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

Autor: Lichtenegger FS; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany.; Present address: Roche Innovation Center Munich Penzberg Germany., Schnorfeil FM; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg Germany.; Present address: Medigene AG Planegg Germany., Rothe M; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany., Deiser K; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany., Altmann T; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany., Bücklein VL; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany., Köhnke T; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany., Augsberger C; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany., Konstandin NP; Department of Medicine III University Hospital, LMU Munich Munich Germany., Spiekermann K; Department of Medicine III University Hospital, LMU Munich Munich Germany., Moosmann A; DZIF Research Group 'Host Control of Viral Latency and Reactivation' (HOCOVLAR) Helmholtz Zentrum München Munich Germany., Boehm S; Max von Pettenkofer Institute LMU Munich Munich Germany., Boxberg M; Institute of Pathology Technical University of Munich Munich Germany., Heemskerk MH; Department of Hematology Leiden University Medical Center Leiden The Netherlands., Goerlich D; Institute of Biostatistics and Clinical Research University of Muenster Muenster Germany., Wittmann G; Department of Transfusion Medicine, Cellular Therapeutics and Hemostaseology University Hospital LMU Munich Munich Germany., Wagner B; Department of Transfusion Medicine, Cellular Therapeutics and Hemostaseology University Hospital LMU Munich Munich Germany., Hiddemann W; Department of Medicine III University Hospital, LMU Munich Munich Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg Germany., Schendel DJ; Medigene AG Planegg Germany., Kvalheim G; Department of Cellular Therapy The Norwegian Radium Hospital Oslo University Hospital Oslo Norway., Bigalke I; Department of Cellular Therapy The Norwegian Radium Hospital Oslo University Hospital Oslo Norway.; Present address: BioNTech IMFS Idar-Oberstein Germany., Subklewe M; Department of Medicine III University Hospital, LMU Munich Munich Germany.; Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg Germany.
Jazyk: angličtina
Zdroj: Clinical & translational immunology [Clin Transl Immunology] 2020 Mar 03; Vol. 9 (3), pp. e1117. Date of Electronic Publication: 2020 Mar 03 (Print Publication: 2020).
DOI: 10.1002/cti2.1117
Abstrakt: Objectives: Innovative post-remission therapies are needed to eliminate residual AML cells. DC vaccination is a promising strategy to induce anti-leukaemic immune responses.
Methods: We conducted a first-in-human phase I study using TLR7/8-matured DCs transfected with RNA encoding the two AML-associated antigens WT1 and PRAME as well as CMVpp65. AML patients in CR at high risk of relapse were vaccinated 10× over 26 weeks.
Results: Despite heavy pretreatment, DCs of sufficient number and quality were generated from a single leukapheresis in 11/12 cases, and 10 patients were vaccinated. Administration was safe and resulted in local inflammatory responses with dense T-cell infiltration. In peripheral blood, increased antigen-specific CD8 + T cells were seen for WT1 (2/10), PRAME (4/10) and CMVpp65 (9/10). For CMVpp65, increased CD4 + T cells were detected in 4/7 patients, and an antibody response was induced in 3/7 initially seronegative patients. Median OS was not reached after 1057 days; median RFS was 1084 days. A positive correlation was observed between clinical benefit and younger age as well as mounting of antigen-specific immune responses.
Conclusions: Administration of TLR7/8-matured DCs to AML patients in CR at high risk of relapse was feasible and safe and resulted in induction of antigen-specific immune responses. Clinical benefit appeared to occur more likely in patients <65 and in patients mounting an immune response. Our observations need to be validated in a larger patient cohort. We hypothesise that TLR7/8 DC vaccination strategies should be combined with hypomethylating agents or checkpoint inhibition to augment immune responses.
Trial Registration: The study was registered at https://clinicaltrials.gov on 17 October 2012 (NCT01734304) and at https://www.clinicaltrialsregister.eu (EudraCT-Number 2010-022446-24) on 10 October 2013.
Competing Interests: DJS is employed by Medigene Immunotherapies GmbH, and holds patents and receives royalties for DC vaccines. All other authors declare that they have no conflict of interest.
(© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.)
Databáze: MEDLINE
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