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Augmentation of antitumor immunity by tumor cells transduced with a
retroviral vector carrying the interleukin-2 and interferon-gamma cDNAs
FM Rosenthal, K Cronin, R Bannerji, DW Golde and B Gansbacher
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York,
NY 10021.
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.
Volume 83,
Issue 5,
pp. 1289-1298,
03/01/1994
Copyright © 1994 by The American Society of Hematology
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