Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon gamma.

Hock, Hanno; Dorsch, Marion; Kunzendorf, Ulrich; Qin, Zhihai; Diamantstein, Tibor; Blankenstein, Thomas

doi:10.1073/pnas.90.7.2774

Cited by 205 publications

(143 citation statements)

References 32 publications

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“…The demonstration that the ACN/IFN-g cells produced NO strongly supported its role in driving the apoptotic signal to the endothelial cells. In this view, it is conceivable that a non-species-specific mediator, like NO, was responsible for inhibition of angiogenesis observed in other human IFN-transfected tumour cells growing in athymic mice (Hock et al, 1993;Fathallah-Shaykh et al, 2000;Ozawa et al, 2001;Izawa et al, 2002;Qin et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

et al. 2006

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Tumour progression in neuroblastoma (NB) patients correlates with high vascular index. We have previously shown that the ACN NB cell line is tumorigenic and angiogenic in immunodeficient mice, and that interferon-g (IFN-g) gene transfer dampens ACN tumorigenicity. As IFN-g represses lymphocyte-induced tumour angiogenesis in various murine models and inhibits proliferation and migration of human endothelial cells, we have investigated the antiangiogenic activity of tumour-derived IFN-g and the underlying mechanism(s). In addition, we characterised the tumour vasculature of the ACN xenografts, using the chick embryo chorioallantoic membrane assay. We show that the ACN/IFN-g xenografts had a lower microvessel density and less in vivo angiogenic potential than the vector-transfected ACN/neo. The vascular channels of both xenografts were formed by a mixed endothelial cell population of murine and human origin, as assessed by the FICTION (fluorescence immunophenotyping and interphase cytogenetics) technique. With respect to ACN/neo, the ACN/IFN-g xenografts showed more terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive human and murine endothelial cells, suggesting that inhibition of angiogenesis by IFN-g was dependent on the induction of apoptosis, likely mediated by nitric oxide. Once the dual origin of tumour vasculature is confirmed in NB patients, the xenograft model described here will prove useful in testing the efficacy of different antiangiogenic compounds.

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Section: Discussionmentioning

confidence: 99%

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

et al. 2006

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“…T, B and NK cells) and NIH III mice (also deficient of T, B and NK cells) (24). Nonetheless, a long latency (about 30 days) existed before tumor nodule became palpable in these immuno-compromised mice.…”

Section: The Mechanism Of Exogenous Il-4-induced Tumor Rejectionmentioning

confidence: 99%

“…In immuno-competent mice, no tumor grew out. Cell depletion study indicated that CD8 + T lymphocyte were important, whereas CD4 + T cells played only a marginal role (24). At present, a biphasic mechanism is considered to be operating for exogenous IL-4-induced tumor rejection during which a rapid, innate immune cell dominant inflammatory response inhibited tumor burden, whereby allowing T cells to be activated and to finally complete tumor rejection (Figure 1).…”

Section: The Mechanism Of Exogenous Il-4-induced Tumor Rejectionmentioning

confidence: 99%

Paradoxical Roles of IL-4 in Tumor Immunity

2009

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“…In vitro, IL-7 is used to support APCinduced T-cell priming with a higher specificity than in the presence of IL-2 (Kos and Millbacher, 1992;Celis et al, 1994). Compared with other cytokines, anti-tumour response induced by paracrine-secreted IL-7 seems to be more strictly dependent on T cells (Hock et al, 1993;Miller et al, 1993), although IL-7 is able to induce LAK activity (Alderson et al, 1990;Bohm et al, 1994), to enhance NK activity (24) and to generate tumoricidal activity in monocytes (Alderson et al, 1991). In a comparative study in a mouse tumour model using a murine plasmocytoma cell line, the IL-7-secreting gene-modified tumour cells showed, in contrast to other cytokine-secreting tumour cells, a dependency of CD4+ T cells on early tumour rejection, whereas CD8+ T cells were required for long-term tumour eradication (Hock et al, 1993).…”

mentioning

confidence: 93%

Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study

Möller

Sun²,

Dorbic³

et al. 1998

Br J Cancer

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Summary Recently, cytokine gene transfer into tumour cells has been shown to mediate tumour regression in animal models via immunomodulation. Consequently, a number of clinical protocols have been developed to treat cancer patients with cytokine gene-modified tumour cells. Here, we report the results of a clinical phase trial using for the first time autologous, interleukin 7 gene-modified tumour cells for vaccination of ten patients with disseminated malignant melanoma. Melanoma cells were expanded in vitro from surgically removed metastases, transduced by a ballistic gene transfer technique and were then injected after in vitro irradiation s.c. at weekly intervals. Clinically, there was no major toxicity except for mild fever, and no major clinical response towards vaccination was observed. Eight of ten patients completed the initial three s.c. vaccinations and were eligible for immunological evaluation. Post vaccination, peripheral mononuclear cells (PBMCs) were found to contain an increased number of tumour-reactive proliferative as well as cytolytic cells, as determined by a limiting dilution analysis. In three of six patients, the frequencies of anti-melanoma cytolytic precursor cells increased between 2.6-and 28-fold. Two of these patients showed a minor clinical response. Analysis of the autologous tumour cell vaccines regarding IL-7 secretion after gene transfer, HLA class and class 11 cell surface expression, secretion of immunosuppressive mediators (TGF-,1, IL-10) and various melanoma-associated tumour antigens revealed a very diverse expression profile. In conclusion, vaccination using gene-modified autologous melanoma cells induced immunological changes in a group of advanced, terminally ill patients. These changes can be interpreted as an increased anti-tumour immune response. However, immunological modulation was most pronounced in patients in good physical condition. Therefore, patients with minimal tumour load or minimal residual disease might preferentially benefit from tumour cell vaccination in further studies. In order to evaluate the effects of the cytokine gene-modified tumour cell vaccines more precisely, an antigenically better defined vaccine is needed.

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Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon gamma.

Abstract: Interleukin (

Cited by 205 publications

References 32 publications

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

Paradoxical Roles of IL-4 in Tumor Immunity

Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study

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