Anti‐metastatic vaccination of tumor‐bearing mice with il‐2‐gene‐inserted tumor cells

Abstract

IL-2 gene was introduced through retroviral vectors into the highly malignant and poorly immunogenic 3LL-D122 clone. Both high and low D122-IL-2 secretors showed elimination of tumorigenicity in syngeneic immune-competent mice; however, in nude mice only the high IL-2 secretor showed reduced tumorigenicity as compared with parental D122 cells. Also, following intravenous inoculation, only the high IL-2 secretor showed reduced generation of metastases, whereas the low IL-2 secretors were as highly metastatic as parental cells. These results seem to indicate that low levels of IL-2 secreted by tumor cells are sufficient to activate T cells, while higher levels are needed in order to activate non-T-cell effectors. D122-IL-2 secretors induced high levels of anti-tumor CTL, while their sensitivity to the lytic activity of these CTL was similar to the sensitivity of D122 cells, thus indicating that the elevation of immunogenicity of IL-2 secretors was essentially due to the secreted IL-2. In accordance with CTL induction, pre-immunization with IL-2 secretors protected mice against subsequent challenge of parental cells. Moreover, immunization in an "immunotherapy protocol" i.e., vaccination of mice carrying an established tumor of parental D122 cells with inactivated D122-IL2 infectants, almost completely eliminated the generation of lung metastases by D122 cells, thus providing a rationale for the use of IL-2 gene transferred tumor cells as a modality for treatment of metastasis.

Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-γ gene into lung cancer

“…32,33 We used lung cancer cell line 3LLSA, which is known to be a very low immunogenic tumor. 34 We did not observe the expression of H -2K (MHC class I ) on 3LLSA cells by FACS analysis ( data not shown ). It would be difficult to establish T cell ± mediated antitumor immunity against low immunogenic tumors such as 3LLSA cell tumors.…”

Modification of PDGFα receptor expression or function alters the metastatic phenotype of 3LL cells

“…Collectively, these data con®rm a partial role for immune functions in control of the metastatic process, a ecting survival time of inoculated mice. In fact, increasing the endogenous immunogenicity of D122 cells by transfection with H-2K b or MHC class I regulator genes, abrogates their metastatic phenotype by enabling the MHC expressing cells to induce an e ective CTL response (Plaksin et al, 1988;Porgador et al, 1993;Yamit-Hezi et al, 1994). Yet, importantly, expression of wild-type PDGFa receptors in 3LL cells is a crucial factor in determining their ability to colonize and expand in the lung.…”

Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model

“…24 To date, many studies involving the treatment of tumor-bearing animals with nonimmunogenic tumor cells engineered to secrete various cytokines have demonstrated the inhibition of pre-established tumors. [1][2][3][4][5][6]10,25 In our previous experiments, ex vivo genetically modified IL-2 or GM-CSF secreting MBT-2 cell preparations were shown to induce effective immune responses against original MBT-2 tumors and cure up to 50% of animals with pre-established MBT-2 bladder tumors. 1,10 Moreover, these antitumor immune responses of initially cured animals were persistent and highly effective against further MBT-2 tumor re-challenges.…”