Targeting activity of a TCR/IL-2 fusion protein against established tumors |
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Authors: | Jinghai Wen Xiaoyun Zhu Bai Liu Lijing You Lin Kong Hyung-il Lee Kai-ping Han Jeffrey L Wong Peter R Rhode Hing C Wong |
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Institution: | (1) Altor Bioscience Corporation, 2810 N Commerce Parkway, Miramar, FL 33025, USA;(2) University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA |
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Abstract: | We have previously reported that a single-chain T cell receptor/IL-2 fusion protein (scTCR-IL2) exhibits potent targeted antitumor
activity in nude mice bearing human tumor xenografts that display cognate peptide/HLA complexes. In this study, we further
explore the mechanism of action of this molecule. We compared the biological activities of c264scTCR-IL2, a scTCR-IL2 protein
recognizing the aa264–272 peptide of human p53, with that of MART-1scTCR-IL2, which recognizes the MART-1 melanoma antigen
(aa27–35). In vitro studies showed that c264scTCR-IL2 and MART-1scTCR-IL2 were equivalent in their ability to bind cell-surface
IL-2 receptors and stimulate NK cell responses. In mice, MART-1scTCR-IL2 was found to have a twofold longer serum half-life
than c264scTCR-IL2. However, despite its shorter serum half-life, c264scTCR-IL2 showed significantly better antitumor activity
than MART-1scTCR-IL2 against p53+/HLA-A2+ tumor xenografts. The more potent antitumor activity of c264scTCR-IL2 correlated with an enhanced capacity to promote NK
cell infiltration into tumors. Similar differences in antigen-dependent tumor infiltration were observed with activated splenocytes
pre-treated in vitro with c264scTCR-IL2 or MART-1scTCR-IL2 and then transferred into p53+/HLA-A2+ tumor bearing recipients. The data support a model where c264scTCR-IL2 activates immune cells to express IL-2 receptors.
Following stable interactions with cell-surface IL-2 receptors, c264scTCR-IL2 fusion molecule enhances the trafficking of
immune cells to tumors displaying target peptide/HLA complexes where the immune cells mediate antitumor effects. Thus, this
type of fusion molecule could be used directly as a targeted immunotherapeutic or in adoptive cell transfer approaches to
activate and improve the anti-cancer activities of immune cells by providing them with pre-selected antigen recognition capability. |
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Keywords: | T cell receptors p53 Cytokines Tumor immunity Natural killer cells |
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