Targeting IDH2R140Q and other neoantigens in acute myeloid leukemia.

For patients with high-risk or relapsed/refractory acute myeloid leukemia (AML), allogeneic stem cell transplantation (alloHSCT) and the graft-versus-leukemia effect mediated by donor T cells, offer the best chance of long-term remission. However, the concurrent transfer of alloreactive T cells can lead to graft-versus-host disease that is associated with transplant-related morbidity and mortality. Furthermore, ~60% of patients will ultimately relapse post-alloHSCT, thus underscoring the need for novel therapeutic strategies that are safe and effective. In this study, we explored the feasibility of immunotherapeutically targeting neoantigens, which arise from recurrent non-synonymous mutations in AML and thus represent attractive targets since they are exclusively present on the tumor. Focusing on 14 recurrent driver mutations over 8 genes found in AML, we investigated their immunogenicity in 23 individuals with diverse HLA profiles. We demonstrate the immunogenicity of AML neoantigens, with 17/23 (74%) reactive donors with IDH2R140Q (n=11/17 responders), IDH1R132H (n=7/17), and FLT3D835Y (n=6/17) identified as immunodominant. In-depth studies of IDH2R140Q-specific T cells revealed the presence of reactive CD4+ and CD8+ T cells capable of recognizing distinct mutant-specific epitopes restricted to different HLA alleles. These neo-T cells could selectively recognize and kill HLA-matched AML targets endogenously expressing IDH2R140Q both in vitro and in vivo. Overall, our findings support the clinical translation of neoantigen-specific T cells to treat R/R AML.