1. Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia
- Author
-
van der Lee, Dyantha I., Reijmers, Rogier M., Honders, Maria W., Hagedoorn, Renate S., de Jong, Rob C.M., Kester, Michel G.D., van der Steen, Dirk M., de Ru, Arnoud H., Kweekel, Christiaan, Bijen, Helena M., Jedema, Inge, Veelken, Hendrik, van Veelen, Peter A., Heemskerk, Mirjam H.M., Falkenburg, J.H. Frederik, and Griffioen, Marieke
- Subjects
Acute myelocytic leukemia -- Care and treatment ,Cell differentiation -- Research ,Hematopoietic stem cell transplantation -- Usage ,Immunotherapy -- Usage ,Gene therapy ,T cells ,Peptides ,Tumors ,Myeloid leukemia ,HLA antigens ,Genes ,Tumor antigens ,Health care industry - Abstract
The most frequent subtype of acute myeloid leukemia (AML) is defined by mutations in the nucleophosmin 1 (NPM1) gene. Mutated NPM1 ([DELTA]NPM1) 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 [DELTA]NPM1-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.sup.+] 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 [DELTA]NPM1 AML after retroviral transfer to [CD8.sup.+] and [CD4.sup.+] T cells. Antitumor efficacy of TCR-transduced T cells was confirmed in immunodeficient mice engrafted with a human AML cell line expressing [DELTA]NPM1. In conclusion, the data show that [DELTA]NPM1-derived peptides are presented on AML and that CLAVEEVSL is a neoantigen that can be efficiently targeted on AML by [DELTA]NPM1 TCR gene transfer. Immunotherapy targeting [DELTA]NPM1 may therefore contribute to treatment of AML., Introduction Acute myeloid leukemia (AML) is characterized by accumulation of malignant myeloid precursor cells that are arrested in differentiation in the bone marrow. Standard therapy of AML consists of induction [...]
- Published
- 2019
- Full Text
- View/download PDF