Harnessing Neoantigen-specific T Cells for Precision Immunotherapy in Hematologic Malignancies

Antigen-specific T-cell immunotherapies are transforming the treatment landscape of hematologic malignancies. Neoantigen-specific therapies that exploit the ability of endogenous T-cell receptors (TCRs) to recognize tumor-derived peptides in a human leukocyte antigen (HLA)-restricted context differ mechanistically from modalities employing chimeric antigen receptor (CAR) T cells, which target surface antigens in an HLA-independent manner. In contrast to approaches targeting tumor-associated antigens (TAAs), neoantigen-specific strategies offer more precise tumor selectivity and reduced off-target toxicity. Advances in immunogenomics, immunopeptidomics, and functional validation have accelerated the identification of both personalized and recurrent neoantigens, and high-resolution sequencing technologies have further facilitated the characterization of their cognate TCRs, which are currently being explored for developing TCR-engineered T cell therapies. Early-phase clinical trials in hematologic malignancies demonstrate that neoantigen-specific strategies are safe and feasible across multiple hematologic cancers, with ongoing studies actively assessing the immunogenicity, clinical efficacy, and durability of these approaches. This review synthesizes recent pre-clinical and clinical advances in the discovery, validation, and therapeutic exploitation of neoantigen-specific strategies in blood cancers, highlighting translational insights for prioritizing immunogenic neoantigens. Particular emphasis is placed on identifying biological and technological barriers that limit the therapeutic efficacy of neoantigen-specific immunotherapies, with the goal of distilling actionable insights to guide their development in hematologic malignancies.