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Leukemia. 2019 Nov 18. doi: 10.1038/s41375-019-0639-x. [Epub ahead of print]

RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade.

Author information

1
Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, University Hospital, LMU Munich, Munich, Germany.
2
Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany.
3
Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany.
4
Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
5
Laboratory for Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany.
6
German Cancer Consortium (DKTK), partner site Munich, Munich, Germany.
7
Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
8
Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, University Hospital, LMU Munich, Munich, Germany. simon.rothenfusser@med.uni-muenchen.de.
9
Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany. simon.rothenfusser@med.uni-muenchen.de.

Abstract

Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic immune receptor sensing viral RNA. It triggers the release of type I interferons (IFN) and proinflammatory cytokines inducing an adaptive cellular immune response. We investigated the therapeutic potential of systemic RIG-I activation by short 5'-triphosphate-modified RNA (ppp-RNA) for the treatment of acute myeloid leukemia (AML) in the syngeneic murine C1498 AML tumor model. ppp-RNA treatment significantly reduced tumor burden, delayed disease onset and led to complete remission including immunological memory formation in a substantial proportion of animals. Therapy-induced tumor rejection was dependent on CD4+ and CD8+ T cells, but not on NK or B cells, and relied on intact IFN and mitochondrial antiviral signaling protein (MAVS) signaling in the host. Interestingly, ppp-RNA treatment induced programmed death ligand 1 (PD-L1) expression on AML cells and established therapeutic sensitivity to anti-PD-1 checkpoint blockade in vivo. In immune-reconstituted humanized mice, ppp-RNA treatment reduced the number of patient-derived xenografted (PDX) AML cells in blood and bone marrow while concomitantly enhancing CD3+ T cell counts in the respective tissues. Due to its ability to establish a state of full remission and immunological memory, our findings show that ppp-RNA treatment is a promising strategy for the immunotherapy of AML.

PMID:
31740809
DOI:
10.1038/s41375-019-0639-x

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