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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Acknowledgments
This work is supported by National Institutes of Health Small Business Innovation Research grant: 2R44CA097550-03 (to H.C.W.). We thank Drs. Richard Morgan and Steven Rosenberg (National Cancer Institute) for kindly providing the MART-1 (aa27–35)/HLA-A2.1-specific TCR alpha and beta genes. We are grateful to Dr. Jeffrey Weber (H. Lee Moffitt Cancer Center) and Dr. Richard A. Morgan for their thoughtful comments and critical review of this manuscript.
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Wen, J., Zhu, X., Liu, B. et al. Targeting activity of a TCR/IL-2 fusion protein against established tumors. Cancer Immunol Immunother 57, 1781–1794 (2008). https://doi.org/10.1007/s00262-008-0504-7
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DOI: https://doi.org/10.1007/s00262-008-0504-7