Abstract
Targeting a mutant NPM1-derived neoantigen has antitumor activity against AML cells.
Major finding: Targeting a mutant NPM1-derived neoantigen has antitumor activity against AML cells.
Concept: NPM1 mutations create a C-terminal alternative reading frame not present in normal blood cells.
Impact: NPM1-mutant AML may be a candidate for neoantigen vaccines or adoptive T-cell therapy.
The majority of tumor neoantigens derive from patient-specific mutations and necessitate the development of personalized vaccine or autologous T-cell therapy approaches. The insertion mutations in nucleophosmin 1 (NPM1) that are found in 30% to 35% of acute myeloid leukemias (AML) result in longer mutant proteins with the same 11-amino acid C-terminal alternative reading frame (ΔNPM1), leading van der Lee and colleagues to hypothesize that the unique C terminus of ΔNPM1 might create neoantigens that could potentially be targeted by immunotherapy. Analysis of the peptides bound by HLA class I surface molecules in primary AMLs revealed that the ligandomes of 7 of 8 NPM1-mutant AMLs included peptides corresponding to the ΔNPM1 C terminus. T cells recognizing part of the ΔNPM1 C terminus could be isolated and expanded from large numbers of peripheral blood mononuclear cells, and these T cells had reactivity against NPM1-mutant AMLs. A TCR recognizing the ΔNPM1 C-terminal segment could be transduced into CD4+ and CD8+ T cells, and these transduced T cells had reactivity against all NPM1-mutant AML samples tested, indicating that TCR gene transfer can result in specific recognition of the endogenous ΔNPM1 C-terminal neoantigen. The TCR-transduced T cells also specifically induced lysis of primary human AML cells expressing ΔNPM1 but not wild-type NPM1 in vitro and significantly prolonged survival of immunodeficient mice engrafted with a human ΔNPM1-expressing AML cell line. These results demonstrate that ΔNPM1 creates a targetable neoantigen and, given the prevalence of NPM1 mutations in AML, raise the possibility that it could potentially be an ideal target for “off-the-shelf” neoantigen vaccines or adoptive transfer of TCR-engineered T cells.
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