Experimental gene therapy of cancer using tumor cells engineered to secrete interleukin‐13

Abstract

Cytokines locally delivered to the site of a tumor boost both specific and nonspecific host anti-tumor defenses. Interleukin (IL)-13 is a recently described cytokine produced by mouse type 2 helper T lymphocytes. The aim of this study was to evaluate the inhibition of tumor growth induced by IL-13 delivered locally within or around transplanted tumor cells in mice. We observed that local administration of IL-13 at the site of transplanted tumor cells in vivo had potent inhibitory effects on growth of both immunogenic (P815 mastocytoma, H-2d) or nonimmunogenic (3LL lung carcinoma, H-2b) tumor cells. Mice injected with transfected P815 cells secreting large amounts of IL-13 rejected the P815 tumor and developed systemic specific anti-tumor immunity leading to long-lasting specific anti-tumor protection. Less efficient anti-tumoral effects were obtained with the nonimmunogenic 3LL tumor model when local administration of IL-13 was achieved by co-inoculating xenogeneic chinese hamster ovary (CHO) IL-13 cells. Several local injections of CHO IL-13 cells were needed to obtain rejection of 3LL tumors and no induction of long-lasting anti-3LL memory was obtained. Several studies were performed to elucidate the IL-13 anti-tumoral effects. Experiments with nude mice indicated that Il-13 can also stimulate nonspecific anti-tumor defenses. The histological examination of P815 IL-13 cells undergoing rejection showed monocytic cells and neutrophils infiltrating the tumor. Studies indicated that IL-13 administered in vitro did not directly stimulate the cytotoxicity of peritoneal macrophages and natural killer cells. However, experiments with Boyden chemotaxis chambers indicated that IL-13 was chemotactic for macrophages. Finally, preliminary experiments in vitro suggest that IL-13 improved antigenic presentation of P815 membranes. Thus, anti-tumor effects of IL-13 in vivo most probably result from pleiotropic effects including recruitment of nonspecific cells and improved stimulation of immune-specific anti-tumor effectors.

Induction of Functional IL-8 Receptors by IL-4 and IL-13 in Human Monocytes

“…The leukocyte infiltrate of IL-13-secreting tumors has a major mononuclear phagocyte component (75). It is tempting to speculate that IL-13 might act directly in the recruitment of monocytes for its chemotactic activity (76), or by inducing the expression of IL-8 receptors on these effector cells.…”

IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

“…Studies with genetically modified tumor cells have highlighted the participation of several types of cells, including neutrophils, eosinophils, mast cells, lymphocytes, and NK cells in tumor rejection (15)(16)(17)(18)(19)(20). To determine the relative roles of lymphocytes in the rejection of IL-21-transduced tumor cells, equal numbers (10 5 ) of B16F1-IL-21 or control B16F1-GFP cells were injected into T and B cell-deficient (SCID) mice.…”

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

“…IL-13 also mediates biological activities in tumor cells. [7][8][9] We have shown that the receptor for IL-13 (IL-13R) in tumor cells exists as two different types. [10][11][12][13][14][15] Type I IL-13R consists of IL-13Ra2 (also known as IL-13Ra), IL-13Ra1 (also known as IL-13Ra 0 ), and IL-4Ra (also known as IL-4Rb) chains, while type II IL-13R consists of IL-13Ra1 and IL-4Ra chains.…”