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

Jonathan T Sockolosky; Eleonora Trotta; Giulia Parisi; Lora Picton; Leon L Su; Alan C Le; Akanksha Chhabra; Stephanie L Silveria; Benson M George; Indigo C King; Matthew R Tiffany; Kevin Jude; Leah V Sibener; David Baker; Judith A Shizuru; Antoni Ribas; Jeffrey A Bluestone; K Christopher Garcia

doi:10.1126/science.aar3246

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

Science. 2018 Mar 2;359(6379):1037-1042. doi: 10.1126/science.aar3246.

Authors

Jonathan T Sockolosky^{1

2}, Eleonora Trotta³, Giulia Parisi⁴, Lora Picton¹, Leon L Su¹, Alan C Le⁵, Akanksha Chhabra⁵, Stephanie L Silveria³, Benson M George^{2

5

6}, Indigo C King⁷, Matthew R Tiffany⁸, Kevin Jude¹, Leah V Sibener^{1

9}, David Baker⁷, Judith A Shizuru⁵, Antoni Ribas^{4

10}, Jeffrey A Bluestone^{3

10}, K Christopher Garcia^{11

2

10

12}

Affiliations

¹ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Diabetes Center and Department of Medicine, University of California, San Francisco, CA 94143, USA.
⁴ Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Blood and Marrow Transplantation, Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Stanford Medical Scientist Training Program, Stanford University, Stanford, CA 94305, USA.
⁷ Department of Biochemistry, Howard Hughes Medical Institute, and Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
⁸ Department of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁰ Parker Institute for Cancer Immunotherapy, 1 Letterman Drive, Suite D3500, San Francisco, CA 94129, USA.
¹¹ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. [email protected].
¹² Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD4-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / immunology*
Cell Engineering / methods*
HEK293 Cells
Humans
Immunotherapy, Adoptive / methods*
Melanoma, Experimental
Mice
Neoplasms / therapy*
Receptors, Interleukin-2 / genetics
Receptors, Interleukin-2 / immunology*

Substances

Receptors, Interleukin-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding