TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in Acute Myeloid Leukemia
Catherine Lai, Jayakumar Vadakekolathu, Stephen Reeder, Sarah E. Church, Carmen Ballesteros-Merino, Ibrahim Aldoss, Anjali S. Advani, John Godwin, Matthew J. Wieduwilt, Martha Arellano, Geoffrey Uy, Farhad Ravandi, Matthew Foster, Emmanuel Gyan, Patrick Stiff, Norbert Vey, Ashkan Emadi, Matteo Carrabba, Peter Sayre, Roland Walter, Kathy Tran, Erin Timmeny, Michael Rettig, Patrick Kaminker, John Muth, Kuo Guo, Tung On Yau, Peter J.M. Valk, Bob Löwenberg, Ivana Gojo, Martin Bornhäuser, John F. DiPersio, Jan K. Davidson-Moncada,Sergio Rutella
Disclosures
- Research funding, NanoString Technologies, Seattle, WA
- Research funding, MacroGenics, Rockville, MD
- Research funding, Kura Oncology, San Diego, CA
Background
- Somatic TP53 mutations and deletions of 17p, to which TP53 is mapped, occur in 8-10% of de novo AML and are associated with chemotherapy resistance, high risk of relapse and dismal prognosis even after hematopoietic stem cell transplantation
- A recent analysis of The Cancer Genome Atlas (TCGA) transcriptomic data from 10,000 non-hematologic tumors has indicated that TP53 mutations correlate with higher proportions of PD-L1-expressing CD8+ T cells, and with increased expression of T-cell effector genes and interferon (IFN)-γ-related genes
- We have recently identified bone marrow (BM) IFN-γ-related transcriptional profiles that stratify patients with AML into an immune- infiltrated and an immune-depleted subtype, and that enrich in patients with chemotherapy-refractory disease (Vadakekolathu J, et al. Sci. Transl. Med. 2020; 12: eaaz0463)
Questions and Study Aims
- Do TP53 abnormalities correlate with the composition and functional orientation of the immunological tumor microenvironment (TME) in AML?
- Are patients with TP53-mutated, relapsed/refractory AML responsive to treatment with flotetuzumab, an investigational CD123×CD3 bispecific DARTⓇ molecule?
Flotetuzumab | Immunological synapse between | |||
Anti-CD3 | Anti-CD123 | T cells and CD123+ AML blasts | ||
(hXR32) | ||||
Patients and Methods
All patients (n=45) | Patients with TP53 mutations | ||||
and/or 17p abnormalities (n=15^) | |||||
Age (years, median and range) | 61 | (27-81) | 61 (27-81) | ||
Males/Females, n/n | 24/21 | 8/7 | |||
AML risk stratification (2017 ELN; n) | |||||
Favorable | 3 | (6.7%) | 0 | (0%) | |
Intermediate | 8 | (17.8%) | 0 | (0%) | |
Adverse | 34 | (75.6%) | 15 (100%) | ||
Secondary AML (n) | 15 | (33.3%) | 7 | (46.7%) | |
Number of prior lines of therapy (median and range) | 2 | (1-9) | 2 | (1-4) | |
- ^BM samples from 13/15 patients were available for immune gene expression profiling. All 15 patients with TP53 mutations/17p abnormalities were treated on the study and included in clinical analyses.
- Microenvironmental RNAs were profiled using the PanCancer IO 360™ gene expression panel on the nCounter® platform.
- Disease status was assessed by modified International Working Group (IWG) criteria. Specifically, overall response rate (ORR), collectively complete response, was defined as <5% bone marrow (BM) blasts (CR, CRh, CRi or morphologic leukemia-free state [MLFS]). Partial response (PR) was defined as >50% decrease or decrease to 5- 25% BM blasts.
TP53 Mutations Associate with High Immune Infiltration in TCGA-AML
B
A
Immune-infiltrated | Immune-depleted |
(n=14 with TP53-mut.) | (n=0 with TP53 mut.) |
CD
N=118 cases with
available information on
prognostic molecular
lesions, including TP53
mutations (n=14)
Vadakekolathu J, et al. Blood Advances 2020; 4 (20): 5011-24.
