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

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

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 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-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.

Citation

Vadakekolathu, J., Lai, C., Reeder, S., Church, S. E., Hood, T., Lourdusamy, A., …Rutella, S. (2020). TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood Advances, 4(20), 5011-5024. https://doi.org/10.1182/bloodadvances.2020002512

• Journal Article Type: Article
• Acceptance Date: Aug 24, 2020
• Online Publication Date: Oct 15, 2020
• Publication Date: Oct 15, 2020
• Deposit Date: Feb 4, 2021
• Publicly Available Date: Feb 5, 2021
• Journal: Blood Advances
• Electronic ISSN: 2473-9529
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 20
• Pages: 5011-5024
• DOI: https://doi.org/10.1182/bloodadvances.2020002512
• Public URL: https://nottingham-repository.worktribe.com/output/4974374
• Publisher URL: https://ashpublications.org/bloodadvances/article/4/20/5011/467894/TP53-abnormalities-correlate-with-immune
• Additional Information: This research was originally published in Blood Advances. 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 Middeke, Marilena Ciciarello, Antonio Curti, Peter J. M. Valk, Bob Löwenberg, Ivana Gojo, Martin Bornhäuser, John F. DiPersio, Jan K. Davidson-Moncada, Sergio Rutella; TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood Adv 2020; 4 (20): 5011–5024. © the American Society of Hematology.