[SUCCESSI] Il paziente tedesco II

[cesar78]

Il trial di fase II Allogeneic Transplant in HIV Patients (BMT CTN 0903) – N. NCT01410344 è stato approvato l’autunno scorso e sta reclutando partecipanti.

Aggiornamento beccato navigando qua e là... ->ClinicalTrials

Allogeneic Transplant in HIV Patients (BMT CTN 0903)
Last updated: July 2012
ClinicalTrials.gov Identifier: NCT01410344
Manufacturer/Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI)/National Cancer Institute (NCI)/Blood and Marrow Transplant Clinical Trials Network
Status: Phase II

Under the leadership of Richard Ambinder at the Johns Hopkins University and Joseph Alvarnas at the City of Hope National Medical Center, the Blood and Marrow Transplant Clinical Trials Network has opened a trial for HIV-positive individuals with chemotherapy-sensitive hematologic malignancies that will attempt to identify stem cell transplant donors homozygous for the CCR5-Delta32 mutation. The goal is to try to duplicate the results obtained in Timothy Brown. A company named StemCyte is pursuing the same goal with a slightly different approach: stem cell transplants derived from cord blood. At a recent conference, Lawrence Getz from StemCyte reported that so far they have identified around 102 cord blood donors homozygous for CCR5-Delta32 out of around 17,000 tested. Although there is no formal trial, an individual with HIV in the Netherlands has recently received such a transplant as part of treatment for a hematologic malignancy, and the same procedure is about to be used in a similar case in Madrid.

E poi da un altro articolo (vi riporto solo la frase interessante):
[http://www.health-e.org.za/news/article ... d=20033650]

This May, another patient with both HIV and leukaemia underwent a stem cell transplant in the Netherlands using cord blood stem cells from a unit with a double CCR5 mutation. It is too early to know if it has worked yet and there could be additional complications for patients with HIV/AIDS, says Jürgen Kuball of the UMC Utrecht team overseeing the research, but he expects to be able to say more in December (a similar transplant due to take place in Spain in June was aborted because of inadequate viability of the stem cells in the cord blood). If successful, the Utrecht patient would be the second after Brown to be cured of HIV.

Potremmo essere molto vicini a un secondo paziente tedesco. Stay tuned!

[Dora]

Stay tuned!

Definitely!

[Dora]

Finalmente è stato tolto l'embargo all'abstract di Kuritzkes ad AIDS 2012.

• - È stato studiato l'effetto sui reservoir virali di un trapianto allogenico di staminali non CCR5-/- in due persone eterozigoti per la delezione Delta 32 del CCR5, con HIV e tumori ematologici, che in precedenza erano già state sottoposte a un trapianto autologo di staminali. Il trapianto di staminali non difettive è stato preceduto da un condizionamento leggero.
  
  - Fra 8 e 17 mesi dopo il trapianto di staminali allogeniche, il DNA virale è diventato irrilevabile nei CD4 del sangue periferico di entrambi i pazienti, mentre se ne era rilevata la presenza - per quanto modesta - prima del trapianto e nei 2 o 3 mesi seguenti.
  
  - Entrambi i pazienti hanno però continuato a prendere la ART. Inoltre, più o meno nel periodo in cui i reservoir provirali hanno cessato di essere rilevabili, entrambi stavano assumendo prednisone o farmaci anti-rigetto a causa di una GvHD cronica.

D.d.D.: non ho capito se tutt'oggi, a due anni dal trapianto, queste persone siano ancora in terapia antiretrovirale. In caso lo fossero, va bene dire che il reservoir dei CD4 è diventato così piccolo da essere irrilevabile, ma come possono sostenere che i pazienti sono presumibilmente curati? Deeks ha un bel dire che

• “These researchers have done some elegant work, and found results that I think are going to be very provocative.”

Resta però da capire la questione della continuazione o meno della ART [se al momento è sospesa e si conferma che almeno una cura funzionale è stata raggiunta, questi due signori passeranno alla storia come "i Pazienti Bostoniani"].



Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation in two HIV-positive individuals

T.J. Henrich1,2, G. Sciaranghella3, J.Z. Li1,2, S. Gallien4, V. Ho2,5, A.S. LaCasce2,5, D.R. Kuritzkes1,2

1Brigham and Women's Hospital, Boston, United States, 2Harvard Medical School, Boston, United States, 3Ragon Institute of MGH, MIT and Harvard, Boston, United States, 4Hopital Saint-Louis, Paris, France, 5Dana-Farber Cancer Institute, Boston, United States

Background: Functional HIV-1 cure has been described in the setting of myeloablative allogeneic stem cell transplant (alloSCT) with ccr5Δ32/ ccr5Δ32 donor cells, but the effects of alloSCT on viral reservoirs are largely unknown. We studied the longitudinal effects of reduced-intensity conditioning (RIC) alloSCT on HIV-1 peripheral blood reservoirs in two infected male patients with hematologic malignancies who previously underwent autologous SCT.

Methods: Analysis of peripheral HIV-1 reservoirs was performed on banked samples (1 pre- and 3 post-RIC-AlloSCT) for both patients, including: 1) quantification of HIV-1 DNA from peripheral blood mononuclear cells (PBMCs), 2) quantification of 2-LTR circles from PBMC episomal DNA, 3) full-length envelope amplification and phenotypic coreceptor usage prediction from proviral DNA, 4) quantification of plasma viremia by a single-copy assay, 5) flow cytometric characterization of lymphocyte subsets and coreceptor expression, and 6) CCR5 genotyping.

Results: No HIV-1 DNA was detected 8 to 17 months after alloSCT in PBMC from both patients despite presence of modest levels of total PBMC-associated HIV-1 DNA prior to and 2-3 months after SCT (87-271 copies/106 PBMCs). 2-LTR circles were not detected at any time-point despite excellent recovery of episomal mitochondrial DNA. Both patients were heterozygous for ccr5Δ32 mutation prior to transplant; a transient reduction in CXCR4 expression was observed following transplant. Pseudoviruses incorporating envelopes from early time-points used predominately CCR5 for entry. Both patients remained virologically suppressed on ART, but were either started on prednisone or continued on tacrolimus/sirolimus immunosuppressive therapy for chronic graft-versus-host disease (GVHD) near the time of loss of HIV-1 reservoir detection.

Conclusions: PBMC HIV-1 DNA became undetectable 8 months after RIC-alloSCT. This finding may be due to a dilutional effect of donor cell engraftment in the setting of protective ART, the additive effect of cytotoxic therapies, and/or GVHD. Confirmation of results by sampling large-volume blood collections and other tissue compartments is warranted.

[skydrake]

Prima di fare i salti di gioia, mi potresti chiarire cosa si intende per:
"a transient reduction in CXCR4 expression was observed following transplant"

[Dora]

Prima di fare i salti di gioia, mi potresti chiarire cosa si intende per:
"a transient reduction in CXCR4 expression was observed following transplant"

Aspettiamo l'articolo. In questo abstract le ambiguità sono enormi.

[Dora]

Aspettiamo l'articolo. In questo abstract le ambiguità sono enormi.

Però, certo che questa dichiarazione di Kuritzkes è interessante:

• "As far as we've been able to measure, we can't find evidence of HIV infection in the patients' blood or blood plasma, and their antibody levels against HIV are dropping," Dr. Daniel Kuritzkes of Brigham and Women's Hospital told Shots. "The antibody evidence tells us there is little if any persisting HIV protein to trigger an anti-HIV response."

E questa, invece, spiega le mie perplessità del post precedente:

• "We can't say we've replicated the Berlin patient's cure at this point because our patients remain on antiretroviral therapy," Kuritzkes says. Only if they stop therapy for months and years, without seeing a rebound of HIV in their blood, can these new bone marrow transplant patients be declared cured.

Alcune delle ragioni di ulteriore interesse nel lavoro dei bostoniani sono elencate qui sotto, perché in qualche modo mettono in crisi l'idea che a curare Timothy sia stato il fatto che le staminali ricevute erano CCR5-/-:

• It's been widely assumed that the magic in Brown's cure resides in the stem cells he got from a bone marrow donor. Those donor cells lack a receptor called CCR5 that HIV uses to enter immune cells.
  
  Not necessarily, the Boston researchers say. That's because the donor cells their patients got did not lack the receptor. So what's happening with them must be different from the Berlin patient.
  
  The Boston researchers think their might-be-cures are due to two factors:
  
  - The patients got a milder form of pre-transplant chemotherapy. As a result, they were able to stay on their anti-HIV drugs. That protected the transplanted donor cells from becoming infected with any HIV that might have been hiding out in their bodies.
  - The donor cells most likely killed off the patients' own HIV-infected immune cells as the bone marrow transplants took effect.
  
