Lysis of allogeneic and autologous melanoma cells by IL-7-induced lymphokine-activated killer cells

Böhm, Markus; Möller, Peter; Kalbfleisch, U; Worm, Margitta; Czarnetzki, B. M.; Schadendorf, Dirk

doi:10.1038/bjc.1994.249

Cited by 18 publications

(9 citation statements)

References 29 publications

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“…Human peripheral blood lymphocytes (PBL) were isolated from a healthy donor (M.B.) by Ficoll-Hypaque centrifugation as described previously (Bö hm et al, 1994) and were stimulated with 20 U per mL IL-2 or 1000 U per mL g-IFN for 4 h (both from R&D Systems).…”

Section: Methodsmentioning

confidence: 99%

Expression of SOCS-1, Suppressor of Cytokine Signalling-1, in Human Melanoma

Metze

Nashan

et al. 2004

Journal of Investigative Dermatology

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Cytokine resistance is a well-established feature of melanoma cell progression and represents also a major obstacle in immunotherapy of patients with metastatic melanoma. To check whether suppressors of cytokine signalling (SOCS) play a role in cytokine resistance and tumor progression of melanoma, we investigated the expression and regulation of SOCS-1, an established negative regulator of interleukin-6 (IL-6) and interferon (IFN) signalling. In vitro SOCS-1 transcripts were detectable by RT-PCR in 8 out of 8 human melanoma cell lines derived from different tumor stages. Normal human melanocytes also expressed SOCS-1 mRNA in the presence or absence of artificial growth factors. Both IL-6 and alpha-IFN induced rapid and transient SOCS-1 mRNA expression in WM35 and WM9 melanoma cells. At the protein level, SOCS-1 was undetectable in normal human melanocytes whereas uniformly expressed in all tested melanoma cell lines. The aberrant SOCS-1 protein expression in melanoma cells was recapitalized in situ as shown by immunohistochemical analysis. SOCS-1 immunoreactivity was closely related to tumor invasion (Clark level), tumor thickness according to Breslow, and stage of the disease. In contrast, melanocytes in normal skin or melanocytic nevi lacked SOCS-1 protein expression. Our findings show that melanoma cells express a member of the SOCS family, SOCS-1, in vitro and in situ. SOCS-1 is a progression marker of human melanoma and may downregulate biological responses by endogenous and/or therapeutically administered cytokines.

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Section: Methodsmentioning

confidence: 99%

Expression of SOCS-1, Suppressor of Cytokine Signalling-1, in Human Melanoma

Metze

Nashan

et al. 2004

Journal of Investigative Dermatology

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“…One-colour analysis was performed on an EPICS XL (Coulter, Krefeld, Germany) as described (Bohm et al, 1994 …”

Section: Flow Cytometrymentioning

confidence: 99%

“…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: 99%

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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“…Modified as a cytotoxicity assay for the quantification of cell-mediated cytotoxicity, 21,22 this test has compared favorably with the 51 Cr release assay in both sensitivity and reproducibility when the long-term cytotoxicity of adherent target cells is measured. …”

Section: Lda Assaymentioning

confidence: 99%

“…Furthermore, a difference in the percentage of lysis between before vaccination (B) and 2 weeks after the third vaccination (A) of Ͼ10% was thought to be necessary for the difference to be considered significant, as tested with PBMCs obtained from healthy donors. 21 Based on these criteria, an enhancement of spontaneous lytic activity against autologous melanoma cells was detected in the PBMCs of 7 of 12 evaluable patients (patients 1, 7, 9, 1b, 2b, 3b, and 6b), whereas a reduction in spontaneous lytic activity in the PBMCs of 3 of 12 patients (patients 5, 8, and 10) was observed after vaccination. Spontaneous lytic activity against the allogeneic melanoma cell line was found to be enhanced in 6 of 12 patients and increased in 4 of 12 patients after vaccination (Fig 2).…”

Section: Spontaneous Lytic Activity Of Pbmcsmentioning

confidence: 99%

Increased non-major histocompatibility complex-restricted lytic activity in melanoma patients vaccinated with cytokine gene-transfected autologous tumor cells

Möller

Sun

et al. 2000

Cancer Gene Ther

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Genetically modified antitumoral vaccines focus on eliciting or increasing the T-cell-mediated antitumoral response. Little is known about non-major histocompatibility complex-restricted responses. In two phase I studies, we have immunized advanced melanoma patients with either interleukin-7 (IL-7) gene-transfected or IL-12 gene-transfected, autologous, irradiated melanoma cells. To monitor the immune response, peripheral blood mononuclear cells were collected before the first vaccination and 2 weeks after the third vaccination. Spontaneous lytic activity and lymphokine-activated killer (LAK) activity after a 5-day culture in the presence of 1000 U/mL IL-2 against autologous and against allogeneic melanoma cells were measured. In parallel, a precursor cytotoxic T-cell frequency analysis was performed using a 25-day limiting dilution analysis assay. A total of 10 of 14 immunologically evaluable patients demonstrated a marked increase in LAK activity, and 7 of 14 showed increased spontaneous lytic activities against autologous melanoma cells after three vaccinations. Remarkably, two patients with a good clinical performance status (Karnofsky index of Ͼ70; Multitest Merieux of Ͼ13.4 mm/3) and the highest cytotoxic T-lymphocyte (CTL) response after vaccination showed the only clear decrease in LAK and spontaneous lytic activity. Otherwise, three patients with no detectable CTL response after vaccination demonstrated an increase in LAK activity and the strongest increase in the autologous spontaneous lytic activity. This group of patients was associated with a poor clinical performance status (Karnofsky index of Ͻ70; Multitest Merieux of Ͻ4 mm/1) and with no clinical response. In conclusion, in accordance with other studies, a good clinical and immunological performance status appears to be the prerequisite for a successful CTL response. However, even strong non-major histocompatibility complex-restricted responses could be generated in patients with reduced clinical performance in vaccination therapies with gene-transfected autologous tumor cells. Cancer Gene Therapy (2000) 7, 976 -984

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Lysis of allogeneic and autologous melanoma cells by IL-7-induced lymphokine-activated killer cells

Cited by 18 publications

References 29 publications

Expression of SOCS-1, Suppressor of Cytokine Signalling-1, in Human Melanoma

Expression of SOCS-1, Suppressor of Cytokine Signalling-1, in Human Melanoma

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

Increased non-major histocompatibility complex-restricted lytic activity in melanoma patients vaccinated with cytokine gene-transfected autologous tumor cells

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