Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation

Abstract

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-CSFsecreting 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.bone marrow transplant ͉ GVL ͉ MICA ͉ NKG2D ͉ tumor immunity

Reduced-intensity conditioned allogeneic SCT in adults with AML

“…146 FLT3 inhibitors for patients with FLT3-ITD mutations and other targeted therapies, as well as post-transplant vaccine approaches 147 are being explored in clinical trials, though definitive results are not yet available.…”

Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies

“…Ho et al conducted a Phase I clinical trial whereby high-risk acute myeloid leukemia or patients with MDS were immunized with autologous, irradiated, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. 67 The immunization was broadly well tolerated with one patient suffering a GVHD type skin reaction. Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, indicative of NK cell tumor specific activity, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment.…”

“…66 A novel approach to augment antigen presenting activity in patients with cancer has been to vaccinate them with irradiated autologous tumor cells engineered to secrete GM-CSF. It is thought that paracrine production of GM-CSF can stimulate the recruitment, maturation, and function of dendritic cells in vivo, 67,68 overcoming the described qualitative and quantitative deficiencies of antigen presenting cells in cancer patients. Ho et al conducted a Phase I clinical trial whereby high-risk acute myeloid leukemia or patients with MDS were immunized with autologous, irradiated, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT.…”

Cancer immunotherapy using recombinantListeria monocytogenes: Transition from bench to clinic

“…Additional advantages of cancer vaccines include exquisite specificity, low toxicity and the potential for a long-lasting treatment effect due to the generation of immunologic memory responses. The major platforms of the cancer vaccines that have been studied in the past two decades include agents such as DNA, 1 peptide, 2,3 protein, 4 cell-based therapies such as whole tumor cell vaccines, 5 dendritic cells, 6 adoptive transfer of cytotoxic T cells, 7 and live agents such as recombinant virus 8 or bacteria. 9 There have been several clinical studies with these agents and the clinical outcomes suggest that most of these approaches are potentially safe and tolerable during phase I/II clinical studies.…”