-770(33.5%) VL-UD
06/20/2016  CD4-850(35.4%) VL-UD

Dr. Mark Wainberg on Dolutegravir:
Video 1: https://youtu.be/wCXOgLJqJAY
Video 2: https://youtu.be/DKiaD7fHO-s

Offline Matts

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If You are accidentally in Berlin You can visit tomorrow from 12.30 til 14.00  "HIV im Dialog" in the Red City Hall.
http://en.wikipedia.org/wiki/Rotes_Rathaus
Gero Hütter ( the man who cured T.Ray  Brown) and Prof. Joachim Hauber ( Tre-recombinase) are speaking about the newest cure research. I think it will be interesting, and it's for free. I am sure that Dr. Hütter will tell something new about CalImmune and his Gene trial.
http://www.hiv-im-dialog.de/index.php?id=40
Dovato

Offline Hoyland

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The latest information released by the CIRM says that the Calimmune HIV trail has produced NO reports of serious safety events and that company is now planning the next trial of Cal-1 which will be conducted outside of the USA.


http://www.cirm.ca.gov/sites/default/files/files/agenda/131009_Agenda_10_Translational_Portfolio_Update_ICOC_1013_final.rev__0.pdf

Offline JungleJungle

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Just a question....blocking CCR5 isn't just the same used by the Entry Inhibitor as Fuzeon or Maraviroc??
I read that side effect about CCR5 receptor: "blocks the CCR5 coreceptor located on some immune system cells, there is a theoretical risk of developing infections and cancers."

Is that really a good choice to carry for a lifetime a genetically mutated immune system which is not effective anymore??
You need coolin', baby, I'm not foolin',
I'm gonna send you back to schoolin',
Way down inside honey, you need it,
I'm gonna give you my love,
I'm gonna give you my love.

Offline Matts

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As far as I know Maraviroc only bends the CCR5 out of shape- it's completely reversible and it only works as long as You take the drug. ZNF and CalImmune destroy the receptor forever. 4-16% of Europeans live quite well with this muation and are naturally immune against HIV. There some studies that MVC can prevent breast and prostate cancer, but You get more vulnerable for the West Nile Virus. I never heard before that there is a "theoretical risk of developing infections and cancers."
You can find more information here:
http://en.wikipedia.org/wiki/CCR5

Dovato

Offline JungleJungle

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It is reported in the side effects of Maraviroc...i just did paste&copy from the drugs section of this website.
« Last Edit: October 11, 2013, 01:02:51 pm by JungleJungle »
You need coolin', baby, I'm not foolin',
I'm gonna send you back to schoolin',
Way down inside honey, you need it,
I'm gonna give you my love,
I'm gonna give you my love.

Offline JazJon

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The latest information released by the CIRM says that the Calimmune HIV trail has produced NO reports of serious safety events and that company is now planning the next trial of Cal-1 which will be conducted outside of the USA.


http://www.cirm.ca.gov/sites/default/files/files/agenda/131009_Agenda_10_Translational_Portfolio_Update_ICOC_1013_final.rev__0.pdf

Interesting :)

I asked about this and got a response.

"Hi Jon,
You know you are my number 1 guy right?! funny you mention CIRM, because they will be here next week! I believe what they are really planning to do is 'planned future ex US trials with same product in a different subgroup of HIV patients'  which means that they are going to look into other groups of patients outside of the US as well. That wont effect your participation in the study at all."

Offline Hoyland

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Did anyone attend the Calimmune and Sangamo presentations at the World Stem Cell Summit yesterday? Being in clinical trials and combining cell and gene technologies seems to give these two programs a high profile.

Offline JazJon

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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!"

Offline Hoyland

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This paper is the latest work published with collaboration from Geoff Symonds of Calimmune. This seems to be a different approach to Cal-1 but because its underpinning technology is the same the two could probably be incorporated into a single treatment at some future stage.

