TY - JOUR
T1 - A TIM-3 Oligonucleotide Aptamer Enhances T Cell Functions and Potentiates Tumor Immunity in Mice
AU - Gefen, Tal
AU - Castro, Iris
AU - Muharemagic, Darija
AU - Puplampu-Dove, Yvonne
AU - Patel, Shradha
AU - Gilboa, Eli
N1 - Publisher Copyright:
© 2017 The American Society of Gene and Cell Therapy
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/10/4
Y1 - 2017/10/4
N2 - T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-γ (IFN-γ) secreting CD4+ T cells and CD8+ T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8+ T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check. Using a combined bead and cell-based systemic evolution of ligands by exponential enrichment (SELEX) protocol, we have isolated nuclease-resistant oligonucleotide aptamer ligands that bind to cell-associated TIM-3 with high affinity and specificity. A trimeric form of the TIM-3 aptamer blocked the interaction of TIM-3 with Galectin-9, reduced cell death, and enhanced survival, proliferation, and cytokine secretion in vitro. In tumor-bearing mice, the aptamer delayed tumor growth as monotherapy and synergized with PD-1 antibody in prolonging the survival of the tumor-bearing mice. Both in vitro and in vivo, the trimeric aptamer displayed superior activity compared to the currently used RMT3-23 monoclonal antibody. This study suggests that multi-valent aptamers could represent an alternative platform to generate potent ligands to manipulate the function of TIM-3 and other immune modulatory receptors. In murine tumor immunotherapy models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity. In this issue of Molecular Therapy, Gefen et al. describe an oligonucleotide TIM-3-binding aptamer that was more effective than anti-TIM-3 antibody in vitro and in vivo.
AB - T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-γ (IFN-γ) secreting CD4+ T cells and CD8+ T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8+ T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check. Using a combined bead and cell-based systemic evolution of ligands by exponential enrichment (SELEX) protocol, we have isolated nuclease-resistant oligonucleotide aptamer ligands that bind to cell-associated TIM-3 with high affinity and specificity. A trimeric form of the TIM-3 aptamer blocked the interaction of TIM-3 with Galectin-9, reduced cell death, and enhanced survival, proliferation, and cytokine secretion in vitro. In tumor-bearing mice, the aptamer delayed tumor growth as monotherapy and synergized with PD-1 antibody in prolonging the survival of the tumor-bearing mice. Both in vitro and in vivo, the trimeric aptamer displayed superior activity compared to the currently used RMT3-23 monoclonal antibody. This study suggests that multi-valent aptamers could represent an alternative platform to generate potent ligands to manipulate the function of TIM-3 and other immune modulatory receptors. In murine tumor immunotherapy models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity. In this issue of Molecular Therapy, Gefen et al. describe an oligonucleotide TIM-3-binding aptamer that was more effective than anti-TIM-3 antibody in vitro and in vivo.
KW - TIM-3 aptamer
KW - aptamer
KW - cancer immunotherapy
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U2 - 10.1016/j.ymthe.2017.06.023
DO - 10.1016/j.ymthe.2017.06.023
M3 - Article
C2 - 28800954
AN - SCOPUS:85027109620
VL - 25
SP - 2280
EP - 2288
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 10
ER -