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.

Keywords: NPM1 mutation; NPM1-mutated-specific T cells; acute myeloid leukemia; adoptive immunotherapy; immune-checkpoint inhibitors; leukemia-specific neoantigen.

Figure 1

Exploiting immunotherapy against NPM1-mutated AML.Autologous or allogeneic NPM1-mutated-specific T-cell responses can naturally occur in patients receiving either conventional chemotherapy/hypomethylating agents or allogeneic HSCT, respectively. Adoptive immunotherapy carried out by infusion of NPM1-mutated-specific T cells, stimulated and expanded directly from patients, could potentially be promising in maintaining complete remission or eradicating persistent measurable residual disease in subjects not candidate to allogeneic HSCT. The selected NPM1-mutated-derived peptides that are most immunogenic are listed. In addition to unmanipulated DLI, neoantigen-specific DLI obtained from healthy donors could represent a therapeutic option in case of morphological or molecular AML relapse after allogeneic HSCT. Genetically engineered T cells directed against NPM1-mutated-derived peptides bound to HLA may also represent a newer immunotherapeutic strategy. Immune-checkpoint inhibitors and NPM1-mutated peptide vaccines could also prospectively be considered to further elicit and stimulate NPM1-mutated-specific immune responses. Finally, CD33 and CD123, antigens strongly expressed on NPM1-mutated blast cell surface, are currently recognized as valuable targets for monoclonal antibodies/T-cell recruiting antibody constructs or CAR-T cells, despite being hampered by “on-target/off-tumor” toxicity.