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

• Type of Material: Article
• Authors: Jayakumar Vadakekolathu, Nottingham Trent University; Catherine Lai, MedStar Georgetown University Hospital; Stephen Reeder, Nottingham Trent University; Sarah E. Church, NanoString Technologies Inc; Tressa Hood, NanoString Technologies Inc; Anbarasu Lourdusamy, University of Nottingham; Michael P. Rettig, Washington University; Ibrahim Aldoss, City Hope National Medical Center; Anjali s. Advani, Cleveland Clinic; John Godwin, Providence Cancer Center; Matthew J. Wieduwilt, University of California San Diego; Martha Arellano, Emory University; John Muth, MacroGenics Inc; Tung On Yau, Nottingham Trent University; Farhad Ravandi, University of Texas MD Anderson Cancer Center; Kendra Sweet, H. Lee Moffitt Cancer Center and Research Institute; Heidi Altmann, Technische Universitat Dresden; Gemma A. Foulds, Nottingham Trent University; Friedrich Stoelzel, Technische Universitat Dresden; Jan Moritz Middeke, Technische Universitat Dresden; Marilena Ciciarello, University Hospital S Orsola Malpighi; Antonio Curti, University Hospital S Orsola Malpighi; Peter J. M. Valk, Erasmus MC; Bob Loewenberg, Erasmus MC; Ivana Gojo, Johns Hopkins University; Martin Bornhaeuser, Technische Universitat Dresden; John F. DiPersio, Washington University; Jan K. Davidson-Moncada, MacroGenics Inc; Sergio Rutella, Nottingham Trent University
• Language: English
• Date: 2020-10-27
• Publisher: American Society for Hematology
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by The American Society of Hematology
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2020002512
• Title of Journal or Parent Work: Blood Advances
• Volume: 4
• Issue: 20
• Start Page: 5011
• End Page: 5024
• Grant/Funding Information: This work was supported by grants from the Qatar National Research Fund (NPRP8-2297-3-494) and the John and Lucille van Geest Foundation (S. Rutella) and by the National Institutes of Health, National Cancer Institute (Outstanding Investigator Award R35 CA210084 [J.F.D.] and Research Specialist Award R50 CA211466 [M.P.R.]).
• Keywords: Signatures; Hematology; Life Sciences & Biomedicine; Acute myeloid leukemia; Science & Technology; Resistance; Landscape; Mutations; Cancer; Karyotype; Expression; Mutant p
• Research Categories: Engineering, Biomedical; Health Sciences, Immunology; Health Sciences, Oncology; Biology, Cell

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 3 CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples frompatientswith 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-kB 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.