Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia
Dyantha I. van der Lee, … , J.H. Frederik Falkenburg, Marieke Griffioen
Dyantha I. van der Lee, … , J.H. Frederik Falkenburg, Marieke Griffioen
Published January 14, 2019
Citation Information: J Clin Invest. 2019;129(2):774-785. https://doi.org/10.1172/JCI97482.
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Research Article Hematology

Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia

Abstract

The most frequent subtype of acute myeloid leukemia (AML) is defined by mutations in the nucleophosmin 1 (NPM1) gene. Mutated NPM1 (ΔNPM1) is an attractive target for immunotherapy, since it is an essential driver gene and 4 bp frameshift insertions occur in the same hotspot in 30%–35% of AMLs, resulting in a C-terminal alternative reading frame of 11 aa. By searching the HLA class I ligandome of primary AMLs, we identified multiple ΔNPM1-derived peptides. For one of these peptides, HLA-A*02:01–binding CLAVEEVSL, we searched for specific T cells in healthy individuals using peptide-HLA tetramers. Tetramer-positive CD8+ T cells were isolated and analyzed for reactivity against primary AMLs. From one clone with superior antitumor reactivity, we isolated the T cell receptor (TCR) and demonstrated specific recognition and lysis of HLA-A*02:01–positive ΔNPM1 AML after retroviral transfer to CD8+ and CD4+ T cells. Antitumor efficacy of TCR-transduced T cells was confirmed in immunodeficient mice engrafted with a human AML cell line expressing ΔNPM1. In conclusion, the data show that ΔNPM1-derived peptides are presented on AML and that CLAVEEVSL is a neoantigen that can be efficiently targeted on AML by ΔNPM1 TCR gene transfer. Immunotherapy targeting ΔNPM1 may therefore contribute to treatment of AML.

Authors

Dyantha I. van der Lee, Rogier M. Reijmers, Maria W. Honders, Renate S. Hagedoorn, Rob C.M. de Jong, Michel G.D. Kester, Dirk M. van der Steen, Arnoud H. de Ru, Christiaan Kweekel, Helena M. Bijen, Inge Jedema, Hendrik Veelken, Peter A. van Veelen, Mirjam H.M. Heemskerk, J.H. Frederik Falkenburg, Marieke Griffioen

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Figure 6

Lysis of primary AMLs after ΔNPM1 TCR gene transfer.

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Lysis of primary AMLs after ΔNPM1 TCR gene transfer. TCR-transduced CD8+...
TCR-transduced CD8+ and CD4+ T cells were tested for cytolytic capacity by a 9-hour 51Cr-release assay on 6 HLA-A*02:01–positive primary AMLs, including 4 samples with ΔNPM1 and 2 samples with WTNPM1. CD8+ (CD8ØNPM1; red circles) and CD4+ (CD4ØNPM1; red squares) T cells transduced with the TCR for ΔNPM1 showed specific lysis of all 4 AMLs with ΔNPM1, whereas none of the AMLs were specifically lysed by CD8+ (CD8ØCMV; blue circles) or CD4+ (CD4ØCMV; blue squares) T cells after transfer of the CMV-specific TCR. The allo-A2 clone (gray triangles) was included as a positive control. Data represent mean percentage of specific lysis in triplicate wells ± SD for donor 2.