# Targeting Transcriptional Regulators for Immunotherapy of Acute Myeloid Leukemia

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $421,762

## Abstract

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.

## Key facts

- **NIH application ID:** 9842284
- **Project number:** 5R01CA213131-04
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Marcin Kortylewski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,762
- **Award type:** 5
- **Project period:** 2017-02-16 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842284

## Citation

> US National Institutes of Health, RePORTER application 9842284, Targeting Transcriptional Regulators for Immunotherapy of Acute Myeloid Leukemia (5R01CA213131-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842284. Licensed CC0.

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