Characterization of tumor-necrosis-factor-gene-transduced tumor-infiltrating lymphocytes from ascitic fluid of cancer patients: analysis of cytolytic activity, growth rate, adhesion molecule expression and cytokine production

Abstract

We characterized tumor-infiltrating lymphocytes (TIL) from ascites of patients with ovarian or pancreatic cancer in which the human tumor necrosis factor (TNF) gene was successfully transduced with retrovirus vector. The TNF-gene-transduced TIL (TNF-TIL) from these patients showed a higher level of TNF production and higher cytotoxic activity against K562 and Daudi cells than did neomycin-phosphotransferase-gene-transduced TIL (neo-TIL). Of these TIL preparations, only that from pancreatic cancer was further characterized since it was collected in a relatively large amount. In spite of the fact that the autologous tumor cells showed resistance to soluble TNF, the TNF-TIL clearly demonstrated enhanced cytotoxicity against them as compared with neo-TIL. The enhanced cytotoxicity was ascribed to autocrine effects of secreted TNF on TIL, which included augmentation of adhesion molecule (CD2 and CD11a) and interleukin-2 receptor expression, and elevation of production of interferon gamma, lymphotoxin and granulocyte/macrophage-colony-stimulating factor and its paracrine effect on target cells to facilitate them to be more susceptible to TIL.

Impaired tumorigenicity of human pancreatic cancer cells retrovirally transduced with interleukin-12 or interleukin-15 gene

“…3,4 However, there are few reports concerning immunogene therapy for pancreatic cancer. [5][6][7] We have shown the effect of human pancreatic cancer cells (AsPC-1) transduced with granulocytemacrophage colony-stimulating factor, 8 interleukin-2 (IL-2), or IL-4 9 cDNA on in vivo tumorigenicity. In this study, we investigated whether the IL-12 or IL-15 secreted from AsPC-1 cells could produce a suppressive effect on their tumor growth.…”

Recent Developments in the Virus Therapy of Cancer

“…Tumor‐necrosis‐factor (TNF) retrovirally transduced human TIL were shown to produce large quantities of TNF relative to nontransduced control TIL (107). In another study, tumor necrosis factor–transduced TIL were capable of increased killing of autologous pancreatic tumor cells compared to controls (108). Current investigations are centering on improving viral vectors to boost cytokine production in TIL.…”

Differentiation of stem and progenitor cells from bone marrow in activated dendritic cells and lymphocytes with anti-malignant properties

“…Because protein Bcl-3 has been characterized as a member of inhibitors from the subfamily the Nuclear Factor-kappaB (NFκB), a regulation mechanism on the apoptosis and survival of activated T-cells, supported by the balance in the concentration of various members of this family, has been suggested (Glymcher and Murphy, 2000;Mitchell et al, 2001). It has also been proposed that the deliberate induction of self-reactivity by use of a recombinant viral vector, could lead to tumor destruction, but CD4+ Tlymphocytes ( Figure 3) are probably an integral part of this process, and hence, targeting tissue differentiation antigens vaccine strategies might be valuable in malignancies, arising from non-essential cells, tissues and organs, such as melanocytes, prostate, testis, breast and ovary (Aruga et al, 1997;Glymcher and Murphy, 2000;Grosenbach et al, 2001;Itoh et al, 1995;1986;Kent et al, 1998;Rosenberg, 1996;Rosenberg et al, 1994;Siders et al, 1998;Wang et al, 1995;Zhai et al, 1996). Treatment of patients with metastatic melanoma with tumor-infiltrating lymphocytes (TILs) and IL-2 has resulted in objective immune responses in them.…”