------
Despite prolonged and intensive application, combined antiretroviral therapy cannot eradicate human immunodeficiency virus (HIV)-1 because it is harbored as a latent infection, surviving for long periods of time. Alternative approaches are required to overcome the limitations of current therapy. We have been developing a short interfering RNA (siRNA) gene silencing approach. Certain siRNAs targeting promoter regions of genes induce transcriptional gene silencing. We previously reported substantial transcriptional gene silencing of HIV-1 replication by an siRNA targeting the HIV-1 promoter in vitro. In this study, we show that this siRNA, expressed as a short hairpin RNA (shRNA) (shPromA-JRFL) delivered by lentiviral transduction of human peripheral blood mononuclear cells (PBMCs), which are then used to reconstitute NOJ mice, is able to inhibit HIV-1 replication in vivo, whereas a three-base mismatched variant (shPromA-M2) does not. In shPromA-JRFL–treated mice, HIV-1 RNA in serum is significantly reduced, and the ratio of CD4+/CD8+ T cells is significantly elevated. Expression levels of the antisense RNA strand inversely correlates with HIV-1 RNA in serum. The silenced HIV-1 can be reactivated by T-cell activation in ex vivo cultures. HIV-1 suppression is not due to offtarget effects of shPromA-JRFL. These data provide “proof-of principle” that an shRNA targeting the HIV-1 promoter is able to suppress HIV-1 replication in vivo.

.....

Using the CD34+ cell–reconstituted NOJ model, we wish to explore a scenario closer to that which we envisage these constructs will be used in human HIV-1 treatment, primarily on cessation of antiretroviral drugs in controlled chronic infection to determine whether lentivirally delivered shPromA constructs can stabilize the viral reservoir on withdrawal of antiretroviral therapy. If the latent viral reservoir could be maintained as effectively silenced by shPromA treatment, these constructs would represent a substantial step forward on the road toward a functional cure, by providing an alternative to the currently proposed eradication strategies than using various viral transcription activating agents, such as histone deacetylase and demethylases.49,60,61 Rather than activating virus and abolishing infected cells, we propose that constructs such as shPromA could be used to lock HIV-1 into latency maintaining transcriptionally inactive virus even in patients ceasing conventional antiretroviral therapy, thus achieving a prolonged remission or functional cure of HIV-1 infection.

http://www.nature.com/mtna/journal/v2/n12/full/mtna201364a.html

Offline Hoyland

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Co-authored by Calimmune and Gero Hutter this paper explains more about the synergy between Cal-1  and the Berlin Patient.

www.mdpi.com/1999-4915/6/1/54/pdf

Quote
Abstract: Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection—this without detrimental effects to the host—and transplantation of CCR5-delta32 stem cells in a patient with HIV (“Berlin patient”) achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase
I/II trials by engineering HIV-resistant hematopoietic cells.

Offline freewillie99

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I look forward to the day when these guys announce they've cured someone.  Big party.
Beware Romanians bearing strange gifts

Offline dico

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So what happened to the cohort 2?

Offline JazJon

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So what happened to the cohort 2?

No update yet, things got delayed until February/March last I heard. 

Offline dico

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It's really unfortunate to see how slow they are !

And you are in the 2nd cohort ?

Offline dico

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So no news about the 2nd Calimmune cohort ?

This clinical trial is the only ''cure'' trial. That's why it is so important to me. I tested poz 2 years ago and I turned 26 one month ago. I hope I can be cured before my 30th birthday.

I really envy those that are part of this trial (especially the 3rd cohort), but I live in Paris... I hope the Phase II/III will involve Parisian people ;)

Offline Hoyland

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Dico, just a rumour but I heard that the next phase will involve patients in the UK and Australia as well as the States.

Offline dico

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Nice !!

And did you hear any news about the gene therapy trial in Europz that was supposed to begin in 2014 ?

I think this trial is under the leadership of Ben Berkhout (Holland) ?

Thanks

Offline Hoyland

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Dico, I have not corresponded with Prof Berkhout for some time now. The last info I had is that he was on target but requires funding.

I suggest you correspond with him directly. He is a very friendly and helpful person and I am sure he will give you an honest opinion of where his team is at.

Offline Hoyland

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Yet another scientific paper supporting Calimmune's approach

http://www.nature.com/mt/journal/v22/n2/abs/mt2013264a.html?WT.ec_id=MT-201402

A lot of good scientific data, if only we could get some good trial data?

Offline dico

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Thank you very much for your answer.

I am pretty certain that the strategy of Calimmune is the good one. The only problem is the low engraftment (less than 20% of the cells) even with the chimio.  But the strategy of silencing hiv gene by Prof. Berkhout is very complimentary to the Calimmune trial. I hope they will merge their strategies in a combined phase II trial. Then this combined action with improved engraftment can really lead to a fonctional cure. Or I hope so. Because if this gene therapy fails, HIV sufferers will not have any hope of cure for the next 20 years.

