TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML

Jayakumar Vadakekolathu, Catherine Lai, Stephen Reeder, Sarah E Church, Tressa Hood, Anbarasu Lourdusamy, Michael P Rettig, Ibrahim Aldoss, Anjali S Advani, John Godwin, Matthew J Wieduwilt, Martha Arellano, John Muth, Tung On Yau, Farhad Ravandi, Kendra Sweet, Heidi Altmann, Gemma A Foulds, Friedrich Stölzel, Jan Moritz MiddekeMarilena Ciciarello, Antonio Curti, Peter J M Valk, Bob Löwenberg, Ivana Gojo, Martin Bornhäuser, John F DiPersio, Jan K Davidson-Moncada, Sergio Rutella

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1 gene expression scores at baseline compared with nonresponders. Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

Original languageEnglish
Pages (from-to)5011-5024
Number of pages14
JournalBlood advances
Volume4
Issue number20
Early online date15 Oct 2020
DOIs
Publication statusPrint publication - 27 Oct 2020
Externally publishedYes

Keywords

  • Antibodies, Bispecific
  • Cytogenetics
  • Humans
  • Immunotherapy
  • Interleukin-3 Receptor alpha Subunit
  • Leukemia, Myeloid, Acute/drug therapy
  • Tumor Suppressor Protein p53/genetics

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