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Author Topic: Dendritic Cell-Based Vaccines  (Read 2558 times)

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Offline Mishma

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  • Posts: 190
    • Marquis de Vauban
Dendritic Cell-Based Vaccines
« on: January 02, 2013, 06:33:56 PM »
Dendritic cells present antigens to naive T cells in our lymph glands. This would be especially important to newly infected patients who have immediately started cART, before the "architecture" of the gland was altered with long term chronic HIV infection.


RESEARCH ARTICLE
HIV
A Dendritic Cell–Based Vaccine Elicits T Cell Responses Associated with Control of HIV-1 Replication
Felipe García1,*,†, Nuria Climent1,*, Alberto C. Guardo1, Cristina Gil1, Agathe León1, Brigitte Autran2, Jeffrey D. Lifson3, Javier Martínez-Picado4,5, Judit Dalmau4, Bonaventura Clotet4, Josep M. Gatell1, Montserrat Plana1,*, Teresa Gallart1,*, For the DCV2/MANON07-ORVACS Study Group
+ Author Affiliations

http://stm.sciencemag.org/content/5/166/166ra2.abstract

1Hospital Clinic-IDIBAPS, HIVACAT, University of Barcelona, 08036 Barcelona, Spain.
2INSERM UMR-S-945, Université Paris-VI Pierre-et-Marie-Curie, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
3AIDS and Cancer Virus Program, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
4AIDS Research Institute IrsiCaixa, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
5Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.
+ Author Notes

↵* These authors contributed equally to this work.

↵†To whom correspondence should be addressed. E-mail: fgarcia@clinic.ub.es
ABSTRACT

Combination antiretroviral therapy (cART) greatly improves survival and quality of life of HIV-1–infected patients; however, cART must be continued indefinitely to prevent viral rebound and associated disease progression. Inducing HIV-1–specific immune responses with a therapeutic immunization has been proposed to control viral replication after discontinuation of cART as an alternative to “cART for life.” We report safety, tolerability, and immunogenicity results associated with a control of viral replication for a therapeutic vaccine using autologous monocyte-derived dendritic cells (MD-DCs) pulsed with autologous heat-inactivated whole HIV. Patients on cART with CD4+ >450 cells/mm3 were randomized to receive three immunizations with MD-DCs or with nonpulsed MD-DCs. Vaccination was feasible, safe, and well tolerated and shifted the virus/host balance. At weeks 12 and 24 after cART interruption, a decrease of plasma viral load setpoint ≥1 log was observed in 12 of 22 (55%) versus 1 of 11 (9%) and in 7 of 20 (35%) versus 0 of 10 (0%) patients in the DC–HIV-1 and DC-control groups, respectively. This significant decrease in plasma viral load observed in immunized recipients was associated with a consistent increase in HIV-1–specific T cell responses. These data suggest that HIV-1–specific immune responses elicited by therapeutic DC vaccines could significantly change plasma viral load setpoint after cART interruption in chronic HIV-1–infected patients treated in early stages. This proof of concept supports further investigation of new candidates and/or new optimized strategies of vaccination with the final objective of obtaining a functional cure as an alternative to cART for life.
« Last Edit: January 02, 2013, 06:36:16 PM by Mishma »
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline Jmarksto

  • Member
  • Posts: 508
Re: Dendritic Cell-Based Vaccines
« Reply #1 on: January 06, 2013, 03:26:21 PM »
Even though the results are short term, these findings seem significant in my mind for a few reasons:

1.) Isn't this the first vaccine to show this much of an impact on viral load across more than 50% of participants for any period of time?  The RV144 trial had a 30% effectiveness, after significant analysis.  I recognize this is a phase I study with 60 participants and the RV 144 study was a phase II study with 16,000 participants - so they are at least two different kinds of apples, but not apples and oranges.

2.) These are the first preliminary efficacy findings of using the whole killed virus rather than a viral vector.  The University of Western Ontario and Sumagen's approach (SAV001) also uses a whole killed virus (but I don't think published phase I efficacy numbers).

It'll be interesting to see where this goes over the next few years.

