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1.
J Clin Invest ; 123(9): 3756-65, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23912587

ABSTRACT

BACKGROUND: Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. METHODS: We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated. RESULTS: At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. CONCLUSION: Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT. TRIAL REGISTRATION: Clinicaltrials.gov NCT00442130. FUNDING: NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines , Hematopoietic Stem Cell Transplantation , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Adult , Aged , Combined Modality Therapy , Disease-Free Survival , Female , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , K562 Cells , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Prospective Studies , Transplantation Conditioning , Transplantation, Autologous , Treatment Outcome , Vaccination
2.
Clin Cancer Res ; 18(20): 5761-72, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22912393

ABSTRACT

PURPOSE: Characterization of an approach to identify leukemia neoantigens arising in the context of drug resistance. EXPERIMENTAL DESIGN: We assessed whether leukemia neoantigens could be generated from drug-resistant mutations in BCR-ABL after imatinib relapse in patients with chronic myelogenous leukemia (CML). RESULTS: We computationally predicted that approximately 70 peptides derived from 26 BCR-ABL mutations would bind eight common alleles of MHC class I (IC(50) < 1,000 nmol/L). Seven of nine imatinib-resistant CML patients were predicted to generate at least 1 peptide that binds autologous HLA alleles. We predicted and confirmed that an E255K mutation-derived peptide would bind HLA-A3 with high affinity (IC(50) = 28 nmol/L), and showed that this peptide is endogenously processed and presented. Polyfunctional E255K-specific CD8+ T cells were detected in two imatinib-resistant HLA-A3+ CML patients concurrent with an effective anti-CML response to further therapy. CONCLUSIONS: Our in vitro studies support the hypothesis that leukemia-driven genetic alterations are targeted by the immune system in association with a clinical response, and suggest the possibility of immunizing relapsed patients with CML against newly acquired tumor neoantigens.


Subject(s)
Immunotherapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Peptides , Adult , Aged , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Benzamides/administration & dosage , CD8-Positive T-Lymphocytes , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Epitopes, T-Lymphocyte/immunology , Female , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/immunology , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Male , Middle Aged , Peptides/chemistry , Peptides/pharmacology , Piperazines/administration & dosage , Pyrimidines/administration & dosage
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