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.
Highlights
The graft-versus-leukemia (GvL) effect associated with allogeneic hematopoietic stem cell transplantation (HSCT) and the efficacy of donor lymphocyte infusion (DLI) to eradicate residual disease after HSCT still represent cornerstones of immunotherapy for the treatment of acute myeloid leukemia (AML) [1]
While allogeneic HSCT is generally recognized as the best therapeutic option in NPM1-mutated AML patients showing FLT3-ITD, at least in cases with a high allelic ratio; this procedure in first complete remission (CR) is generally not recommended in patients harboring NPM1 gene mutations without FLT3-ITD [8,53,54]
In order to expand the opportunity to track the occurrence and clinical significance of NPM1-mutated-specific T-cell immunity, it could be possibly suggested to utilize for future immunological experiments a combination of at least AIQDLCLAV, AIQDLCVAV, CLAVEEVSL, LAVEEVSLR, AVEEVSLRK 9-mer, and CLAVEEVSLRK 11-mer immunogenic peptides, representative of the more common NPM1 mutation types and able to efficiently bind to at least most common Human Leukocyte Antigen (HLA) types, such as A*02:01 and A*03:01, which are frequently found in the Caucasian population (Table 1) [4,15,16,18,19,20,21,25]
Summary
The graft-versus-leukemia (GvL) effect associated with allogeneic hematopoietic stem cell transplantation (HSCT) and the efficacy of donor lymphocyte infusion (DLI) to eradicate residual disease after HSCT still represent cornerstones of immunotherapy for the treatment of acute myeloid leukemia (AML) [1]. Apart from mediating the beneficial GvL effect, the immune system, mainly through antigen-reactive T cells, may induce graft-versus-host disease (GvHD), leading to potentially harmful post-transplant complications. These observations suggest the need for innovative suitable immunotherapeutic approaches aiming to obtain robust anti-leukemic activity while avoiding T-cell cytotoxicity directed against healthy tissues [1]. While leukemia-associated antigens (LAA) are overexpressed on AML cells relative to normal tissues but are not usually lineage-specific and may be found on non-hematopoietic cells, leukemia-specific antigens, resulting from aberrant proteins encoded by ideally leukemogenic mutations, are exclusively expressed in malignant clones, representing optimal candidate targets for anti-leukemic immunity [1,2,3]. Based upon the above indicated biological requirements, NPM1-mutated protein may be considered an ideal target antigen for AML immunotherapy [1,2]
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