Lack of correlation between peripheral blood lymphokine‐activated killer (lak) cell function and clinical response in patients with advanced malignant melanoma receiving recombinant interleukin 2

Ghosh, Anna K; Dazzi, H; Thatcher, Nick; Moore, Michael G.

doi:10.1002/ijc.2910430311

Cited by 43 publications

(24 citation statements)

References 24 publications

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“…FAA has been shown to have high anti-tumour activity and a possible host mediated mechanism of toxicity including augmentation of NK cell activity (Ching & Baguley, 1987; cancer. In our previous study of rIL-2 alone (Ghosh et al, 1989), increased NK activity was observed in 16 of 20 patients while on treatment. showed maximal NK cell activity in the peripheral blood of mice at 48 h, which persisted for 6 days after FAA administration.…”

Section: Lak Cell Precursorsmentioning

confidence: 75%

“…This combined adoptive immunotherapy is, however, expensive and labour intensive, and toxicity is severe when high doses of IL-2 are used. In our previous phase I/II clinical trial of intrasplenic and intravenous rIL-2 less toxicity was achieved and partial clinical responses were observed in 15% of patients with progressing advanced melanoma (Thatcher et al, 1989). These encouraging results stimulated interest in using rIL-2 in combination with other biological response modifiers or with chemotherapeutic drugs in the hope that better clinical responses could be achieved.…”

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confidence: 94%

“…Further clinical details from these patients are described elsewhere (Thatcher et al, 1990). Interleukin-2/flavone acetic acid administration Recombinant IL-2 (kindly supplied by Eurocetus BV, Amsterdam) was administered as described previously by Thatcher et al (1989). Briefly, the initial dose (intrasplenic) was followed 4 h later by intravenous administration followed by three alternate day i.v.…”

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confidence: 99%

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confidence: 99%

“…A maximum of three such courses was given at 21-day intervals after the FAA administration. The doses given (11 x 106 Cetus units mr2) were taken from the preceding phase I/II study of rIL-2 alone (Thatcher et al, 1989) Cytotoxic activity of PBMC in patients receiving FAA and rIL-2 treatment NK activity Ten of the 26 patients studied showed positive cytotoxicity (greater than 10% lysis) against the cultured K562 cell line before treatment with values ranging from 11 to 59%. In 23/26 patients significant increases in NK activity were observed while receiving FAA/IL-2 treatment, ranging from 2 to 20 times increase in cytotoxicity or from 12 to 91% lysis.…”

mentioning

confidence: 99%

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Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: immunological studies

Ghosh

Mellor²,

Prendiville³

et al. 1990

Br J Cancer

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Summary Natural killer (NK) cell activity and lymphokine activated killer (LAK) cell cytotoxicity were measured in patients receiving recombinant interleukin 2 (rIL-2) and flavone acetic acid (FAA) for treatment of progressing metastatic melanoma. NK activity was increased in 23 of 26 patients and LAK activity induced in 13 of 26 patients. However, levels of cytotoxicity in the present study were not significantly greater than a previous study using rIL-2 alone. LAK cell precursors demonstrated by in vitro incubation of pretreatment lymphocytes with IL-2 and subsequent cytotoxicity were no different in the patients compared to normal controls. Analysis of cell surface phenotypes failed to reveal any significant changes in the cell populations examined, including IL-2R and Leu 19. Although five patients had tumour response, one being complete, there was no correlation with the immunological parameters examined.Several studies have shown that the administration of interleukin 2, either alone or in conjunction with broadly cytotoxic lymphokine activated killer cells (LAK) generated by in vitro co-culture with IL-2 have resulted in tumour regression in a range of established human tumours including melanoma (Rosenberg et al., 1987;Rosenberg, 1988;West et al., 1987; Hank et al., 1988). This combined adoptive immunotherapy is, however, expensive and labour intensive, and toxicity is severe when high doses of IL-2 are used. In our previous phase I/II clinical trial of intrasplenic and intravenous rIL-2 less toxicity was achieved and partial clinical responses were observed in 15% of patients with progressing advanced melanoma (Thatcher et al., 1989). These encouraging results stimulated interest in using rIL-2 in combination with other biological response modifiers or with chemotherapeutic drugs in the hope that better clinical responses could be achieved.Flavone acetic acid (FAA) is a synthetic flavonoid found to have an antitumour effect against a spectrum of murine solid tumours and to augment natural killer cell activity in spleen and other tissues in normal mice (Finlay et al., 1988;Zaharko et al., 1986;Ching & Baguley, 1987). This suggested that FAA may act as a biological response modifier as well as functioning as a chemotherapeutic drug. NK cells have been shown to be the major effector cell population contributing to the generation of LAK activity by rIL-2 (Itoh et al., 1985;Ferrini et al., 1987;Herberman et al., 1987 without local radiotherapy, although no patients had received anti-tumour treatment 4 weeks before entry into the study. Further clinical details from these patients are described elsewhere (Thatcher et al., 1990).Interleukin-2/flavone acetic acid administration Recombinant IL-2 (kindly supplied by Eurocetus BV, Amsterdam) was administered as described previously by Thatcher et al. (1989). Briefly, the initial dose (intrasplenic) was followed 4 h later by intravenous administration followed by three alternate day i.v. doses. A maximum of three such courses was given at 21-day intervals after the...

