5 replies to this topic

[John Schloendorn]

Nearly a decade ago, Bonini et al demonstrated the control of graft-versus-host disease (GVHD) in human allogenic bone-marrow transplant recipients by coinjection of suicide-gene transduced donor T-cells with the T-cell depleted graft, while maintaining the graft-versus-leukemia (GVL) effect.
Why does GVHD continue to be a major cause of post-transplant mortality today? What's wrong with the suicide gene approach? Why was it not pursued much more intensively in the past decade?

[henri]

So one would have to inject the T cells every time there is a virus infection and induce the apoptosis every time they start attacking the host? Wouldn't this be a bit impractical, or did I misunderstand this?

[John Schloendorn]

Well, replacement lymphocytes will soon be forthcoming from the transplanted stem cells, and these will tolerate the host due to normal thymic and extrathymic selection (and not have a suicide gene).

The problem in GVHD are mature donor lymphocytes co-injected with the donor stem cells. These are essential to clear residual leukemia cells that the radiation therapy missed (graft-versus-leukemia, GVL). GVHD is the subsequent attack of these mature lymphocytes on the healthy host tissues. That's why it is so hard do find the perfect bone-marrow donor. One has to maximize GVL by decreasing immune compatibility with the host and minimize GVHD by increasing immune compatibility.

Suicide genes would installed only in mature donor mature lymphocytes (not the stem cells) and activated to clear them once and for all after completion of GVL, but before they kill the host by GVHD. So one could in theory use much more dissimilar bone marrow donors and thereby get even better GVL than possible today.

Actually, there are now multicenter phase III clinical trials of the suicide gene approach in preparation.

[caliban]

I'm not so current on clinical politics, but here is your answer, I think:
http://www.bloodjour...04/10/3408#REF4

As you know there are a number of strageties to deal with GVHD vs GVL.
I would agree that the suicide approach is among the most promising. But there with all these there seems to be the problem of turning acute breakdown into chronic issues.

[John Schloendorn]

Hmm, so these authors conclude from two out of three patients with graft failure:

minimum numbers of donor CD3+ cells are required after transplantation, not only to facilitate engraftment, but also to prevent late rejection.

Interesting, and a reason for concern. If true, then why might it be? However, this has to be seen in contrast with several studies by Bonini et al, with more patients or animals who did not report such an effect. Perhaps this would have to be evaluated in a direct suicide gene vs. traditional non-t-cell depleted vs. traditional t-cell depleted graft study. Or the phase III trials mentioned above (by Bonini et al) will also tell us more.

[John Schloendorn]

One alternative explanation for the graft failure might be loss of the long-term repopulating stem cells due to the condidtions used in the cell culture and gene therapy experiments.