Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Abstract

Key Points• WT1 mRNA-electroporated DCs can prevent or delay relapse in 43% of patients with AML in remission after chemotherapy.• OS compares favorably with the new survival data from the Swedish Acute Leukemia Registry and correlates with molecular and WT1-specific CD8 1 T-cell responses.Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P 5 .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age £65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8 1 T cells. Long-term OS was correlated with interferon-g 1 and tumor necrosis factor-a 1 WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8 1 T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8 1 T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224. (Blood. 2017;130(15):1713-1721

Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: results of a phase I trial

“…In the younger cohort, however, only two of seven patients relapsed, and six of seven were still alive at data cut‐off. This is in line with a recent publication, in which an overall survival benefit was dominantly observed in the patient cohort below 65 years of age . This might be related to the larger pool of naive T cells in younger AML patients, which are required for the induction of novel anti‐leukaemic immune responses .…”

“…This is in line with a recent publication, in which an overall survival benefit was dominantly observed in the patient cohort below 65 years of age. 10 This might be related to the larger pool of naive T cells in younger AML patients, which are required for the induction of novel anti-leukaemic immune responses. 21 Moreover, immune responses against WT1 and PRAME correlated to prolonged OS and RFS (Figure 5e and f).…”

“…Within a phase II trial, an anti‐leukaemic response was detected in 13/30 patients vaccinated with DCs loaded with wilms tumor 1 ( WT1 ) mRNA. A molecular remission defined by WT1 qPCR in the peripheral blood was achieved in 9/30 patients, and RFS and OS at 5 years were 30.8% and 50.0%, respectively . In both publications, DC maturation was achieved by a combination of pro‐inflammatory cytokines and prostaglandins .…”

“…A molecular remission defined by WT1 qPCR in the peripheral blood was achieved in 9/30 patients, and RFS and OS at 5 years were 30.8% and 50.0%, respectively. 10 In both publications, DC maturation was achieved by a combination of pro-inflammatory cytokines and prostaglandins. 11 While this protocol was designed to promote migratory and immunostimulatory properties of DCs, no IL-12p70 production was induced.…”

Advances in Immunotherapy for Acute Myeloid Leukemia

“…After developing Bell's palsy and undergoing cortisone therapy, this patient's peripheral blasts increased with an accompanying increase in marrow WT-1 signaling. More recently, a Phase II study evaluated the capability of vaccination with DCs electrocorporated with WT-1 mRNA as postremission therapy for 30 AML patients at very high risk for relapse [63]. Three WT-1 constructs were utilized to generate mRNA by in vitro transcription: construct 1 (WT-1) encoded full-length WT-1, construct 2 (WT-1-DC-LAMP) incorporated a Sig-DC-LAMP MHCII skewing signal with deletion of the WT-1 nuclear localization signal, and construct 3 (WT-1-DC-LAMP-OPT was a codon-optimized version of construct 2).…”