TP53 Mutations Associate with High Immune Infiltration in Primary AML Samples - SAL Cohort
C | D |
A | TP53 status |
TP53 status | Mutated | WT/NA/ND |
B
20/23 TP53-mut. | 21/28 TP53-mut. | 1/13 TP53-mut. |
87% | 75% | 8% |
High | Intermediate | Low |
Immune infiltration
In collaboration with Martin Bornhäuser, Technische Universität Dresden, Germany
Vadakekolathu J, et al. Blood Advances 2020; 4 (20): 5011-24.
TP53 Mutations Associate with Immune Infiltration and with Response to Flotetuzumab
A
High | Intermediate | Low | ||||
(50% TP53/17p) | (31.8% TP53/17p) | (20% TP53/17p) |
Immune infiltration int.-to-high in 10/13 (77%)
patients with mutated TP53
B | |||||||||||||||||||||||||||||
CR | |||||||||||||||||||||||||||||
CR | * | ||||||||||||||||||||||||||||
SD | |||||||||||||||||||||||||||||
SD | * | ||||||||||||||||||||||||||||
CR | |||||||||||||||||||||||||||||
MLFS | |||||||||||||||||||||||||||||
PD | |||||||||||||||||||||||||||||
CR | |||||||||||||||||||||||||||||
PR | |||||||||||||||||||||||||||||
CRi | Time on treatment | ||||||||||||||||||||||||||||
CRi | Time to HSCT | ||||||||||||||||||||||||||||
PD | |||||||||||||||||||||||||||||
Time to death/last FU | |||||||||||||||||||||||||||||
PR | |||||||||||||||||||||||||||||
SD | * | Alive at last FU | |||||||||||||||||||||||||||
PD | |||||||||||||||||||||||||||||
0 | 3 | 6 | 9 | 12 | 15 | 18 | 21 | 24 |
Months from study entry
Overall response rate in evaluable patients with TP53 mutations and/or 17p abnormalities was 60% (9/15), with 47% (7/15) achieving complete response (<5% BM blasts on study)
In responders with TP53 mutations, median OS
was 10.3 months (range 3.3-21.3)
TP53 Mutations Associate with Immune Infiltration and with Response to Flotetuzumab
A | 350 | B |
325 | ||
300 | ||
100 | TP53 mut/17p abn | |
(%) | 75 | TP53-WT |
Change | 50 | |
25 | ||
BM | 0 | |
-25 | ||
Best | ||
-50 | ||
-75 | D | |
-100 | ||
C | E | |
Mike Rettig, WashU
Top-ranking genes associated with response | AUROC (CD8B) = 0.879 |
Conclusions
- TP53 mutations in AML are associated with higher T cell infiltration, expression of immune checkpoints and IFN-γ-driven transcriptional programs
- The above gene expression profiles, which have previously been shown to enrich in patients with chemotherapy resistance, correlate with disease control in response to flotetuzumab (51.2% reduction of BM blasts; 60% [9/15] overall response rate; 47% [7/15] complete response rate)
- These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML
Acknowledgements
Co-authors and Collaborators
Funding Sources
Stephen Reeder
Payton Tau
Jayakumar Vadakekolathu
PhD Students
Jenny Ashforth
Melissa Courtney
Mark D. Minden
Toronto, Canada
Ivana Gojo
Leo Luznik
Sidney Kimmel Comprehensive
Cancer Centre
Baltimore, MD
Heidi Altmann
Martin Bornhäuser
Jörn Meinel
Marc Schmitz
SAL Studienallianz Leukämie
Dresden, Germany
NANOSTRING
Joseph M. Beechem
Alessandra Cesano
Michael Bailey
James Gowen-MacDonald Thomas Smith
Sarah E. Church
Tressa Hood
Sarah E. Warren
Seattle, WA
MACROGENICS
Patrick Kaminker
Jan K. Davidson-Moncada
John Muth
Rockville, MD
National Priorities Research Programme,
2016-2020
Mainstream QR funding, 2017-2019
Tasleema Patel
Sarah K. Tasian
Philadelphia, PA
Please email your questions to sergio.rutella@ntu.ac.uk
John and Lucille van Geest Foundation
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MacroGenics Inc. published this content on 06 December 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 07 December 2020 09:14:07 UTC