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

Felix S Lichtenegger; Frauke M Schnorfeil; Maurine Rothe; Katrin Deiser; Torben Altmann; Veit L Bücklein; Thomas Köhnke; Christian Augsberger; Nikola P Konstandin; Karsten Spiekermann; Andreas Moosmann; Stephan Boehm; Melanie Boxberg; Mirjam Hm Heemskerk; Dennis Goerlich; Georg Wittmann; Beate Wagner; Wolfgang Hiddemann; Dolores J Schendel; Gunnar Kvalheim; Iris Bigalke; Marion Subklewe

doi:10.1002/cti2.1117

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

Clin Transl Immunology. 2020 Mar 3;9(3):e1117. doi: 10.1002/cti2.1117. eCollection 2020.

Authors

Felix S Lichtenegger^{1

2

3}, Frauke M Schnorfeil^{1

2

4

5}, Maurine Rothe^{1

2}, Katrin Deiser^{1

2}, Torben Altmann^{1

2}, Veit L Bücklein^{1

2}, Thomas Köhnke^{1

2}, Christian Augsberger^{1

2}, Nikola P Konstandin¹, Karsten Spiekermann¹, Andreas Moosmann⁶, Stephan Boehm⁷, Melanie Boxberg⁸, Mirjam Hm Heemskerk⁹, Dennis Goerlich¹⁰, Georg Wittmann¹¹, Beate Wagner¹¹, Wolfgang Hiddemann^{1

4}, Dolores J Schendel¹², Gunnar Kvalheim¹³, Iris Bigalke^{13

14}, Marion Subklewe^{1

2

4}

Affiliations

¹ Department of Medicine III University Hospital, LMU Munich Munich Germany.
² Laboratory for Translational Cancer Immunology Gene Center LMU Munich Munich Germany.
³ Present address: Roche Innovation Center Munich Penzberg Germany.
⁴ German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg Germany.
⁵ Present address: Medigene AG Planegg Germany.
⁶ DZIF Research Group "Host Control of Viral Latency and Reactivation" (HOCOVLAR) Helmholtz Zentrum München Munich Germany.
⁷ Max von Pettenkofer Institute LMU Munich Munich Germany.
⁸ Institute of Pathology Technical University of Munich Munich Germany.
⁹ Department of Hematology Leiden University Medical Center Leiden The Netherlands.
¹⁰ Institute of Biostatistics and Clinical Research University of Muenster Muenster Germany.
¹¹ Department of Transfusion Medicine, Cellular Therapeutics and Hemostaseology University Hospital LMU Munich Munich Germany.
¹² Medigene AG Planegg Germany.
¹³ Department of Cellular Therapy The Norwegian Radium Hospital Oslo University Hospital Oslo Norway.
¹⁴ Present address: BioNTech IMFS Idar-Oberstein Germany.

Abstract

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.

Keywords: acute myeloid leukaemia; cancer vaccines; clinical trials; dendritic cell vaccination; immunotherapy.

Associated data

ClinicalTrials.gov/NCT01734304