JM



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

Offline hiv_positive_BG

  • Member
  • Posts: 58
Re: Dendritic Cell-Based Vaccines
« Reply #2 on: January 07, 2013, 12:13:27 AM »
Hello, I hope my question doesn't sound naive, but how could one benefit from that new discovery? If you go to that hospital in Spain, could you also become a "test patient", who would benefit from one year free of medications?

I live in Bulgaria and wonder could I go to Spain and get the "one year off" vaccine...

Offline Mishma

  • Member
  • Posts: 190
    • Marquis de Vauban
Re: Dendritic Cell-Based Vaccines
« Reply #3 on: January 07, 2013, 12:29:09 AM »
Here in the US we have a portal to clinical trials throughout the US via the internet ( http://www.clinicaltrials.gov). I do not know how they do their recruiting anywhere else.

This was a small proof of concept study. Given their results it is sure to be expanded. You could contact the authors of this study and tell them you are interested in becoming a study participant.

There are a number of Brits on these boards, I bet they would know better how things work in the EU.   
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline hiv_positive_BG

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  • Posts: 58
Re: Dendritic Cell-Based Vaccines
« Reply #4 on: January 07, 2013, 10:26:20 AM »
Thanks a lot for your answer!

Offline Markmt

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  • Posts: 175
Re: Dendritic Cell-Based Vaccines
« Reply #5 on: January 07, 2013, 03:12:28 PM »
These last few months have been amazing with so many reliable breakthroughs from all over the world. California, San Antonio, Canada, Japan, Spain, France Switzerland, SouthAfrica and so on!... While its good to keep feet on the ground it really seems like its all heading in the right direction, with very interesting years ahead. All fingers crossed. 
"Live to love and love to live."

Leo Buscaglia

Offline Mishma

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  • Posts: 190
    • Marquis de Vauban
Re: Dendritic Cell-Based Vaccines
« Reply #6 on: January 07, 2013, 04:00:13 PM »
I can not recommended enough a Immnology Textbook I've been reading for the last 20+ years and now in its Seventh Edition: Cellular and Molecular Immunology by Abul K Abbas, Andrew Lichtman and Shiv Pillai ISBN: 978-1-4377-1528-6. The book is used for  first or second year  medical students throughout the US. Besides being a fantastic textbook with great graphics, the book is a great reference book. For example you might wonder, what the heck is a Dendritic cell and where did it come from?

Another reference to Dendritic Cells and their function in spreading HIV to CD4 cells comes from the front page of POZ News:
http://www.sciencedaily.com/releases/2012/12/121218203506.htm
« Last Edit: January 09, 2013, 02:53:17 PM by Mishma »
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

Offline elf

  • Member
  • Posts: 607
Re: Dendritic Cell-Based Vaccines
« Reply #7 on: January 08, 2013, 11:45:34 PM »
Well, dendritic cells are antigen-presenting cells,
CD4+-receptor cells, the main responsible for acquiring of HIV infection during anal sex.
(That's why you don't need blood at all (where other CD4+ cells like CD4+T-lymphocytes, or monocytes are) to get infected, even a tiniest tear in rectal mucosa can ''expose'' the dendritic cells)


http://en.wikipedia.org/wiki/Antigen-presenting_cell
« Last Edit: January 08, 2013, 11:47:47 PM by elf »
Let's have a Kiki!

Offline YellowFever

  • Member
  • Posts: 163
Re: Dendritic Cell-Based Vaccines
« Reply #8 on: January 09, 2013, 02:48:37 PM »
heat-inactivated HIV? If only cure therapy was as simple as eating cooked HIV....
08/2010 HIV- 08/2012 HIV+
10/2012 CD4 415(15%)
04/2013 CD4 457(15%)
10/2013 CD4 520 (20%) VL 650 (wtf?)
02/2014 CD4 410(20%) VL 390 (yay!)
08/2014 CD4 580(?%)

