A tailored cancer vaccine was generated in this study, in which patient-derived acute myeloid leukemia (AML) cells were fused with autologous dendritic cells, resulting in a hybridoma that potently stimulated wide antitumor responses. The results suggest that the vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells.
19 patients with newly diagnosed or first relapsed AML with the median age was 63 years. Eleven patients had intermediate or high-risk disease, and eight patients had favorable risk disease.
Vaccine generation
Mononuclear cells were isolated by Ficoll density gradient centrifugation and cryopreserved in 10% dimethyl sulfoxide (DMSO)/90% autologous plasma. Patients underwent a single leukapheresis collection for DC. Adherent cells were cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) (1000 U/ml) and IL-4 (500 IU/ml) for 5 to 7 days and matured in the presence of tumor necrosis factor–a (25 ng/ml) for 2 to 3 days. The DC and thawed autologous AML preparations were analyzed by immunocytochemical staining and then co-cultured with polyethylene glycol to generate DC/tumor fusions.
DC is administered as a sub- cutaneous (SC) injection in the upper thigh at 4-week intervals for a total of three doses. GM-CSF (100 mg) was administered at the vaccine site on the day of vaccination and for 3 days thereafter.
Adverse events
Vaccination was well tolerated, and no evidence of symptomatic auto- immunity was observed. Potential related adverse events were transient and of grade 1 to 2 intensity. The most common adverse event was erythema, pruritis, and/or induration at the vaccine site. 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.
Cellular immunologic response
AML-specific T cells were nearly undetectable in the peripheral blood and bone marrow. Vaccination resulted in a 5.4-fold increase in AML-specific CD4+ T cells and a 15.7-fold increase in AML-specific
CD8+ T cells, comparing pre-vaccination numbers to peak numbers after vaccination. Circulating leukemia- reactive T cells remained elevated 6 months after the last vaccination at the time of last assessment. In HLA-A*0201 patients, vaccination resulted in the expansion of peripheral blood T cells recognizing MUC1 (4.4-fold increase), WT1 (2.7-fold increase), and NY-ESO (3.8-fold increase) tumor
antigens. Vaccination was associated with a 4.7-fold increase in leukemic reactive CD8+ T cells in the bone marrow from before vaccination to 1 month after the last vaccination. An expansion in bone marrow–infiltrating T cells recognizing MUC1 (ninefold increase) and WT1 (eightfold increase) was observed from before vaccination to 1 month after vaccination.
Clinical response
Thirteen of 19 patients who completed vaccine generation are in re- mission [68%; 90% confidence interval (CI), 51 to 86%]. Twelve of 17 patients who received at least one dose of vaccine remain alive and in remission (71%; 90% CI, 52 to 89%) at 16.7 to 66.5 months from initiating vaccination, with a median follow-up of 57 months.
As a notable example, a 77-year-old female who relapsed within 1 year of primary induction chemotherapy underwent vaccination after achieving a second remission. She remains in remission at 53 months of follow- up from vaccination. No patient has relapsed 1 year after completing the vaccination. The 4-year progression-free survival (PFS) rate is 71% (90% CI, 52 89%).
The results demonstrate that personalized vaccination of AML patients in remission induces the expansion of leukemia-specific T cells and may be protective against disease relapse.
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