Enhanced interleukin-2 production in human tumor-infiltrating lymphocytes engineered by 3'-truncated interleukin-2 gene

• Published in: Journal of immunotherapy with emphasis on tumor immunology Vol. 16; no. 4; p. 262
• Main Authors: Yamaue, H, Kashmiri, S V, De Filippi, R, Nieroda, C, Yannelli, J R, Tsang, K Y, Schlom, J
• Format: Journal Article
• Language: English
• Published: United States 01.11.1994
• Subjects: Base Sequence; Cell Division; Cytotoxicity, Immunologic; Drug Resistance, Microbial; Flow Cytometry; Humans; Interleukin-2 - genetics; Interleukin-2 - metabolism; Interleukin-2 - pharmacology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - physiology; Melanoma - genetics; Melanoma - pathology; Melanoma - therapy; Molecular Sequence Data; Phenotype; Time Factors; Transduction, Genetic; Tumor Cells, Cultured
• ISSN: 1067-5582
• DOI: 10.1097/00002371-199411000-00002

Tumor-infiltrating lymphocytes (TILs), T lymphocytes associated with solid tumors that can be grown with interleukin (IL)-2 in vitro, preferentially accumulate at tumor sites after adoptive transfer. Therefore, TILs can be considered for use as cellular vehicles in gene therapy. We transduced melanoma TILs with the IL-2 gene and clarified functional characteristics of the TIL transductants. TILs transduced with 3'-end-truncated IL-2 gene (480 bp) produced high amounts of IL-2 detected in supernatants when compared to TILs transduced with the native IL-2 gene containing 3'-end adenine-thymidine (AT)-rich sequences (650 bp). The level of IL-2 in supernatants was higher with the addition of anti-Tac antibody (Ab) to block the consumption of IL-2 by the TILs. These TILs could proliferate autonomously in the absence of exogenous IL-2, and the proliferation of TILs could be completely blocked by anti-IL-2 Ab or anti-IL-2 receptor Ab. Thus TILs transduced with IL-2 gene can proliferate through the autocrine loop. However, the expression of IL-2 from TILs transduced with the IL-2 gene was downregulated after 2 to 3 weeks of G418 selection. Our study indicates the feasibility of transduction and expression of a truncated 480-bp IL-2 gene into TILs and the possibility of employing adoptive immunotherapy protocols using TILs modified with this IL-2 gene.