Clinical Trial Evaluating DC/AML Fusion Cell Vaccination in AML Patients Who Achieve a Chemotherapy-Induced Remission
Year: 2014
Type: article
Study design: Clinical Trial
Abstract: We have developed a promising leukemia vaccine in which patient derived AML cells are fused with autologous dendritic cells (DCs), presenting a broad array of antigens. We are conducting a clinical trial in which AML patients undergo vaccination with DC/AML fusion cells following chemotherapy induced remission. Twenty-six patients underwent collection of AML cells at disease presentation for vaccine generation and immune monitoring studies. Median age of the patients is 66 years. Tumor was collected from either a bone marrow aspirate (N=16), 20 cc of peripheral blood (N=7), or leukapheresis product (N=3) at the time of presentation with newly diagnosed AML (N=25) or first relapsed AML (N=1). The mean yield of AML cells was 109 x 106 cells with a mean viability of 91%. Eligible patients achieving CR (N=16) underwent leukapheresis for DC generation. Adherent peripheral blood mononuclear cells were cultured in the presence of GM-CSF and IL-4 for 5-7 days, and exposed to TNFα for 48-72 hours to generate mature DCs. Fusion cells were generated by co-culture of DCs with AML cells in the presence of 50% polyethylene glycol and identified as cells co-expressing antigens that were unique to the DC and tumor cells. Mean fusion efficiency and viability was 38% and 85%, respectively. Vaccination with DC/leukemia fusion cells was initiated within 12 weeks from count recovery following the final cycle of chemotherapy. 13 patients received at least two monthly vaccinations at a dose of 5x106 fusion cells. 8 patients had intermediate risk cytogenetics, 3 patients had good risk cytogenetics, and 2 patients had a complex karyotype. Vaccination was well tolerated, and importantly, was not associated with clinically significant auto-immunity. Biopsy of vaccine site reactions demonstrated a dense infiltrate of CD4 and CD8 T cells consistent with recruitment of reactive T cell populations to the vaccine bed. To date, 9 patients remain in remission (69%), with a mean follow up of 23 months. Peripheral blood samples were collected prior to each vaccination and at 1, 3, and 6 months following completion of vaccination. Vaccination resulted in the potent induction of leukemia specific immunity as measured by an 8 fold increase (mean, n=6) in CD8 T cells expressing IFNγ in response to ex vivo exposure to autologous leukemia cell lysates. Bone marrow derived T cells were isolated prior to and following vaccination in patients who are HLA2.1+. Vaccination resulted in the expansion of bone marrow infiltrating T cells recognizing MUC1 (9 fold increase), WT1 (5 fold increase), PRAME (12 fold increase) tumor antigens by tetramer analysis (n=2). In conclusion, DC/AML fusion cell vaccination results in the potent expansion of leukemia reactive T cells and durable remissions following chemotherapy. Enrollment to a second cohort in which patients receive DC/AML fusion cell vaccination in combination with antI-PD1 antibody is planned.
Authors: Jacalyn Rosenblatt, Richard M. Stone, Lynne Uhl, Donna Neuberg, Baldev Vasir, Poorvi Somaiya, Robin Joyce, James D. Levine, Vassiliki A. Boussiotis, Jeffrey Zwicker, Jon E. Arnason, Katarina Luptakova, David P. Steensma, Daniel J. DeAngelo, Ilene Galinsky, Carol Delaney, Heidi Mills, Emma Breault, Dina Stroopinsky, Donald Kufe, David Avigan
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2132014561