Application of interleukin 12 to antitumor cytokine and gene therapy

Abstract

In vivo administration of interleukin 12 (IL-12) at 2000 U/mouse induced IL-12-activated killer (IL-12AK) cells in parallel with an elevation in serum interferon-gamma (IFN-gamma) activity. Although NK1.1+CD3- natural killer cells are the major precursor of IL-12AK cells, asialoGM1+CD8+ T-cells were also demonstrated to be novel precursors. Such anomalous killer cells may play an important role in the early stages of the host defense mechanisms against tumors. It was also shown that IL-12 is effective in inducing tumor-specific cytotoxic T-lymphocytes. Consistent with these data, IL-12 had marked activity against various kinds of established tumors when given systemically. Mice cured of tumors by IL-12 treatment acquired tumor-specific T-cell immunity. Moreover, we initially demonstrated that IL-12 was effective in preventing and inhibiting the growth of primary tumors induced by the chemical carcinogen methylnitrosourea using c-Ha-ras transgeneic mice. Finally, we investigated the application of IL-12 to antitumor gene therapy. Transfer of the IL-12 gene into A20 B-lymphoma cells resulted in the continuous production of IL-12 and caused abrogation of in vivo tumorigenicity. Tumor cells transfected with the IL-12 gene are potentially a good tool as a tumor vaccine, as they effectively induced IL-12AK cells, IFN-gamma production, and tumor-specific protective immunity. Although B16-BL-6 melanoma cells, which are a highly metastatic subclone of B16 melanoma cells, showed resistance to IL-12 gene therapy, combination therapy with the B7-1 gene and systemic IL-12 administration almost completely inhibited tumor metastasis. Similar results were obtained using B16-BL-6 melanoma cells transfected with both B7-1 and IL-12 genes. These results suggest that IL-12 is a promising cytokine for antitumor cytokine and gene therapy.

Effectiveness of cancer vaccine therapy using cells transduced with the interleukin-12 gene combined with systemic interleukin-18 administration

“…1 IL-12 exerts a variety of biological effects on T and NK cells in vitro, 20 and its exogenous administration has been shown to have a dramatic effect on the suppression of tumor growth and metastasis. 8 Several investigations have described IL-12 gene transduction, [21][22][23][24][25][26][27][28][29] and some have shown that a tumor vaccine based on IL-12-transduced tumor cells is quite effective. We also demonstrated that irradiated RenCa secreting IL-12 suppressed the tumor growth of parental RenCa injected at contralateral sites, whereas irradiated parental RenCa did not.…”

Tumor and CD4 T-cell interactions: tumor escape as result of reciprocal inactivation

“…These have included transfecting tumor cells with costimulatory molecules, 31,32 using dendritic cell (DC)-based vaccine therapy, 33-42 and transferring cytokines or cytokine genes into the hosts. 43,44 Although successful induction of CD4 immune responses resulting in tumor rejection has been widely reported, it is less clear whether such immune responses are able to protect against re-emerging tumor cells once the acute response has terminated and T cells have differentiated to resting memory cells.The aim of this study was to assess the contribution of CD4 T cells in different activation states in controlling tumor growth. For this, we made use of an experimental system previously described by us that allows the in vivo generation of pure effector or memory CD4 T cells from naive T-cell precursors.…”

Vaccination with IL-12 gene-modified autologous melanoma cells: preclinical results and a first clinical phase I study

“…Furthermore, IL-12 gene transfer induced a T H1 response and generated a strong antitumor immunity. [7][8][9][10][11][12][13][14][15][16] IL-12 is a heterodimeric cytokine originally cloned from B lymphoblastoid cell lines. The cDNAs encoding the two IL-12 subunits are unrelated and encode for two distinct proteins which have molecular masses of 35 kDa and 40 kDa.…”