Offline Mishma

  • Member
  • Posts: 190
    • Marquis de Vauban
Re: Dendritic Cell-Based Vaccines
« Reply #9 on: January 10, 2013, 02:39:33 PM »
Another story on this same proof of concept study:

http://www.medpagetoday.com/HIVAIDS/HIVAIDS/36686?ic=700100

Therapeutic HIV Vaccine Shows Promise
By Michael Smith, North American Correspondent, MedPage Today
Published: January 03, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points
An experimental therapeutic vaccine against HIV was able temporarily to lower the level of virus in the blood of infected volunteers.
Note that although the effect did not persist, it is "proof of concept" that such a vaccine might lead to what is called a functional cure, defined as control of HIV replication without antiretroviral drugs.
An experimental therapeutic vaccine against HIV was able temporarily to lower the level of virus in the blood of infected volunteers, researchers reported.

In a randomized, blinded, placebo-controlled trial, the vaccine – using modified antigen-presenting dendritic cells – lowered the so-called viral set point for several months, according to Felipe Garcia, MD, of Spain's University of Barcelona in Barcelona, and colleagues.

Although the effect did not persist, it is "proof of concept" that such a vaccine might lead to what is called a functional cure, defined as control of HIV replication without antiretroviral drugs, Garcia and colleagues concluded online in Science Translational Medicine.

Such control is already seen in the small minority of HIV-positive people known as "elite controllers," whose immune systems are able to keep the virus in check for decades without the aid of drugs, the researchers noted.

The new findings "open the possibility that a therapeutic vaccine could be used as a strategy to obtain a functional cure," Garcia said in a video interview with the journal.

Dendritic cells play a key role in the immune response to infectious disease, presenting antigens to the T cells so that they can identify the invading pathogens.

But in HIV infection, the dendritic cells can also carry live virus to the CD4-positive T cells, causing them to die instead of mount an immune response, Garcia and colleagues noted.

To avoid that in this study, they pulsed the patients' own monocyte-derived dendritic cells with virus collected from their blood and rendered inactive with heat.

The 36 patients were all on long-term combined antiretroviral therapy; 24 were randomly assigned to get three injections of the HIV pulsed cells and 12 to get three shots of unmodified cells.

Antiretroviral therapy was then stopped, and the patients were followed for up to 48 weeks.

The goal was to see if the vaccine lowered the plasma viral set point of HIV from a baseline established during an earlier interruption of therapy, Garcia and colleagues reported.

The vaccine was safe, they reported, and well tolerated; the main adverse effects were asymptomatic lymph node enlargement in four patients and one case each of local redness at the injection site and flu-like symptoms.

On the other hand, several patients in each arm had to resume therapy when their CD4 cell count dropped below prespecified levels.

Twelve weeks after antiretroviral drugs were stopped, 12 of 22 patients remaining in the active arm had at least a 10-fold reduction in the plasma viral load set point, compared with one of 11 in the control arm. The difference was significant at P=0.02.

After another 12 weeks, seven of the 20 remaining patients in the active arm still had at least a 10-fold drop in the viral load set point, compared with none of the remaining 10 patients in the control arm. The difference was significant at P=0.03.

The decrease in plasma viral load was associated with increases in HIV-specific T cell responses, Garcia and colleagues reported.

Despite the declines, however, viral load rebounded to detectable levels in all patients.

Garcia and colleagues cautioned that the goal of any therapeutic vaccine would be to keep viral load undetectable without the use of drugs and "this objective has not been reached with this vaccine."

One possible reason is that the patients were off medication for several weeks about 12 months before the first shot, in order to allow the collection of autologous cells and virus. That, Garcia and colleagues argued, might have "compromised the results" by allowing viral replication despite a subsequent drop to below the level of detectability.

Also, they noted, the vaccine did not prevent a drop in CD4 cells, which meant that several vaccinated patients had to resume therapy.
2016 CD4 25% UD (less than 20). 27+ years positive. Isentress, Truvada, Acyclovir, Clonazepam, Zolpidem, Bupropion, Lisinopril, Pravastatin, Quetiapine, Doxcycline, Testosterone, Suatriptan/Naproxen, Restasis, Dorzolamide, Latanoprost, Asprin, lortab, Levothyroxine, Fioricet, Restasis, Triamclinolone, Nitrostat.

 


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