Acute myeloid leukemia (AML) frequently relapses after standard therapies. A promising new treatment strategy could be immunotherapy directed against neoantigens. Especially public neoantigens encoded by common recurrent driver mutations are relevant targets, since they are shared between patients and carry a low risk of being lost during immune escape.
We have identified three public neoantigens on AML that are encoded by frequent driver mutations in NPM1 and DNMT3A and presented by common HLA class I or II molecules. We demonstrated that these neoantigens can be recognized on leukemic cells by T-cells isolated from healthy individuals. For two CD8 T-cells directed against HLA-A*02:01- and HLA-A*11:01-binding NPM1 neoantigens, the T-cell receptor (TCR) was sequenced and introduced into CD8 and CD4 T-cells from other individuals. CD8 as well as CD4 T-cells engineered with the HLA-A*02:01-restricted TCR showed recognition and lysis of leukemic cells, whereas...
Show moreAcute myeloid leukemia (AML) frequently relapses after standard therapies. A promising new treatment strategy could be immunotherapy directed against neoantigens. Especially public neoantigens encoded by common recurrent driver mutations are relevant targets, since they are shared between patients and carry a low risk of being lost during immune escape.
We have identified three public neoantigens on AML that are encoded by frequent driver mutations in NPM1 and DNMT3A and presented by common HLA class I or II molecules. We demonstrated that these neoantigens can be recognized on leukemic cells by T-cells isolated from healthy individuals. For two CD8 T-cells directed against HLA-A*02:01- and HLA-A*11:01-binding NPM1 neoantigens, the T-cell receptor (TCR) was sequenced and introduced into CD8 and CD4 T-cells from other individuals. CD8 as well as CD4 T-cells engineered with the HLA-A*02:01-restricted TCR showed recognition and lysis of leukemic cells, whereas only CD8 T-cells reacted against leukemic cells after introduction of the HLA-A*11:01-restricted TCR. T-cells engineered with the HLA-A*02:01-restricted TCR also mediated an anti-leukemic response in an immunodeficient mouse model. The identified neoantigens may form attractive targets for T-cell-based immunotherapies against AML. The HLA-A*02:01-restricted NPM1 neoantigen-specific TCR is currently evaluated in a clinical trial to treat patients with NPM1-mutated AML.
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