CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells.
Herrmann, Andreas 1; Priceman, Saul J. 1; Kujawski, Maciej 1; Xin, Hong 1; Cherryholmes, Gregory A. 1; Zhang, Wang 1; Zhang, Chunyan 1; Lahtz, Christoph 1; Kowolik, Claudia 2; Forman, Steve J. 3; Kortylewski, Marcin 1; Yu, Hua 1
[Article]
Journal of Clinical Investigation.
124(7):2977-2987, July 1, 2014.
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: Intracellular therapeutic targets that define tumor immunosuppression in both tumor cells and T cells remain intractable. Here, we have shown that administration of a covalently linked siRNA to an aptamer (apt) that selectively binds cytotoxic T lymphocyte-associated antigen 4 (CTLA4apt) allows gene silencing in exhausted CD8 T cells and Tregs in tumors as well as CTLA4-expressing malignant T cells. CTLA4 expression was upregulated in CD8 T cells in the tumor milieu; therefore, CTLA4apt fused to a STAT3-targeting siRNA (CTLA4apt-STAT3 siRNA) resulted in internalization into tumor-associated CD8 T cells and silencing of STAT3, which activated tumor antigen-specific T cells in murine models. Both local and systemic administration of CTLA4apt-STAT3 siRNA dramatically reduced tumor-associated Tregs. Furthermore, CTLA4apt-STAT3 siRNA potently inhibited tumor growth and metastasis in various mouse tumor models. Importantly, CTLA4 expression is observed in T cells of patients with blood malignancies, and CTLA4apt-STAT3 siRNA treatment of immunodeficient mice bearing human T cell lymphomas promoted tumor cell apoptosis and tumor growth inhibition. These data demonstrate that a CTLA4apt-based siRNA delivery strategy allows gene silencing in both tumor-associated T cells and tumor cells and inhibits tumor growth and metastasis.
Copyright (C) 2014 The American Society for Clinical Investigation, Inc.