Donor Th2 Cells to Prevent Graft-Versus-Host Disease in Bone Marrow Transplants

Allogeneic peripheral blood stem cell transplantation (PBSCT) is primarily limited by graft-versus-host disease (GVHD). In murine models, we found that donor CD4+ Th1 cells (secretion of IL-2 and IFN-Gamma) mediate GVHD. In contrast, donor Th2 cells (secretion of IL-4 and IL-10) do not generate GVHD, and abrogate Th1-mediated GVHD. We also found that murine allografts enriched with Th2 cells reduced GVHD without impairing the ability of donor T cells to prevent graft rejection. These studies indicate that donor Th2 cells may be a new approach to reducing GVHD. In addition to GVHD, allogeneic PBSCT has been limited by toxicity associated with conventional myeloablative preparative regimens. Although non-myeloablative regimens may reduce regimen-related toxicity, such transplants have been associated with a 30 to 40% incidence of severe acute GVHD (similar to rates observed with myeloablative regimens). Because non-myeloablative regimens appear to have reduced regimen-related toxicity, we have conducted this pilot study of Th2 cells in the setting of an immunoablative (non-myeloablative) preparative regimen. In this protocol, patients with lymphoid or hematologic malignancy receive induction therapy (fludarabine and EPOCH) and transplant chemotherapy (fludarabine and cytoxan) to deplete host T cells that mediate graft rejection. In our initial NCI cohort receiving HLA-matched sibling, G-CSF mobilized PBSCT on this protocol (n=19), graft rejection was prevented in all cases, with most recipients having 100% donor chimerism by day 28 post-SCT. With this reduced intensity regimen, GVHD remained a significant complication, with 6/19 recipients having grade II and 6/19 recipients having grade III acute GVHD. Importantly, potent graft-versus-tumor responses were observed, with 9/19 patients remaining in complete remission at a median of 17 months post-SCT. Given that this allogeneic SCT regimen achieves engraftment and durable anti-tumor responses, yet is associated with GVHD, this protocol represents an appropriate setting for evaluation of donor Th2 cells. Initial patients will receive Th2 cells in a phase I manner. Three patients will receive 5 x 10(6) Th2/kg, six patients will receive 2.5 x 10(7) Th2/kg, and six patients will receive 1.25 x 10(8) Th2/kg. The highest dose of Th2 cells that results in an acceptable toxicity profile (not more than 1/6 serious adverse events) and a favorable rate of acute GVHD (not more than 2/6 cases of grade II or greater acute GVHD) will be selected for the phase II study arm. Eighteen patients will be treated with allogeneic SCT and Th2 cells on this phase II study arm. In the event that Th2 recipients have reduced GVHD, further clinical trials involving Th2 cells will be warranted.