Journal
SCIENCE
Volume 359, Issue 6379, Pages 1037-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aar3246
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Funding
- NIH [R37 AI051321, R35 CA197633]
- HHMI
- Stanford Molecular and Cellular Immunobiology NIH training grant [5T32 AI072905]
- PhRMA Foundation Translational Medicine and Therapeutics postdoctoral award
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Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal (ortho) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts. Introduction of orthoIL-2R beta into T cells enabled the selective cellular targeting of orthoIL-2 to engineered CD4(+) and CD8(+) T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. OrthoIL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells.
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