Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

Abstract

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.

Multiparametric Flow Cytometry for MRD Monitoring in Hematologic Malignancies: Clinical Applications and New Challenges

“…It is conceivable that some relevant immunological factors may directly be implied in such “pre-clinical” tumor progression, in line with the general notion that most if not all neoplasms are under immune control and have to escape host immunity to outgrow. In this view, contextually to MRD detection, the MFC-based approach could also allow to investigate the frequencies and functionality of tumor-specific T cells, which are emerging as a fundamental protective factor against neoplastic outgrowth, both in hematologic and solid cancers [ 56 , 57 , 58 , 136 , 137 , 138 , 139 , 140 , 141 ].…”

Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation

“…Another targeted-therapy approach on the rise is cancer immunotherapy treatments. As mentioned previously, NPM1 is a highly specific and stable mutation with relapses usually detected by increasing MRD [ 149 ]. Due to the nature of NPM1 -mutated AML, with the driving factor being an oncoprotein, immunotherapy is an ideal approach that focuses on either targeting mutant NPM1-derived neoantigens or genetically engineering T cells specific for NPM1-mutated peptides.…”

“…Efficient HLA presentation has been seen targeting 11 residues of the NPM1-mutated C-terminus due to the distinct amino acid sequence not normally found in human tissues. Specifically, HLA class I ligandomes: AIQDLCLAV, AIQDLCVAV, AVEEVSLRK 9-mer, CLAVEEVSL, LAVEEVSLR, and CLAVEEVSLRK have been studied [ 149 , 150 , 151 , 152 ]. Single-cell RNA sequencing has exhibited upregulation of immune responses and major metabolic pathways caused by increased cytokine-induced memory-like NK cells; the pathways activated relate to mitochondrial maintenance and show similar activity upon IL-15 activation of NK cells.…”

Molecular Immunology in Hematological Disorders

“…Therefore, there is a close pathophysiological relationship between hematological diseases and the immune system, and the elucidation of these molecular mechanisms will advance the diagnosis and treatment of benign and malignant hematologic, infectious, and autoimmune diseases. Contemporary studies [ 1 , 2 , 3 , 4 , 5 , 6 ] have focused on the applications of molecular immunology in hematology, providing fresh insights into the molecular immunological mechanisms involved in the diagnosis and treatment of hematologic diseases.…”

“…There are few leukemia-specific antigens with known utility against acute myeloid leukemia; hence, clinically available CAR-T cell therapies against it currently do not exist. Forghieri et al [ 5 ] summarized that neoantigens, such as peptides derived from NPM1 gene mutant proteins that are not present in normal human tissues, can be considered to be leukemia-specific antigens. NPM1 gene mutations are the most common mutations (30%) in acute myeloid leukemia.…”