CELL INTELLIGENCE · 肿瘤细胞治疗研究

Accumulation of genetic mutations in malignant myeloid precursor cells leads to an extremely poor prognosis for patients with acute myeloid leukemia (AML). Immunogenic neoantigens recognized by T cell receptor (TCR) can elicit effective immune responses against malignant cells with corresponding somatic mutations. To broaden the range of targeted treatments for AML, in this study, we explored the feasibility of immunotherapy targeting neoantigens arising from recurrent mutations, which are exclusively present on leukemic cells.

We used data-driven methods to select seven neoantigens from four frequently mutated genes (NPM1, FLT3, TP53, and DNMT3A) associated with HLA-A * 02:01-positive AML patients. Functional assays demonstrated that neoantigens derived from NPM1/W288fs, FLT3/D835H, and FLT3/D835Y were shown to induce specific T cell responses in AML patients.

We further identified the specific TCR sequences from healthy donors capable of recognizing these neoantigens. In-depth studies of their specific T cells revealed the presence of dominant αβTCRs that could specifically recognize NPM1/W288fs and FLT3/D835H in an HLA-A * 02:01-restricted manner. T cells engineered with each αβTCR selectively recognized and killed HLA-A * 02:01-positive AML targets endogenously expressing corresponding mutations.

Overall, our findings support the clinical translation of adoptive neoantigen-specific TCR-engineered T cells as a novel therapeutic strategy for treating AML.