Hit-and-run programming of therapeutic cytoreagents using mRNA nanocarriers

H. F. Moffett, M. E. Coon, S. Radtke, S. B. Stephan, L. McKnight, A. Lambert, B. L. Stoddard, H. P. Kiem and M. T. Stephan ()
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H. F. Moffett: Clinical Research Division, Fred Hutchinson Cancer Research Center
M. E. Coon: Clinical Research Division, Fred Hutchinson Cancer Research Center
S. Radtke: Clinical Research Division, Fred Hutchinson Cancer Research Center
S. B. Stephan: Clinical Research Division, Fred Hutchinson Cancer Research Center
L. McKnight: Clinical Research Division, Fred Hutchinson Cancer Research Center
A. Lambert: Fred Hutchinson Cancer Research Center
B. L. Stoddard: Fred Hutchinson Cancer Research Center
H. P. Kiem: Clinical Research Division, Fred Hutchinson Cancer Research Center
M. T. Stephan: Clinical Research Division, Fred Hutchinson Cancer Research Center

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Therapies based on immune cells have been applied for diseases ranging from cancer to diabetes. However, the viral and electroporation methods used to create cytoreagents are complex and expensive. Consequently, we develop targeted mRNA nanocarriers that are simply mixed with cells to reprogram them via transient expression. Here, we describe three examples to establish that the approach is simple and generalizable. First, we demonstrate that nanocarriers delivering mRNA encoding a genome-editing agent can efficiently knock-out selected genes in anti-cancer T-cells. Second, we imprint a long-lived phenotype exhibiting improved antitumor activities into T-cells by transfecting them with mRNAs that encode a key transcription factor of memory formation. Third, we show how mRNA nanocarriers can program hematopoietic stem cells with improved self-renewal properties. The simplicity of the approach contrasts with the complex protocols currently used to program therapeutic cells, so our methods will likely facilitate manufacturing of cytoreagents.

Date: 2017
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DOI: 10.1038/s41467-017-00505-8

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