Addressing Treatment Limitations in GVHD
Claudio Anasetti, MD:The major unmet need in graft-versus-host disease [GVHD] is the development of regimens that will be tolerance-inducing, yet sparing the graft-versus-tumor activity of the transplant. The standard of care for prevention of graft-versus-host disease has been a calcineurin inhibitor. Calcineurin is downstream of the T-cell receptor signaling, which is signal 1, and therefore is expected to inhibit tolerance induction. Hence, one of the key agents that we’ve used for the past 30 years is actually not rational in its use based on current knowledge of immunology.
Glucocorticoid therapy is the standard of care for the treatment of GVHD, but they are nonselective. Therefore, not even the glucocorticoids are appropriate in the management of graft-versus-host disease from a point of view of inducing tolerance.
What is rational in terms of inducing tolerance is actually blocking signaling downstream from signal 2 and signal 3 in T-cell activation. Signal 2 is predominantly downstream from co-stimulation molecules such as CD28, and that involves the mammalian target of rapamycin [mTOR] that can be inhibited by sirolimus. And then, in terms of signal 3, we have already discussed the JAK1 and JAK2 signaling molecules.
The most rational combination of agents that we can foresee at this time is actually a combination of an mTOR inhibitor and the JAK1/JAK2 inhibitor that should be able to promote tolerance induction, sparing STAT5 signaling through other co-receptor signaling that is important for tumor control, yet promoting immunological tolerance and preventing GVHD. Hence, a clinical question that is of interest at this time is whether ruxolitinib can actually be combined with sirolimus in an effective and safe manner to promote tolerance induction and manage graft-versus-host disease.
Transcript edited for clarity.
