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Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes

2018; American Association for the Advancement of Science; Volume: 359; Issue: 6379 Linguagem: Inglês

10.1126/science.aar3246

1095-9203

Jonathan T. Sockolosky, Eleonora Trotta, Giulia Parisi, Lora K. Picton, Leon Su, Alan Le, Akanksha Chhabra, Stephanie Silveria, Benson M. George, Chris King, Matthew Tiffany, Kevin M. Jude, Leah V. Sibener, David Baker, Judith A. Shizuru, Antoni Ribas, Jeffrey A. Bluestone, K. Christopher García,

Immunotherapy and Immune Responses

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-2Rβ 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.