Interleukin-2-independent proliferation of human melanoma-reactive T lymphocytes transduced with an exogenous IL-2 gene is stimulation dependent.
A major obstacle limiting the efficacy of adoptive T-cell transfer (adoptive immunotherapy) to treat patients with cancer is the short survival of the transferred cells. These in vitro activated T cells depend on the growth factor, interleukin (IL)-2, and may undergo apoptosis in vivo when they are transferred. The authors previously reported that the need for an exogenous source of IL-2 could be abrogated in vitro by retrovirally transducing antitumor T lymphocytes with an exogenous IL-2 gene. Here they report that this growth of IL-2 transductants depended on restimulation of the T-cell receptor complex and appeared to be regulated at the transcriptional level of the transduced IL-2 gene. The transduced IL-2 transcript was barely detectable in IL-2-transductants just before they died without restimulation, and they expressed a low level of the CD25 molecule, the alpha chain of the IL-2 trimeric receptor complex. Melanoma-specific tumor-infiltrating lymphocytes (either bulk or CD8+ cells alone), when transduced with an IL-2 retroviral vector, could produce IL-2 upon tumor stimulation and proliferated after the destruction of autologous tumor cells in the absence of added IL-2. Control vector-transduced tumor-infiltrating lymphocytes failed to do so under the same conditions. These findings provide a foundation for the development of clinical efforts to adoptively transfer melanoma-specific tumor-infiltrating lymphocytes transduced with an IL-2 retroviral vector for the treatment of patients with metastatic melanoma to evaluate the fate and therapeutic effect of these IL-2 gene-modified antitumor T lymphocytes in vivo.
Liu
Ke
K
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ke_liu@nih.gov
Rosenberg
Steven A
SA
D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000502:physiology; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D014161:Transduction, Genetic
D007376:Interleukin-2