I emailed Prof Alain Lafeuillade which is a French researcher very involved in the strategy of ''forever keeping the latent HIV dormant in the cells". He is angry to see all the millions that are spent on vaccines and other strategies doomed to failure. He thinks the Sangamo way of acting to be dangerous and unpratical. I agree with him.

I emailed Prof. berkhout today and I am waiting an answer. I hope he will answer.

If anyone has news about the clinical trial of Prof Berkhout or the Calimmune trial, it would be a pleasure to know more about them.

If Calimmune plans to do clinical trial in France, I will be among those that will be eager to be part of such a trial
« Last Edit: February 03, 2014, 12:47:04 pm by dico »

Offline dico

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Dico, I have not corresponded with Prof Berkhout for some time now. The last info I had is that he was on target but requires funding.

I suggest you correspond with him directly. He is a very friendly and helpful person and I am sure he will give you an honest opinion of where his team is at.

Unfortunately Prof Berkhout did not answer to my numerous mails... You are luckier than me. :(

Offline freewillie99

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I emailed Prof Alain Lafeuillade which is a French researcher very involved in the strategy of ''forever keeping the latent HIV dormant in the cells". He is angry..."

An angry Frenchman.  Shocker.
Beware Romanians bearing strange gifts

Offline Hoyland

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More pre-clinical data.

http://www.nature.com/articles/mtm201311#affiliations

Quote
Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self-inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA) for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4+ T lymphocytes, and CD34+ hematopoietic stem/progenitor cells (HSPC). CCR5-targeted shRNA (sh5) and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5- and CXCR4-tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease.

Offline freewillie99

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More pre-clinical data.

http://www.nature.com/articles/mtm201311#affiliations

It's humbling reading down through all those supporting references (a few of which go back to 1996) just how much work has been carried out to get to this point.  May there be a second Nobel for Dr. Baltimore and company in the near future. 
Beware Romanians bearing strange gifts

Offline dico

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Hi Hoyland.

Just wanted to tell you that prof. Berkhout does not answer to my mails...

And is anybody here who is included in the cohort 2 of the Calimmune clinical trial? When it will begin ?

Thank you

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 ŕ 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
2/2008 - 5/2015 - undetectable on Atripla
May, 2015 - UD, switched to Complera
September, 2015 - UD, 980 cd4, switched to Stribild (Complera interacted with acid reflux medication)
January, 2016 - Stribild, UD, 950 cd4
June, 2016 - UD, 929 cd4

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.   
Don't be fancy, just get dancey

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.
Don't be fancy, just get dancey

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 »
Dovato

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.
Dovato

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

Offline dico

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Hi all,

What about the third group with high busulfan dose ?

Did they    begin the treatment ? I know the JonJaz wanted to take part in the third group, did you begin the treatment or not yet ?

Thanks

Offline Matts

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The Charite Hospital Berlin has published a roadmap for a functional HIV cure using
 autologous hematopoietic stem cell (HSC). If somebody has full Access for the Agenda I would be thankful. Do they talk about 10, 20 or 30 years ? :)

http://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(14)00137-3

"A roadmap toward clinical translation of genetically-modified stem cells for treatment of HIV


Highlights


•We established a collaborative project between academia and regulatory agencies.
•This roadmap aims to facilitate the process of providing access to a cure for HIV.
•We identified steps and challenges for clinical translation of gene therapy.



During the past decade, successful gene therapies for immunodeficiencies were finally brought to the clinic. This was accomplished through new gene therapy vectors and improved procedures for genetic modification of autologous hematopoietic stem cells. For HIV, autologous hematopoietic stem cell (HSC) gene therapy with ‘anti-HIV genes’ promises a functional cure for the disease. However, to develop such a therapy and translate it into a clinical application is rather challenging. The risks and benefits of such a therapy have to be understood, and regulatory hurdles need to be overcome. In this joint paper by academic researchers and regulators, we are, therefore, outlining a high level roadmap for the early stage development of HSC gene therapy as a potential functional cure for HIV."
----------------------------------
The offical press release of the Charite is only available in german so far. I think a translation will follow:

http://www.charite.de/charite/presse/pressemitteilungen/artikel/detail/schritt_fuer_schritt_zu_einer_gentherapie_bei_hiv/

Dr. Hütter cured Mr. Brown in the Charite; now working for CalImmune. I think that they all are in connection and work in an international network for a possible solution the future.


