Through an immune-mediated graft-versus-
leukemia effect, allogeneic
hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with
hematologic malignancies. Nonetheless, subjects with high-risk
acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify
tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated
tumor cells engineered to secrete
GM-CSF generates a potent antitumor effect without exacerbating the toxicities of
graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk
acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous,
GM-CSF-secreting
tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a
calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-
tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12-43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D
ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous,
GM-CSF-secreting
leukemia cell
vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial
immunotherapy might potentiate graft-versus-
leukemia in patients.