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

• Main Authors: Fabio Forghieri, Giovanni Riva, Ivana Lagreca, Patrizia Barozzi, Francesca Bettelli, Ambra Paolini, Vincenzo Nasillo, Beatrice Lusenti, Valeria Pioli, Davide Giusti, Andrea Gilioli, Corrado Colasante, Laura Galassi, Hillary Catellani, Francesca Donatelli, Annalisa Talami, Rossana Maffei, Silvia Martinelli, Leonardo Potenza, Roberto Marasca, Enrico Tagliafico, Rossella Manfredini, Tommaso Trenti, Patrizia Comoli, Mario Luppi
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: International Journal of Molecular Sciences
• Subjects: <i>NPM1</i> mutation; acute myeloid leukemia; leukemia-specific neoantigen; NPM1-mutated-specific T cells; adoptive immunotherapy; immune-checkpoint inhibitors
• Online Access: https://www.mdpi.com/1422-0067/22/17/9159
• ISSN: 1661-6596; 1422-0067

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 <i>NPM1</i>-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 <i>NPM1</i>-mutated AML patients.