« Last Edit: November 19, 2014, 02:29:03 pm by Matts »
Dovato

Offline Jmarksto

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Matts;  Thanks for posting this -- it is very interesting.  In terms of 10,20, or 30 years, this excerpt is somewhat telling:

"In this joint paper by academic researchers and regulators, we are, therefore, outlining a high level roadmap for the early stage development of HSC gene therapy as a potential functional cure for HIV."


The fact that this is a combination of researchers and regulators -- and the private sector is not included, with the use of the terms "high level road map" and "early stage development" all indicate more than 10 years.  Just looking at the speed of science I would guess less than 30 years -- so that puts us at 20 years.  That said, who would have thought we would be where we are today with gene therapy and stem cell research ten years ago.
03/15/12 Negative
06/15/12 Positive
07/11/12 CD4 790          VL 4,000
08/06/12 CD4 816/38%   VL 49,300
08/20/12 Started Complera
11/06/12 CD4   819/41% VL 38
02/11/13 CD4   935/41% VL UD
06/06/13 CD4   816/41% VL UD
10/28/13 CD4 1131/45% VL 25
02/25/14 CD4   792/37% VL UD
07/09/14 CD4 1004/39% VL UD
11/03/14 CD4   711/34% VL UD
03/13/15 CD4   833/36% VL UD
04/??/15 Truvada & Tivicay
06/01/15 CD4 1100/50% VL UD
10/16/15 CD4   826/43% VL UD
??/??/2017 Descov & Tivicay
2017 VL UD, CD4 stable around 850
2018 VL UD, CD4 stable around 850

Offline buginme2

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I'd say more like 30 years but thats just a personal opinion.

If your interested in autologous hematopoietic stem cell transplants the fred hutchinson cancer research institute in the united states is currently conducting clinical trials.  Currently they are limiting participation only to those who are hiv+ AND have a blood cancer such as lymphoma or leukemia.

This will never move to the general public ie hiv+ without cancer, unless these trials show specific benefit errr cure in the cancer cohort.

So, at least 30 years.


http://defeathiv.org/clinical-studies/eligibility/
Don't be fancy, just get dancey

Offline Matts

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thx for the link. It seems to be quite difficult with all the chemo and radiation.

The Charite answered my email, but it was the same I can read in the newspapers here: ' they work at full speed on the thing and the first Patient will be treated in 2016; taking haemocytoblasts, altering them with synthetic Anti-HIV genes and injecting them back or something like that.
Allegedly the science is not the problem, more the bureaucratic hurdles.

Ok we will see in 2017 or later :)

http://www.b-crt.de/presse/pressemitteilungen/single-news/?tx_ttnews%5Btt_news%5D=154&cHash=5855cdc7dc15866dbd7126949e6892af&L=1

 
Dovato

Offline Hoyland

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Geoff Symonds is providing an update on the Calimmune project in Miami on Dec 10.

http://www.informedhorizons.com/hivdart2014/pdfs/PreliminaryProgram_HIVDART2014.pdf

Offline Matts

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G. Symond's abstract is online: (page 4)

http://www.informedhorizons.com/hivdart2014/pdfs/EBook_HIVDART2014_FinalV2.pdf

Quote
Background
While ART has the ability to reduce viral load and maintain CD4 count thereby reducing morbidity and mortality, it must be taken daily lifelong, leading to cumulative side effects and resistance can develop due to compliance issues . Cell-delivered HIV gene therapy involves the introduction of anti-HIV-1 genes into blood cells to provide a population of protected cells . Transplantation of CCR5-/- hematopoietic stem cells has recently proven effective as a clinical approach for treatment of HIV-1 infection and cell-delivered gene therapy may inhibit HIV-1 replication and maintain CD4 counts . It has the potential to reduce the reservoir and eliminate or reduce the need for ART .

Methods
We have produced a self-inactivating lentiviral vector (LVsh5/C46) that contains i) a short hairpin RNA directed to the CCR5 HIV co-receptor under the control of the H1 promoter and ii) a C46 fusion inhibitor under the control of the Ubiquitin C promoter . This vector has been used to transduce hematopoietic cell lines and primary hematopoietic cells . The cells have then been tested for viability, phenotype and ability to inhibit replication of HIV-1 . In addition we have conducted studies in the humanized bone marrow, liver, thymus (BLT) mouse in which a control group received non-modified human CD34+ hematopoietic stem/progenitor cells (HSPC), while the treatment group was transplanted with HSPC transduced with LVsh5/C46 .

