TP53abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

Abstract

Purpose: Somatic TP53 mutations and 17p deletions with genomic loss of TP53 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 TP53 mutated AML and to determine whether TP53 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 TP53 mutated AML (n=42) or TP53 wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (11 cases with TP53 mutations and/or 17p deletion with genomic loss of TP53) who received immunotherapy with flotetuzumab, an investigational CD123×CD3 bispecific DART ® molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort and a Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (HOVON) cohort. Results: All TCGA cases with TP53 mutations (n=13) expressed higher levels of negative immune checkpoints, inflammatory chemokines, interferon (IFN)-γ-inducible molecules, and had a higher tumor inflammation signature (TIS) score, compared with TCGA cases with other riskdefining molecular lesions. The comparison between TP53 mutated and TP53 wild type primary BM samples showed higher expression of IFNG, FoxP3, immune checkpoints and markers 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 heightened expression of IFN-γ and inflammation pathway genes in KG-1 cells (loss-of-function mutation of TP53) compared with Kasumi-1 cells (gain-of-function mutation of TP53). Finally, 5 out of 11 (45.5%) patients with R/R AML and TP53 abnormalities showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS, FoxP3, CD8 T-cell abundance, inflammatory chemokine and PD1 gene expression scores at baseline compared with non-responders. Conclusions:This study provides evidence for a correlation between IFN-γ-dominant immune subtypes and TP53 abnormalities. The anti-leukemic activity with flotetuzumab encourages further study of this immunotherapeutic approach in this patient subgroup.further studies of T-cell targeting immunotherapeutic approaches in patients with TP53 mutations.

TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype

“…As proof-of-principle activity of immunomodulatory therapy in TP53 mutant AML, recent data with the CD3xCD123 DART flotetuzumab showed antileukemic activity in 5 of 11 patients. 43 We have provided evidence that the mir34a-MYC-PD-L1 signaling cascade is involved in enhanced PD-L1 expression in patients with TP53 mutations, but we acknowledge that there are other pathways involved in the upregulation of PD-L1, including other transcription factors that can bind and transactivate PD-L1, such as HIF1-a, NF-kB, AP-1, STAT 1/3, and that further exploration of these factors in MDS/AML is warrented. 44 Objective responses to immune checkpoint therapy have been observed in only a small subset of patients with MDS/sAML, and insight into which subgroups may best benefit from immunotherapy is lacking.…”

Is There a Place for PD-1-PD-L Blockade in Acute Myeloid Leukemia?

“…A study from 2018, conducted on 55 patients, demonstrated that the incidence of PD-L1 expression is higher in patients with leukocytosis [30]. Other studies showed a correlation between TP53 mutation and the overexpression of PD-L1 [2,104].…”

The Problem of TP53-Mutant MDS/AML

“…14,15 Importantly, TP53 mutant AML patients have been strongly associated with an adverse immune microenvironment and potentially may be an optimal molecular subset for novel immunomodulatory agents. 16…”