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Myeloid cell-targeted miR-146a mimic alleviates NF-κB-driven cytokine storm without interfering with CD19-specific CAR T cell activity against B cell lymphoma

Kortylewski, Marcin and Su, Yu-Lin and Wang, Xiuli and Mann, Mati and Moreira, Dayson and Zhang, Zhuoran and Ouyang, Ching and Swiderski, Piotr and Forman, Stephen and Baltimore, David and Li, Ling and Marcucci, Guido and Boldin, Mark (2019) Myeloid cell-targeted miR-146a mimic alleviates NF-κB-driven cytokine storm without interfering with CD19-specific CAR T cell activity against B cell lymphoma. Journal for ImmunoTherapy of Cancer, 7 (S1). Art. No. O61. ISSN 2051-1426. https://resolver.caltech.edu/CaltechAUTHORS:20191205-103005796

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Abstract

Background: NF-κB is a key regulator of inflammation, myeloproliferation and cancer progression, with an important role in leukemogenesis. Despite therapeutic potential, targeting NF-κB proved challenging. However, in non-malignant myeloid cells NF-κB activity is tightly regulated through many molecular mechanisms, including miRNA. Methods: Here, we describe an original approach to NF-κB inhibition using miR146a, which targets upstream regulators of NF-κB signaling. We generated a myeloid cell-targeted NF-κB inhibitor by tethering a chemically-modified miR146a mimic oligonucleotide to a scavenger receptor (SR)/Toll-like receptor 9 (TLR9) ligand (C-miR146a). Results: Unlike an unconjugated miR-146a molecule, C-miR146a was rapidly internalized and delivered to cytoplasm of target myeloid cells such as macrophages or myeloid leukemia cells. C-miR146a reduced protein levels of classic miR-146a targets, IRAK1 and TRAF6, thereby efficiently blocking NF-κB activation in target cells. Intravenous injections of C-miR146a mimic to miR-146-deficient mice prevented excessive NF-κB activation in myeloid cells, thereby alleviating myeloproliferation and exaggerated inflammatory responses to bacterial challenge. The NF-κB-driven release of IL-1 and IL-6 from monocytes is known to be responsible for cytokine release syndrome (CRS), which can occur in response to bacterial infections, antibody-based therapies and relatively frequently as a serious adverse effect of chimeric antigen receptor (CAR) T-cell therapies. While low expression of miR146a has not yet been implicated in CRS, C-miR146a treatments did reduce pro-inflammatory activity of human monocytes, at the level of IL-1 and IL-6 production, induced by the CD19-specific but not by the naive CAR T cells in vitro. Repeated systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent CRS in xenotransplanted B-cell lymphoma model without impeding the on-target therapeutic effects of CAR T-cells against lymphoma cells. Conclusions: Our results demonstrate potential of using myeloid cell-targeted miR146a mimics for treatment of inflammatory diseases and prevention of potential side effects of immunotherapies. The SR/TLR9-targeted miR-146a mimic design provides an outline for the development of miRNA therapeutics for a variety of myeloid cell-related diseases.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1186/s40425-019-0764-0DOIAbstracts
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Boldin, Mark0000-0003-4593-0669
Additional Information:© 2019 BioMed Central Ltd. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Published 06 November 2019. This work was supported in part by the National Cancer Institute/NIH awards R01CA213131 (to M.K.), Lymphoma SPORE P50CA107399 (to S.F.) and P30CA033572 (to the COH).
Funders:
Funding AgencyGrant Number
NIHR01CA213131
NIHP50CA107399
NIHP30CA033572
Issue or Number:S1
Record Number:CaltechAUTHORS:20191205-103005796
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191205-103005796
Official Citation:34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): part 2. j. immunotherapy cancer 7, 283 (2019) doi:10.1186/s40425-019-0764-0
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100206
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Dec 2019 18:40
Last Modified:05 Dec 2019 18:40

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