Results
This dual therapeutic vector showed robust expression in blood cells and strong and sustained inhibition of HIV-1 replication against both R5 and X4 strains of HIV-1 in all cell types tested . In the mouse experiments, splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 . For the LVsh5/C46 treated group, there was no impact on engraftment or multi-lineage differentiation compared the control group and when challenged in vivo with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks post-infection . LVsh5/C46 gene-marking and transgene expression was confirmed stable at 26 weeks post-transplantation

Conclusions
This pre-clinical data strongly support the use of LVsh5/C46 lentiviral vector in cell-delivered gene therapy for HIV and has paved the way forward to clinical testing.

good to know that it works against CCCR5 and CXCR4.

If somebody finds another interesting abstract in the PDF, please post it :)

« Last Edit: January 11, 2015, 02:41:57 pm by Matts »
Dovato

Offline Hoyland

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Unfortunately this material is very old and one has to wonder why the company is resorting to presenting pre-clinical data at a time when it already knows the results of the first cohort of patients in its human trial. What is it that the company is being so coy about?


Offline Hoyland

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The Kirby Institute in Australia has collaborated with Calimmune. Their latest paper deals with an approach to HIV latency.

http://www.nature.com/mtna/journal/v4/n1/full/mtna201467a.html

On the work with Calimmune:

Quote
We have recently demonstrated the TGS activity of our Prom A construct in an in vivo study using the (NOD)/SCID/Janus kinase 3 (NOJ) knockout humanized mouse model (Figure 2),120 where we employed a lentiviral vector to deliver the short hairpin (sh) form of PromA. After the shRNA expression unit is transcribed from the U6 promoter by RNA polymerase III, which terminates at a poly(T) motif coded within the expression unit, both sense and antisense strands are hybridized with a loop sequence linking both strands. The loop sequence is then processed by cellular ribonucleases to form mature/processed double-stranded siRNA-PromA.129 We demonstrated the potential of this approach by reconstituting mice with human PBMC transduced with the lentiviral shPromA construct. This mimics a CD4+ T-cell delivery approach. Upon challenge with HIV-1JRFL, mice reconstituted with untransduced PBMCs had an acute, progressive HIV-1 infection with high viral loads, massive CD4+ T-cell depletion and profound immunodeficiency that occurred within 2 weeks.130,131 Despite this acute, rapidly progressive and aggressive infection, pVL in the mice transplanted with PBMC expressing shPromA was significantly lower than in mice treated with the control mutated shPromA-M2 construct, which does not efficiently suppress the virus in vitro. Mononuclear cells were recovered at sacrifice (day 14 after HIV-1 infection) from the peritoneal cavity and spleen, and CD4+ T cells were markedly reduced relative to CD8+ T in the control mice, while the ratio was relatively preserved in mice transplanted with shPromA-transduced cells. Experiments using mice reconstituted with transduced human CD34 cells are currently underway. The aim is to provide sufficient data using this model system to warrant therapeutic development of these constructs. Our proposed therapeutic strategy would be to use these constructs to enforce latency in patients who have been pretreated with cART and have a residual latent viral reservoir. This strategy offers an alternative approach as a “functional cure,” which is the antithesis of a viral activation or “kick and kill” approach. We hypothesize that this new approach could be used in order to induce and maintain HIV-1 latency, enforcing transcriptionally inactive virus even in patients ceasing cART.

And in conclusion to this paper:

Quote
In the future, ncRNA-based approaches may lead to novel therapies that either enforce HIV-1 latent infection or induce activation of HIV from latently infected cells, allowing control of the reservoir in the absence of traditional antiretroviral drugs.


Offline Hoyland

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More pre-clinical work by Calimmune's partner, UCLA, confirms the CCR5 blocking strategy using HSPC's should work.

http://www.nature.com/mtna/journal/v4/n2/full/mtna20153a.html

Quote
In this study, we characterized selective protection of sh1005-mediated CCR5 downregulated CD4+ T lymphocytes in vivo in HIV-1–challenged hu BLT mice. Our results showed that CD4/CD8 ratios in sh1005-gene modified populations were stably maintained in peripheral blood and lymphoid tissues in CCR5 (R5) tropic HIV-1–challenged BLT mice. sh1005-modified memory CD4+ T cells were also well maintained in lymphoid tissues, suggesting that sh1005-mediated CCR5 downregulation can protect memory CD4+ T cells, the primary target of R5-tropic HIV-1. The frequencies of HIV-1 infected cells were significantly reduced in the sh1005-modified splenocytes, measured by viral reactivation by ex vivo cell stimulation. These results demonstrated that sh1005 is a potent early-step anti-HIV reagent that provides HIV-1 resistance to CD4+ T lymphocytes by stable CCR5 downregulation and can be effective in HSPC gene therapy strategies for HIV-1 disease.

