Breast cancer gene therapy: transgenic immunotherapy

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Abstract
A number of studies have demonstrated that potent anti-tumor immunity can be induced using cytokine gene transfer, a strategy termed transgenic immunotherapy. Our aim is to express cytokine genes in the vicinity of tumor cells, either by transducing tumor cells themselves, or by delivering cytokine-expressing endothelial cells to tumor sites. We compared the ability of cytokine-expressing tumor cells or endothelial cells to inhibit the tumorigenesis of MDA-MB-435 breast cancer cells in athymic nude mice. Retroviral vectors containing either human interleukin 2 (hIL-2) or interleukin 1 (hIL-1α) were used to transduce MDA-MB-435 cells or human umbilical vein endothelial cells (HUVEC). Using a modified MTT bioassay and an ELISA specific for hIL-2, 43 of 70 MDA-MB-435 clones transduced with IL-2 were found to secrete between 100–800 units of IL-2/106 cells/24 hr. hIL-2 and hIL-1α-transduced HUVEC secreted 40 ng/IL-2/106/24 hr and 1.8 ng/106/24 hr, respectively. To facilitatein vivo tracking of tumor cells, both nontransduced and IL-2-expressing MDA-MB-435 cells were genetically-marked with the E. colilacZ gene and selected using flow cytometry. To studyin vivo tumorigenicity, cells were injected into the mammary fat pad of athymic nude mice: (1)lacZ/MDA-MB-435 cells injected alone formed tumors in all animals ;(2) IL-2-expressinglacZ/MDA-MB-435 cells did not form any tumors; (3) co-inoculation of MDA-MB-435/IL-2, HUVEC/IL-2, or HUVEC/IL-1α withlacZ/MDA-MB-435 cells prevented or delayed tumor growth. These results suggest that local cytokine secretion was capable of activating natural killer cell activity in host animals. Transgenic immunotherapy is a promising approach that may be useful for the eradication of minimal residual disease.