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

Vadakekolathu, J. ORCID: 0000-0002-2671-4285, Lai, C., Reeder, S., Church, S.E., Hood, T., Lourdusamy, A., Rettig, M.P., Aldoss, I., Advani, A.S., Godwin, J., Wieduwilt, M.J., Arellano, M., Muth, J., Yau, T.O. ORCID: 0000-0002-3283-0370, Ravandi, F., Sweet, K., Altmann, H., Foulds, G.A., Stölzel, F., Middeke, J.M., Ciciarello, M., Curti, A., Valk, P.J.M., Löwenberg, B., Gojo, I., Bornhäuser, M., DiPersio, J.F., Davidson-Moncada, J.K. and Rutella, S. ORCID: 0000-0003-1970-7375, 2020. TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood Advances, 4 (20), pp. 5011-5024. ISSN 2473-9529

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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 (less than 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.

Item Type: Journal article
Publication Title: Blood Advances
Creators: Vadakekolathu, J., Lai, C., Reeder, S., Church, S.E., Hood, T., Lourdusamy, A., Rettig, M.P., Aldoss, I., Advani, A.S., Godwin, J., Wieduwilt, M.J., Arellano, M., Muth, J., Yau, T.O., Ravandi, F., Sweet, K., Altmann, H., Foulds, G.A., Stölzel, F., Middeke, J.M., Ciciarello, M., Curti, A., Valk, P.J.M., Löwenberg, B., Gojo, I., Bornhäuser, M., DiPersio, J.F., Davidson-Moncada, J.K. and Rutella, S.
Publisher: American Society of Hematology
Date: 27 October 2020
Volume: 4
Number: 20
ISSN: 2473-9529
Identifiers:
NumberType
10.1182/bloodadvances.2020002512DOI
1378627Other
Rights: © 2020 by The American Society of Hematology.
Divisions: Schools > School of Science and Technology
Record created by: Jill Tomkinson
Date Added: 19 Oct 2020 11:08
Last Modified: 19 Oct 2020 11:08
URI: http://irep.ntu.ac.uk/id/eprint/41346

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