Abstract CT035: <i>TP53</i> abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia
Authors: Jayakumar Vadakekolathu, Catherine Lai, Stephen Reeder, Sarah E. Church, Tressa Hood, John Muth, Heidi Altmann, Marilena Ciciarello, Antonio Curti, Peter J. Valk, Bob Löwenberg, Martin Bornhäuser, John F. DiPersio, Jan K. Davidson-Moncada, Sergio Rutella
Journal: Cancer Research (2020)

Abstract Background: Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. TP53 mutations and 17p (TP53) deletions occur in 37-46% of 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 determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy approaches. Patients and Methods: We used the following transcriptomic data sets and patient cohorts (C) for in silico and wet-lab analyses: 1) The Cancer Genome Atlas (TCGA; 162 adult AML patients, 13 with TP53 mutations); 2) Beat AML Master Trial (281 adult AML patients, 17 with TP53 mutations); 3) HOVON (618 adult AML patients, 14 with TP53 mutations); 4) 24 diagnostic bone marrow (BM) samples from patients with TP53-wild-type AML (Bologna series); 5) 36 diagnostic BM samples from patients with TP53-mutated AML (Studien Allianz Leukämie [SAL] series); 6) 30 BM samples from patients with relapsed/refractory (R/R) AML (10 cases with TP53 mutations and/or 17p deletion) that received immunotherapy with flotetuzumab, a CD123×CD3 bispecific DART molecule (NCT02152956). Microenvironmental immune gene expression profiles (wet-lab cohorts, C4 and C5) were analyzed using the Pan-Cancer IO 360 Panel (NanoString Technologies, Seattle, WA). Immune cell type-specific and biological activity signature scores were computed as recently published (JITC 2017; 5: 18). Results: Compared with TCGA-AML cases (C1) with favorable-risk and intermediate-risk molecular features, all patients with TP53 mutations showed high levels of immune infiltration, including genes associated with adaptive immune responses and an interferon (IFN)-γ-dominant tumor microenvironment (TME), and a higher tumor mutational burden (14 versus 10 mutations on average in patients with TP53-mutated and TP53-wild-type AML, respectively; p=0.02). Similarly, 16 out of 17 (94%) TP53-mutated Beat AML cases (C2) expressed high levels of IFN signaling molecules, CD8 and markers of cytotoxicity (GZMB). Compared with patients with TP53-wild-type AML (C4), primary BM samples from patients with TP53-mutated AML (C5) showed higher levels of CD8A, markers of cellular senescence (EOMES, KLRD1, HRAS), IFN-γ-inducible genes (IRF1) and negative immune checkpoints including LAG3, IDO1, PDL1 and VSIR (VISTA). Interestingly, 10 patients with R/R AML (C6) had TP53 abnormalities and 5 of 6 patients evaluated for immune gene profiles had an immune-infiltrated TME. In patients with TP53 abnormalities, the overall response rate (ORR) was 40% to flotetuzumab (2 patients with CR, 1 patient with CRh, and 1 patient with morphologic leukemia-free state). The overall decrease of BM blasts averaged 42%. Stable disease was observed in 3 patients. Median overall survival (OS) was 3.5 months (range 1.25-21.25), which favorably compares with survival estimates for TP53-mutated cases with PIF in large AML series, such as HOVON (C3; median OS=1.16 months). Conclusions: This study provides evidence for a correlation between IFN-γ-dominant immune subtypes of AML and TP53 abnormalities. The ORR seen in this patient subgroup encourages further study of this immunotherapeutic approach. Citation Format: Jayakumar Vadakekolathu, Catherine Lai, Stephen Reeder, Sarah E. Church, Tressa Hood, John Muth, Heidi Altmann, Marilena Ciciarello, Antonio Curti, Peter J. Valk, Bob Löwenberg, Martin Bornhäuser, John F. DiPersio, Jan K. Davidson-Moncada, Sergio Rutella. TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT035.