  This second phenomenon is called graft-versus-host disease. The donor cells see the patients' native cells as foreigners and attack them. "The success of a bone marrow transplant depends on having the right amount of graft-versus-host disease," Kuritzkes says. "You need a little bit. You hope not to have so much that you get clinically sick from it."
  
  The Berlin patient also had episodes of graft-versus-host disease. That could help explain why his HIV infection was extinguished – or driven to such low levels that his new immune system is able to control it.
  
  It's possible that the lack of CCR5 receptors on the donor cells did contribute to the Berlin patient's cure. But scientists are excited by the possibility that a cure may not require donor cells lacking CCR5 receptors. That would widen the donor pool, since very few people are lucky enough to lack CCR5.

[cesar78]

But scientists are excited by the possibility that a cure may not require donor cells lacking CCR5 receptors. That would widen the donor pool, since very few people are lucky enough to lack CCR5.

Non so cosa ci sia da essere così eccitati, quando questa notizia, se fosse confermata, spazzerebbe via tutti i lavori di Cannon & co. sui CCR5-. Che facciamo? Ci mettiamo a trapiantare tutti i siero+ con tutti i rischi del caso? Esiste per caso un metodo di replicazione non dannosa di una GVHD (se è proprio questa che ha curato l'infezione)?

[nordsud]

It's been widely assumed that the magic in Brown's cure resides in the stem cells he got from a bone marrow donor. Those donor cells lack a receptor called CCR5 that HIV uses to enter immune cells.

Not necessarily, the Boston researchers say. That's because the donor cells their patients got did not lack the receptor. So what's happening with them must be different from the Berlin patient.

The Boston researchers think their might-be-cures are due to two factors:

.........

The donor cells most likely killed off the patients' own HIV-infected immune cells as the bone marrow transplants took effect.



But scientists are excited by the possibility that a cure may not require donor cells lacking CCR5 receptors. That would widen the donor pool, since very few people are lucky enough to lack CCR5.

Le mie connessioni neuronali si sono fuse dopo aver letto quanto sopra.

[cesar78]

Le mie connessioni neuronali si sono fuse dopo aver letto quanto sopra.

Non solo le tue nordsud, credo che ci sia molta confusione e secondo me non sanno nemmeno bene loro cosa in effetti succeda dopo un trapianto: attendiamo il paziente olandese a fine anno e ne sapremo di più.

[skydrake]

Non so cosa ci sia da essere così eccitati, quando questa notizia, se fosse confermata, spazzerebbe via tutti i lavori di Cannon & co. sui CCR5-. Che facciamo? Ci mettiamo a trapiantare tutti i siero+ con tutti i rischi del caso?

No.
Questi due casi sono estremamente importanti in quanto sono la "prof of concept" che una volta eliminato il recettore CCR5 ( sostituito da uno CCR5-delta32), la principale porta d'ingresso del virus, quest'ultimo non puo' nemmeno utilizzare la "porta di servizio", il recettore CXCR4. Era questa la grande paura.

Questo metodo di eradicazione tuttavia non è applicabile a normali pazienti hiv+, a meno che abbiano "il midollo da buttare" (gli affetti da leucemia, mieloma ecc.)
Lo stesso Timothy Brown (quello a cui trapiantarono l'intero midollo da un donatore con la mutazione CCR5delta-32) una volta dichiarò che stava meglio prima. I farmaci antirigetto sono pesantissimi. Lui stesso ha avuto dei danni al cervelletto e problemi di memoria.

La quadratura del cerchio potrebbe essere l'utilizzo di cellule staminali ematopoietiche CCR5-delta32 monozigote autologhe.
Autologhe perchè estratte dal proprio organismo, quindi non sarebbero necessari i farmaci antirigetto, ma poi occorre eliminare le sequenze genetiche che codificano i CCR5 (con quelle CCR5-delta32 monozigote).
Le terapie geniche candidate a queste sono quelle "a dita di zinco", ma sono ben lungi dall'essere a posto (specie con le staminali). In fondo qui stiamo parlando di modificare il codice genetico a cellule umane. I rischi sono tanti.
La direzione è giusta, ma lunga è la via per Damasco.