Abstract
Introduction:
Patients with acute myeloid leukemia (AML) often carry the same gene mutations. Neoantigens encoded by these mutations are attractive targets for immunotherapy.
Methods:
We searched for public human leukocyte antigen (HLA) class II-restricted neoantigens on AML using an in vitro T cell stimulation method. Peptides from 26 recurrent genetic aberrations were assessed for predicted HLA class II binding, and 24 long neopeptides encoded by 10 recurrent mutations were synthesized. Naive CD4 T cells from healthy individuals were cocultured with autologous dendritic cells pulsed with neopeptides.
Results:
Multiple CD4 T cell clones were isolated that recognized neopeptides encoded by 5 different genetic aberrations. Two of these peptides, one from the well-known DNMT3A-R882H hotspot mutation and one from a long alternative reading frame created by frameshift mutations in RUNX1, were recognized by CD4 T cell clones after endogenous processing and presentation on cell lines transduced or CRISPR-Cas9-edited with the mutation of interest. The T cell clone for DNMT3A-R882H was also activated upon stimulation with primary AML samples from HLA-DQB1*06:02 or -DQB1*06:03 positive patients with the mutation.
Conclusion:
We here identified a public HLA class II-restricted neoantigen encoded by a driver mutation occurring in 10% of patients with AML that could become an important target for immunotherapy to treat patients with DNMT3A-R882H-mutated AML.