General AML

Post-remission therapy with DC vaccination in AML

Sébastien Anguille from the Antwerp University Hospital and University of Antwerp, Antwerp, Belgium, et al. reported results of their phase II study (NCT00965224), which aimed to evaluate the therapeutic efficacy of Wilms Tumor Gene (WT1) mRNA-electroporated autologous Dendritic Cell (DC) vaccination in patients with Acute Myeloid Leukemia (AML) in Blood on 22nd August 2017.

Overall, 30 AML patients (median age = 65 years) in remission after chemotherapy who were at high-risk of relapse were vaccinated intradermally with autologous DCs loaded with WT1 antigen by means of mRNA electroporation (allows human leukocyte antigen haplotype-independent multi-epitope presentation to T-cells).

The key results of the study were:
  • Clinical response rate; 43% (13/30)
  • Molecular Response (MR); 30% (9/30)
  • 5-year Overall Survival (OS) in responders (n = 13) and non-responders (n = 16) to DCs vaccine; 53.8% vs 25.0%, P = 0.01
  • Relapse reduction rate in patients that received DC vaccine in First Complete Remission (CR1); 25%
  • 5-year Relapse Free Survival (RFS) in responders and non-responders to DC vaccine; 50% vs 7.7%, P < 0.0001
  • Long-term clinical response in patients correlated significantly with increased frequencies of poly-epitope WT1-specific CD8+ T-cells; P = 0.018

In summary, vaccination of AML patients in remission with WT1 mRNA-electroporated DCs lead to improved OS rates, which correlated with the induction of WT1-specific CD8+ T-cell responses.

The authors concluded by proposing that vaccination with WT1/DCs should be considered as a “non-toxic, post-remission strategy to prevent or delay relapse of AML in an adjuvant setting”.

Abstract

Relapse is a major problem in acute myeloid leukemia (AML) and adversely impacts survival. In this phase II study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) mRNA as post-remission treatment in 30 AML patients at very high risk of relapse. There was a demonstrable anti-leukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which are 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 non-responders (53.8% vs. 25.0%; P=0.01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25% and the 5-year relapse-free survival was higher in responders than in non-responders (50% vs. 7.7%; P<0.0001). In patients ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared to 51.7% and 18% in the Swedish Acute Leukemia Registry (SALR). Long-term clinical response was correlated with increased circulating frequencies of poly-epitope WT1-specific CD8+ T-cells. Long-term OS was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in delayed type hypersensitivity-infiltrating CD8+ T-lymphocytes. In conclusion, vaccination of AML patients 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+ T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224.

References
  1. Anguille S. et al. Dendritic cell vaccination as post-remission treatment to prevent or delay relapse in acute myeloid leukemia. Blood. 2017 Aug 22. DOI: 10.1182/blood-2017-04-780155. [Epub ahead of print].