Journal Article

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

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

2018

Overview

Interleukin-2 (IL-2) is an important cytokine that helps T cells destroy tumors and virus-infected cells. IL-2 has great therapeutic promise but is limited by toxic side effects and its capacity to both activate and repress immune responses. Sockolosky et al. set out to improve IL-2–based immunotherapy by engineering synthetic IL-2–receptor pairs (i.e., IL-2 and its receptor, IL-2R) (see the Perspective by Mackall). Engineered complexes transmitted IL-2 signals but only interacted with each other and not with endogenous IL-2/IL-2R. Treatment of mice with IL-2 improved the ability of engineered T cells to reject tumors with no obvious side effects. This type of approach may provide a way to mitigate toxicities associated with some cytokine-based immunotherapies. Science , this issue p. 1037 ; see also p. 990 Engineered cytokines are able to improve immunotherapy in mouse tumor models. 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 ortho IL-2Rβ into T cells enabled the selective cellular targeting of ortho IL-2 to engineered CD4 + and CD8 + T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. Ortho IL-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.

• Publisher: The American Association for the Advancement of Science
• Subject: Animals / Biocompatibility / Cancer / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell Engineering - methods / Cell survival / Cytokines / HEK293 Cells / Humans / Immune response / Immunotherapy / Immunotherapy, Adoptive - methods / Interleukin 2 / Interleukin 2 receptors / Lymphocytes / Lymphocytes T / Melanoma, Experimental / Mice / Neoplasms - therapy / Pleiotropy / Receptors, Interleukin-2 - genetics / Receptors, Interleukin-2 - immunology / Side effects / Toxicity / Tumors / Viruses