Composition and method for treating graft-versus-host disease

Patent Number: 7,173,016

Graft versus host disease (GVHD) is one of the major limitations of bone marrow, or for that matter, any type of allogeneic hematopoietic stem cell transplant. Essentially, GVHD is the result of donor derived T cells attacking the allogeneic recipient. Previously attempts were made to reduce GVHD by “purging” the stem cell graft of T cells using various antibodies or tissue culture approaches. Patients receiving these grafts had a reduction in GVHD but mortality was unaffected, or in some cases even increased. The reason for this was because when T cells were depleted, not only was GVHD reduced, but also the graft versus leukemia (GVL) was reduced. Patients were therefore not dieing of GVHD but dieing of increase relapse.

The current patent covers the use of any adenosine deaminase inhibitor for treatment of GVHD. Adenosine deaminase converts adenosine, to inosine, which generally is converted to hypoxanthine and various other compounds. The adenosine deaminase enzyme is critical for proper T cell function. This is seen in a disease called severe combined immunodeficiency (SCID) in which patients lack T cells. The patent teaches that if you reproduce the state of SCID by temporarily blocking adenosine deaminase activity, then it is possible to obtain a temporary suppression in T cell activity, which would subsequently result in an inhibition of GVHD. The patent provides pentostatin as a compound useful for the blocking of adenosine deaminase activity.

Important questions about this approach are whether there is selectivity in inhibiting particular types of T cells. For example, in GVHD it may be beneficial to preferentially inhibit CD4+ CD25- T cells but not to inhibit T regulatory cells that have a suppressor function and are characterized by the phenotype CD4+ CD25+. It is known that immune suppressants that are generally non-specific do in fact display some selectivity in terms of T cell subsets that they inhibit. For example, cyclosporine inhibits both CD4+ CD25- and CD4+ CD25+ T cells, whereas rapamycin seems to selectively inhibit CD4+ CD25-. It will be interesting to see the activities of pentostatin in this regard.

There are some clinical descriptions of pentostatin treatment of GVHD. For example, Bolanos-Meade et al. (Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol 23:2661, 2005) treated 23 patients with acute GVHD with escalating doses of pentostatin. All treated patients developed lymphopenia but neutrophil counts were not affected. This supports the general notion of the patent that treatment with pentostatin may be useful for temporarily duplicating the state of SCID clinically. Of the 23 patients, all tolerated pentostatin treatment and 14 patients achieved complete responses (63%) while three patients achieved partial responses (13%). Given the selective effects of pentostatin on lymphodepletion, this drug may be useful for cancer treatment in order to prime patients for homeostatic expansion based protocols.

View this patent on the USPTO website.