MacroGenics : TP53 Abnormalities - Response to Flotetuzumab in AML (Rutella)

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

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John and Lucille van Geest Foundation