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WILMS' TUMOR 1 (WT1) RNA-ELECTROPORATED DENDRITIC CELL VACCINATION AS POST-REMISSION TREATMENT TO PREVENT OR DELAY RELAPSE IN ACUTE MYELOID LEUKEMIA: FINAL RESULTS OF A PHASE II STUDY IN 30 PATIENTS
Author(s): ,
Zwi Berneman
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Sébastien Anguille
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Ann Van de Velde
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Viggo Van Tendeloo
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Nathalie Cools
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Griet Nijs
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Barbara Stein
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Eva Lion
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Ann Van Driessche
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Irma Vandenbosch
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Anke Verlinden
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Alain Gadisseur
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Wilfried Schroyens
Affiliations:
Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Katrien Vermeulen
Affiliations:
Laboratory Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Marie-Berthe Maes
Affiliations:
Laboratory Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Kathleen Deiteren
Affiliations:
Laboratory Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
,
Ronald Malfait
Affiliations:
Laboratory Hematology,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
Evelien Smits
Affiliations:
Center for Cell Therapy and Regenerative Medicine,ANTWERP UNIVERSITY HOSPITAL,Edegem,Belgium
(Abstract release date: 05/18/17) EHA Library. Berneman Z. 06/23/17; 181428; S141
Prof. ZN Berneman
Prof. ZN Berneman
Contributions
Abstract

Abstract: S141

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 11:30 - 11:45

Location: Room N109

Background

Relapse is a major problem in acute myeloid leukemia (AML) and adversely impacts survival. 

Aims
The aim of this phase II study was to determine the clinical efficacy of dendritic cell (DC) vaccine therapy in AML, and, more specifically, whether this form of immunotherapy can be applied in the post-remission adjuvant setting to decrease the risk of relapse following chemotherapy and to improve survival.

Methods
We vaccinated 30 AML patients in remission following polychemotherapy, but at very high risk of relapse with autologous DCs loaded with the Wilms' tumor 1 (WT1) antigen by means of mRNA electroporation, a technique that allows for human leukocyte antigen haplotype-independent, multi-epitope antigen presentation to T-cells. The vaccines were administered intradermally. 

WT1 mRNA levels in blood and marrow were followed as a measure of minimal residual disease. 
Circulating WT1-specific CD8+ T-cells obtained before vaccination and after the 4th dose of DCs were stained with WT1 peptide-HLA-A*0201 tetramers.To assess cell-mediated immunity in vivo, delayed type hypersensitivity (DTH) skin testing was performed 2 weeks after the 4th DC vaccination by intradermal injection; DTH-infiltrating lymphocytes collected from skin biopsies were expanded for 2-3 weeks in medium with interleukin-2, harvested and tested for WT1 specificity and reactivity.

Results
There was a demonstrable anti-leukemic response in 13/30 patients (overall response rate 43%). 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, including 1 patient who went from partial remission to complete remission by DC vaccination only. In the remaining 4 responding patients, the clinical response was characterized by stable disease as demonstrated by elevated but stable WT1 transcript levels in blood for 3-12 months and stable blood values without blasts. 

Five-year overall survival was 40%, as compared to 24.7% in the SEER data of the National Cancer Institute; it was significantly 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 significantly 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 overall survival was 69.2% and 30.8% respectively. Of the 30 patients, 11 are alive in CR, including 5 who relapsed after DC vaccination; 2 proceeded to allogeneic stem cell transplantation, while the 3 other patients were brought back into CR by chemotherapy alone, 2 of them surviving more than 7 and 4 years respectively after reachieving CR. Long-term clinical response was correlated with increased circulating frequencies of poly-epitope WT1-specific tetramer+ CD8+ T-cells.  Long-term overall survival was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in DTH-infiltrating CD8+ T-lymphocytes. 

Conclusion
Vaccination of AML patients with WT1 mRNA-electroporated DCs can be an effective and non-toxic strategy to prevent or delay leukemia relapse after standard chemotherapy, translating into improved overall survival rates, which are correlated with the induction of WT1-specific CD8+ T-cell responses.

Session topic: 24. Gene therapy, cellular immunotherapy and vaccination

Keyword(s): WT1, Relapse, Dendritic cell vaccine, Acute Myeloid Leukemia

Abstract: S141

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 11:30 - 11:45

Location: Room N109

Background

Relapse is a major problem in acute myeloid leukemia (AML) and adversely impacts survival. 

Aims
The aim of this phase II study was to determine the clinical efficacy of dendritic cell (DC) vaccine therapy in AML, and, more specifically, whether this form of immunotherapy can be applied in the post-remission adjuvant setting to decrease the risk of relapse following chemotherapy and to improve survival.

Methods
We vaccinated 30 AML patients in remission following polychemotherapy, but at very high risk of relapse with autologous DCs loaded with the Wilms' tumor 1 (WT1) antigen by means of mRNA electroporation, a technique that allows for human leukocyte antigen haplotype-independent, multi-epitope antigen presentation to T-cells. The vaccines were administered intradermally. 

WT1 mRNA levels in blood and marrow were followed as a measure of minimal residual disease. 
Circulating WT1-specific CD8+ T-cells obtained before vaccination and after the 4th dose of DCs were stained with WT1 peptide-HLA-A*0201 tetramers.To assess cell-mediated immunity in vivo, delayed type hypersensitivity (DTH) skin testing was performed 2 weeks after the 4th DC vaccination by intradermal injection; DTH-infiltrating lymphocytes collected from skin biopsies were expanded for 2-3 weeks in medium with interleukin-2, harvested and tested for WT1 specificity and reactivity.

Results
There was a demonstrable anti-leukemic response in 13/30 patients (overall response rate 43%). 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, including 1 patient who went from partial remission to complete remission by DC vaccination only. In the remaining 4 responding patients, the clinical response was characterized by stable disease as demonstrated by elevated but stable WT1 transcript levels in blood for 3-12 months and stable blood values without blasts. 

Five-year overall survival was 40%, as compared to 24.7% in the SEER data of the National Cancer Institute; it was significantly 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 significantly 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 overall survival was 69.2% and 30.8% respectively. Of the 30 patients, 11 are alive in CR, including 5 who relapsed after DC vaccination; 2 proceeded to allogeneic stem cell transplantation, while the 3 other patients were brought back into CR by chemotherapy alone, 2 of them surviving more than 7 and 4 years respectively after reachieving CR. Long-term clinical response was correlated with increased circulating frequencies of poly-epitope WT1-specific tetramer+ CD8+ T-cells.  Long-term overall survival was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in DTH-infiltrating CD8+ T-lymphocytes. 

Conclusion
Vaccination of AML patients with WT1 mRNA-electroporated DCs can be an effective and non-toxic strategy to prevent or delay leukemia relapse after standard chemotherapy, translating into improved overall survival rates, which are correlated with the induction of WT1-specific CD8+ T-cell responses.

Session topic: 24. Gene therapy, cellular immunotherapy and vaccination

Keyword(s): WT1, Relapse, Dendritic cell vaccine, Acute Myeloid Leukemia

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