This LSC specific mechanism of immune evasion could be overcome by treatment with PARP1 inhibitors, which in conjunction with functional NK cells holds promise to eradicate LSCs and promote immune-mediated cure of AML. L.: Sanofi, Novartis, Otsuka (consultancy); Roche (research funding) Abstract already published.
NKG2DL expression was repressed by PARP1 recruitment at NKG2DL promoters.
PARP1 inhibition (PARPi) induced NKG2DL surface expression in LSCs and co-treatment with PARPi and NK cells (but not with either alone) suppressed leukemogenesis in patient derived xenograft (PDX) models (Fig. Low NKG2DL surface or high PARP1 m RNA expression associated with poor outcome in AML patients.
Conditioning was myeloablative in 71% and reduced in 29%, donors were matched siblings (48%), unrelated (41%), haploidentical (6%) and cord blood (5%).
After allo SCT, 111 patients developed HR, 23 MR and 6 had persisting MRD.
AML cells co-cultured or not with NK cells (control or anti-NKG2D pre-treated) were co-stained for additional stem/immunological markers.
PARP1 expression was analysed by q RT-PCR and immunoblot, and binding to NKG2DL promoters by chromatin immunoprecipitation.
Fifty-eight patients were treated with TKI only (dasatinib, n=50, nilotinib, n=3, ponatinib, n=5), while 82 received additional treatment such as DLI, chemotherapy, or second allo SCT.
Main toxicities of dasatinib were effusion, edema, or other pulmonary complaints (10 - 15% of patients) and infections (13%).
Results: Acute myeloid leukemia (AML) was the most common indication for haplo (76%) and approximately 45% of patients were transplanted in CR1.