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Targeting Transcriptional Regulators for Immunotherapy of Acute Myeloid Leukemia

Award Number: R01CA213131
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/16/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Targeting Transcriptional Regulators for Immunotherapy of Acute Myeloid Leukemia - Signal Transducer and Activator of Transcription 3 (STAT3) is an oncogenic transcription factor (TF) and a central immune checkpoint regulator. Tumorigenic and tolerogenic roles of STAT3 in acute myeloid leukemia (AML) and other human cancers, as well as in the tumor-associated immune cells are well-defined and provide solid scientific premises for therapeutic STAT3 inhibition. To overcome the challenge imposed by lack of pharmacological inhibitors of STAT3, we recently developed a strategy for myeloid cell-selective STAT3 inhibition in vivo. Tethering to a synthetic Toll-like Receptor 9 (TLR9) agonists, CpG ODNs, allowed for targeted delivery of a STAT3 decoy oligodeoxynucleotide (STAT3dODN) into myeloid cells, such as AML cells and tumor-associated immune cells. Our preliminary studies demonstrated that intravenous injections of CpG-STAT3dODN lead to regression of disseminated human and mouse acute myeloid leukemia (AML) in murine models. In immunocompetent mice, STAT3-blocking/TLR9-stimulation triggered differentiation of leukemic cells to antigen-presenting cell (APC) phenotype rather than direct cytotoxicity. The immunogenicity of AML-APCs induced systemic CD8/CD4 T cell-mediated immunity and eliminated disseminated leukemia, including leukemic stem/progenitor cells, with no detectable toxicities to normal immune/hematopoietic stem cells. We propose to elucidate molecular/cellular mechanisms of CpG- STAT3dODN-induced AML immunogenicity and to characterize role of T cell-mediated immunity in AML rejection. Better understanding of the CpG-STAT3dODN effect on leukemia cell and T cell compartments will allow for the design of optimal combination of TLR9-targeted STAT3 inhibition with T cell-based therapies which will be validated within this proposal. These studies will accelerate development of novel, effective and safe nucleotide-based immunotherapeutic strategies for cell-selective targeting of STAT3 in AML and potentially other hematologic malignancies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$21,519 )
2024	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	5	10/13/2023	NON-COMPETING CONTINUATION	-$21,519
														Subtotal = -$21,519

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	5	1/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $430,377 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	5	12/18/2020	NON-COMPETING CONTINUATION	$408,858
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	5	1/21/2021	NON-COMPETING CONTINUATION	$21,519
														Subtotal = $430,377

Issue Date FY: 2020 ( Subtotal = $421,762 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	4	1/14/2020	NON-COMPETING CONTINUATION	$42,176
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	4	12/6/2019	NON-COMPETING CONTINUATION	$379,586
														Subtotal = $421,762

Issue Date FY: 2019 ( Subtotal = $413,286 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	3	12/21/2018	NON-COMPETING CONTINUATION	$413,286
														Subtotal = $413,286

Issue Date FY: 2018 ( Subtotal = $430,377 )
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	2	12/14/2017	NON-COMPETING CONTINUATION	$387,339
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	2	5/22/2018	NON-COMPETING CONTINUATION	$43,038
														Subtotal = $430,377

Issue Date FY: 2017 ( Subtotal = $428,441 )
2017	2017	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	1	2/16/2017	NEW	$428,441
														Subtotal = $428,441

Grand Total All Awards = $2,102,724

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Targeting Transcriptional Regulators for Immunotherapy of Acute Myeloid Leukemia

Award Number: R01CA213131

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/16/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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