As the strategy is now being tested in the clinic, I am left wondering about the value of this additional pre-clinical work. It cannot be long before the final cohort in the Calimmune trial is dosed and the early results for patients in cohorts 1&2 should be known and I would have thought that those results would be more revealing than additional work in mice.


Offline tryingtostay

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http://m.bizjournals.com/sanfrancisco/blog/biotech/2015/03/hiv-aids-cirm-stem-cells-sangamo-sgmo-usc.html?r=full

FDA said Ok to stem cell trial.

Does this only address the CD4 cells?  Aren't there the macrophages and other cells HIV infects?

Offline Hoyland

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The theory is that Hematopoietic Progenitor/Stem Cells (HSC) proliferate and  differentiate into a wide variety of blood cells and so genetic modifications at the progenitor/stem cell level get passed on to daughter cells of various types. This includes CD4 cells and macrophages.

This is why both Calimmune and Sangamo are targeting these HSC cells. They represent the greatest coverage of modified cell types from a single infusion.

Offline tryingtostay

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The theory is that Hematopoietic Progenitor/Stem Cells (HSC) proliferate and  differentiate into a wide variety of blood cells and so genetic modifications at the progenitor/stem cell level get passed on to daughter cells of various types. This includes CD4 cells and macrophages.

This is why both Calimmune and Sangamo are targeting these HSC cells. They represent the greatest coverage of modified cell types from a single infusion.

Thanks Hoyland

Offline Hoyland

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In a National Cancer Institute sponsored trial, the Fred Hutchinson Cancer Research Center in Seattle will use Calimmune's Cal-1 to treat AIDS patients that have Lymphoma. The trial will start in April.

https://www.clinicaltrials.gov/ct2/show/NCT02378922

Offline xman

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the biggest problem to overcome is that hiv could adapt itself to the modified immune system by using the other coreceptor to enter the cell. i must admit that i'm very skeptic about this approach. the risk is to fail after several years of testing.

Offline tryingtostay

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the biggest problem to overcome is that hiv could adapt itself to the modified immune system by using the other coreceptor to enter the cell. i must admit that i'm very skeptic about this approach. the risk is to fail after several years of testing.

Aren't they including the cxcr4 receptor also???  That's a big oversight.  Is the cxcr4 receptor even studied???

Offline Hoyland

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CXCR4 tropic patients are excluded from the current trial but Calimmune is researching how to target this strain of HIV. The company is going to start another clinical trial in Australia in a few months time. It is possible that the new trial will include both CCR5 and CXCR4 tropic patients. No details of the trial have been released.

Offline POZnLA

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Is there any one who has participated in the first 2 cohorts of the study.? I almost was in the first one and I am trying again for the 3rd. I just went off Meds.

Offline Hoyland

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POZnLA, those on the trial will be bound by a non-disclosure agreement and so, publicly at least, they will not be able to say much.

Meanwhile, Calimmune continues to publish pre-clinical data supporting its treatment.

http://www.nature.com/mtna/journal/v4/n4/full/mtna201510a.html

Quote
Ex vivo challenge experiments with splenocytes from the treatment group displayed protection from both R5-tropic and X4-tropic HIV-1 infection, with inhibition of HIV-1 replication as measured by p24 ELISA of culture supernatant.Twelve weeks after human CD34+ HSPC transplantation, high-dose intravenous infection of R5-tropic HIV-1 exists. Treatment group animals maintained CD4+ T-cell levels and reduced viral loads within the peripheral blood and lymphoid tissues. Interestingly, the treatment group of animals displayed background levels of HIV-1 detection within the peripheral blood and lymphoid tissues tested at 14 weeks postinfection. The lack of substantial evidence of HIV-1 detection within the treatment group suggests that LVsh5/C46-modified cells were able to systemically control the infection or potentially completely inhibit the initial viral challenge infection. Furthermore, LVsh5/C46 gene-marking and transgene expression was stable up to 6 months post-transplantation of transduced CD34+ HSPC, and a reporter version of the construct was able to demonstrate significant downregulation of CCR5 in vector-modified cells in vivo.

 


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