title: 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-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.
authors.affiliation: Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.forename: Matthew
authors.initials: M
authors.lastname: Vanneman
authors.forename: Haesook
authors.initials: H
authors.lastname: Kim
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sasada
authors.forename: Yoon Joong
authors.initials: YJ
authors.lastname: Kang
authors.forename: Mildred
authors.initials: M
authors.lastname: Pasek
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.forename: Edwin
authors.initials: E
authors.lastname: Alyea
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sarantopoulos
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Christine
authors.initials: C
authors.lastname: Canning
authors.forename: Jeffery
authors.initials: J
authors.lastname: Kutok
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.forename: Robert
authors.initials: R
authors.lastname: Soiffer
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000494:pharmacology*; D003131:Combined Modality Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D015395:Histocompatibility Antigens Class I / Q000097:blood; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000097:blood; D011994:Recombinant Proteins; D013997:Time Factors; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
chemical_list: D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor