Augmentation of antitumor immunity by tumor cells transduced with a retroviral vector carrying the interleukin-2 and interferon-gamma cDNAs.
Therapeutic models using gene transfer into tumor cells have pursued three objectives: (1) to induce rejection of the tumor transduced with therapeutic genes, (2) to induce immune-mediated regression of metastatic disease, and (3) to induce long-lasting immunity to protect against challenge with tumor cells or clinical regrowth of micrometastatic disease. Because in vivo therapy for patients with cancer using gene transfer would, as a first step, attempt to eliminate the existing tumor, we have investigated whether antitumor immunity induced by tumor cells secreting a single cytokine could be increased by cotransfer of a second cytokine gene. To test this approach, CMS-5, a murine fibrosarcoma, was transduced with retroviral vectors carrying interleukin-2 (IL-2), interferon-gamma (IFN-gamma), or granulocyte-macrophage-colony-stimulating factor (GM-CSF) cDNA alone or IL-2 cDNA in combination with IFN-gamma or GM-CSF cDNA. Single cytokine-secreting clones were selected to match levels of cytokine production by double cytokine-secreting clones so that similar amounts of cytokine were secreted. IFN-gamma- and IL-2/IFN-gamma-secreting CMS-5 cells showed increased levels of major histocompatability complex class I expression compared with IL-2- and GM-CSF-secreting or parental CMS-5 cells, IL-2/IFN-gamma-secreting CMS-5 cells were always rejected by syngeneic mice, whereas the same number of CMS-5 cells secreting only one of these cytokines or mixtures of single cytokine-secreting CMS-5 cells were not rejected. In vivo depletion of CD4+, CD8+, or natural-killer effector cell subpopulations showed that CD8+ cytotoxic T cells were primarily responsible for rejection of IL-2/IFN-gamma-transduced tumor cells. Our data show the successful use of a single retroviral vector to stably transduce two cytokine genes into the same tumor cell, leading to an increased effect on the in vivo induction of antitumor immunity.
Rosenthal
F M
FM
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Cronin
K
K
Bannerji
R
R
Golde
D W
DW
Gansbacher
B
B
D000818:Animals; D005354:Fibrosarcoma / Q000276:immunology / Q000628:therapy; D005434:Flow Cytometry; D015316:Genetic Therapy; D005822:Genetic Vectors; D006084:Graft Rejection; D007109:Immunity; D007167:Immunotherapy; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000502:physiology*; D007376:Interleukin-2 / Q000502:physiology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012190:Retroviridae; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy*; D014162:Transfection
D007376:Interleukin-2; D007371:Interferon-gamma