TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

Purpose: Somatic TP53 (p53) mutations and 17p deletions with genomic loss of p53 occur in 37-46% of acute myeloid leukemia (AML) cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to characterize the immune landscape of p53 mutated AML and to determine whether p53 abnormalities identify a patient subgroup that may benefit from T-cell targeting immunotherapy approaches. Experimental Design: The NanoString Pan-Cancer IO 360 assay was used for the immune transcriptomic analysis of 64 diagnostic bone marrow (BM) samples from adults with p53 mutated AML (n=42) or p53 wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (10 cases with p53 mutations and/or 17p deletion with genomic loss of p53) who received immunotherapy with flotetuzumab, an investigational CD123xCD3 bispecific DART molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort (147 adults with non-promyelocytic AML; 13 with p53 mutations) and the HOVON cohort (618 adults with non-promyelocytic AML; 14 with p53 mutations). Results: All TCGA cases with p53 mutations showed high levels of immune infiltration, negative immune checkpoints, inflammatory chemokines, interferon (IFN)-γ-inducible molecules and a higher tumor inflammation signature (TIS) score relative to TCGA cases with other risk-defining molecular lesions. The comparison between p53 mutated and p53 wild type primary BM samples showed higher expression of IFN-γ, FoxP3, negative immune checkpoints and molecules associated with features of exhaustion and senescence in the former cohort and allowed the computation of a 34-gene immune classifier prognostic for overall survival. In vitro modeling experiments with AML cell lines showed an increased expression of IFN-γ and inflammation pathway genes in KG-1 cells with a loss-of-function mutation of p53 compared with Kasumi-1 cells with a gain-of-function mutation of p53. Finally, 5 out of 10 (50%) patients with R/R AML and p53 mutations and/or 17p deletion with genomic loss of p53 showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS, Treg, CD8, inflammatory chemokine and PD1 scores at baseline compared with non-responders. Conclusions: This study provides evidence for a correlation between IFN-γ-dominant immune subtypes and p53 abnormalities. The favorable overall response rate to flotetuzumab encourages the implementation of this immunotherapeutic approach in this patient subgroup.