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 February 1, 2019; First published January 14, 2019
Citation Information: J Clin Invest. 2019;129(2):774-785. https://doi.org/10.1172/JCI97482.
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Categories: 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 7

In vivo antitumor efficacy after ΔNPM1 TCR gene transfer.

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In vivo antitumor efficacy after ΔNPM1 TCR gene transfer. Male NSG mice ...
Male NSG mice were engrafted with 1 × 106 HLA-A*02:01–positive OCI-AML3 cells with ΔNPM1. OCI-AML3 cells were transduced with luciferase to follow in vivo tumor growth by bioluminescence imaging. Two weeks after tumor inoculation, mice were either left untreated or injected i.v. with 4 × 106 CD8+/CD4+ T cells (2:3 ratio) transduced with the TCR for ΔNPM1 or with the CMV-specific control TCR. TCR-transduced T cells were produced from HLA-A*02:01–positive healthy donor 3. (A and B) After T cell injection, tumor burden was followed twice per week for 21 days. In mice receiving CD8+/CD4+ T cells transduced with the TCR for ΔNPM1 (ΔNPM1 T cells; n = 5; red), tumor load was significantly reduced within 2 weeks of T cell transfer, resulting in delayed tumor outgrowth as compared with that in untreated mice (no T cells; n = 4; black) and mice treated with CD8+/CD4+ T cells transduced with the CMV-specific control TCR (CMV T cells; n = 2; blue). (C) Kaplan-Meier curve showing better overall survival of mice treated with the ΔNPM1-specific TCR (n = 5; red line) as compared with untreated mice (n = 4; black line) or mice treated with the CMV-specific control TCR (n = 2; blue line). P = 0.0206, log-rank (Mantel-Cox) test.