️ 33: Mis-splicing-derived Neoantigens — A New Avenue for Immunotherapy in Leukemia

️ Episode 33: Mis-splicing-derived Neoantigens — A New Avenue for Immunotherapy in Leukemia In this episode of Base por Base, we examine groundbreaking research by Kim et al. (2025), recently published in Cell, that uncovers a promising immunotherapeutic strategy targeting leukemia-associated splicing factor mutations. The study identifies recurrent neoantigens arising from mis-splicing events in SRSF2 and ZRSR2 mutant myeloid leukemias, which can be exploited for T cell receptor (TCR)-based therapies. Study highlightsThe researchers discovered that somatic mutations in RNA splicing factors lead to highly stereotyped mis-splicing events, generating neoantigens shared across patients. These aberrant splicing isoforms yield peptides capable of being presented by HLA class I molecules and recognized by CD8⁺ T cells. Using high-throughput screening, the team isolated neoantigen-reactive TCRs from both healthy donors and leukemia patients. They demonstrated that T cells engineered with these TCRs could selectively recognize and kill leukemia cells harboring splicing mutations, particularly those affecting the SRSF2 gene.Importantly, these mis-splicing-derived neoantigens are minimally expressed in healthy tissues, improving the specificity and safety profile of the proposed immunotherapy. The study also provides evidence of functional impairment in patient-derived neoantigen-reactive T cells, but shows that adoptively transferred engineered T cells retain robust cytotoxicity. In vivo models confirmed tumor control and increased survival with TCR-T cell therapy targeting the CLK3-derived neoantigen. ConclusionThis work positions RNA mis-splicing as a fertile source of “public” neoantigens that are both recurrent and targetable across genetically defined subtypes of leukemia. It opens new doors for TCR-based therapies and possibly neoantigen vaccines, especially in the context of allogeneic stem cell transplantation. The implications for personalized immunotherapy in myeloid malignancies are profound and set the stage for future clinical translation. ReferenceKim, W. J., Crosse, E. I., De Neef, E., et al. (2025). Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias. Cell, 188, 1–19. https://doi.org/10.1016/j.cell.2025.03.047 LicenseThis episode is based on an open access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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