Bcl-2 overexpression enhances tumor-specific T-cell survival.
Although immunotherapy based on the adoptive transfer of tumor-specific T lymphocytes has been shown to result in dramatic clinical responses in some patients, the relatively low levels of engraftment and persistence of the adoptively transferred cells may limit these responses in many patients. In an attempt to develop strategies for prolonging the survival of adoptively transferred T cells, we have carried out studies in which T cells obtained from healthy donors as well as tumor-specific T cells were transduced with a retrovirus expressing the human Bcl-2 gene. Our results indicate that these transduced T cells overexpress Bcl-2, are resistant to death, and have a survival advantage following interleukin-2 withdrawal compared with control T cells transduced with a retrovirus expressing green fluorescent protein. Tumor-specific T cells overexpressing Bcl-2 maintained their ability to specifically recognize and respond to target cells. Furthermore, we show that adoptive immunotherapy of an established B16 tumor can be significantly enhanced by overexpressing Bcl-2 in melanoma-specific T-cell receptor transgenic T cells. Our data suggest that adoptive immunotherapy approaches to the treatment of cancer patients may be enhanced using Bcl-2-modified tumor-reactive T cells.
Charo
Jehad
J
Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. j.charo@mdc-berlin.de
Finkelstein
Steven E
SE
Grewal
Navrose
N
Restifo
Nicholas P
NP
Robbins
Paul F
PF
Rosenberg
Steven A
SA
D000818:Animals; D002470:Cell Survival / Q000276:immunology / Q000502:physiology*; D003433:Crosses, Genetic; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014019:Tissue Donors; D014161:Transduction, Genetic; D058951:gp100 Melanoma Antigen
D007376:Interleukin-2; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen; D049452:Green Fluorescent Proteins