Flotetuzumab and other T-Cell Immunotherapies Upregulate MHC Class II Expression on Acute Myeloid Leukemia Cells

Acute myeloid leukemia (AML) relapse is one of the most common and significant adverse events following allogeneic hematopoietic cell transplantation (allo-HCT). Downregulation of major histocompatibility class II (MHC-II) surface expression on AML blasts may represent a mechanism of escape from the graft-versus-malignancy effect and facilitate relapse. We hypothesized that T-cell immunotherapies targeting AML antigens would upregulate MHC-II surface expression via localized release of interferon gamma (IFN-γ), a protein known to upregulate MHC-II expression via JAK-STAT signaling. We demonstrate that flotetuzumab (FLZ), a CD123xCD3 bispecific DART® molecule, and chimeric antigen receptor expressing T-cells (CAR-T) targeting CD123, CD33, or CD371 upregulate MHC-II surface expression in vitro on a THP-1 AML cell line with intermediate MHC-II expression and four primary AML samples from patients relapsing after HCT with low MHC-II expression. We additionally show that FLZ upregulates MHC-II expression in a patient-derived xenograft model and in relapsed/refractory AML patients treated with flotetuzumab in a clinical trial. Finally, we report that FLZ-induced MHC-II upregulation is mediated by IFN-γ. In conclusion, we provide evidence that T-cell immunotherapies targeting relapsed AML can kill AML via both MHC-independent mechanisms and by an MHC-dependent mechanism through local release of IFN-γ and subsequent upregulation of MHC-II expression.