Potent antitumor activity of a tumor-specific soluble TCR/IL-2 fusion protein

• Published in: Clinical Immunology 2006-10, Vol.121 (1), p.29-39
• Main Authors: Belmont, Heather J., Price-Schiavi, Shari, Liu, Bai, Card, Kimberlyn F., Lee, Hyung-il, Han, Kai-ping, Wen, Jinghai, Tang, ShaMay, Zhu, Xiaoyung, Merrill, Jane, Chavillaz, Pierre-Andre, Wong, Jeffrey L., Rhode, Peter R., Wong, Hing C.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cell Line, Tumor; CHO Cells; Cricetinae; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; HT29 Cells; Humans; IL-2; Immunopathology; Interleukin-2 - genetics; Interleukin-2 - immunology; Interleukin-2 - therapeutic use; Male; Medical sciences; Mice; Mice, Nude; Mice, Transgenic; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - therapeutic use; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - therapeutic use; Solubility; TCR; Transplantation, Heterologous; Tumor; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - immunology; Tumor Suppressor Protein p53 - therapeutic use
• ISSN: 1521-6616; 1521-7035; 1365-2567
• DOI: 10.1016/j.clim.2006.05.005

We previously have generated a single-chain T cell receptor-cytokine fusion protein (264scTCR/IL-2) comprising interleukin-2 genetically linked to a soluble HLA-A2.1-restricted TCR recognizing a peptide of human p53 protein. In this report, we show that 264scTCR/IL-2 inhibits the growth of primary tumors derived from the A375 (p53 +/HLA-A2.1 +) human melanoma and exhibits significantly better antitumor activity than recombinant human IL-2 alone. Moreover, treatment with 264scTCR/IL-2 results in tumor growth retardation in mice bearing large A375 tumors and other p53 +/HLA-A2.1 + human tumors but does not affect tumor outgrowth of HLA-A2.1-negative tumors. This suggests that antigen targeting plays a substantial role in the efficacy of 264scTCR/IL-2 against p53 +/HLA-A2 + tumors. Further, the antitumor activity of 264scTCR/IL-2 was found to be likely mediated by NK cell activation and tumor infiltration. A biologically active chimeric version of the molecule (c264scTCR/IL-2) also exhibits favorable pharmacokinetic properties required of a clinical candidate for this novel class of potent antitumor activities and targeted anticancer immunotherapeutics.