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Section: Lak Cell Precursorsmentioning

confidence: 75%

mentioning

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: immunological studies

Ghosh

Mellor²,

Prendiville³

et al. 1990

Br J Cancer

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Preliminary validation of an activation assay for ex vivo activated T cells utilized in cancer immunotherapy

Hamilton¹,

Goodwin²,

Clarke³

et al. 1994

Biotech & Bioengineering

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An in vitro assay that measures the activation level of ex vivo activated (EVA) T cells currently being used in the adoptive immunotherapy of metastatic renal cell carcinoma has been developed. This assay is based on the ability of activated, but not resting. T cells to proliferate in response to the protein kinase C activator, phorbol myristate (PMA). To utilize this assay for in-process monitoring and control, we have begun an initial validation of the overall reproducibility of this assay. The proliferation of activated T cells in response to PMA, as measured by the mean cpm values of (3)H-thymidine incorporated, was demonstrated to have intra-assay coefficients of variation (cv's) for individual analysts that were typically less than 10% and rarely exceeded 20%. Activated T cells could be frozen and stored for at least 6 weeks with little or no deterioration in their ability to proliferate in response to PMA. Using these cells, inter-assay cv's that were typically less than 15% were obtained by individual analysts, and overall cv's of 10% to 25% were obtained for different samples assayed by different analysts at different times. This level of variability is very reasonable for a cellular assay. Further validation of this assay will address the issues of sensitivity, linearity and selectivity. To date, this assay has been used to analyze over 90 patient EVA cell samples and has revealed a broad range of proliferative responses to PMA. Taken together, these results suggest that this assay may be useful in defining the potency of the activated T cell used therapeutically.

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TCR‐independent cytokine stimulation induces non‐MHC‐restricted T cell activity and is negatively regulated by HLA class I

et al. 2006

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Recent evidence suggests that the functional status of T cells activated independently from their TCR differs substantially from classical MHC-restricted T cells. Here, we show that TCR-independent, short-term stimulation via the common c-chain of the IL-2/IL-15 receptor induces non-MHC-restricted cytotoxicity and sustained cytokine secretion in purified CD4 + or CD8 + T cells. NK-like cytotoxicity is directed against MHC class Inegative targets and can be inhibited by classical and non-classical HLA class I molecules. Known inhibitory receptors, such as CD85j (ILT2) and leukocyte-associated Ig-like receptor-1, are not responsible for this HLA-mediated inhibition. NK-like cytotoxicity can be costimulated by NKG2D (CD314) triggering, but 2B4 (CD244) and DNAM-1 (CD226) are not involved. NK-like T cells display an activated phenotype and secrete various cytokines, including IFN-c, TNF-a, IL-5, IL-13 and MIP-1b. Under normal conditions, HLA class I-mediated inhibition may function as a safety mechanism to prevent unbalanced cytokine production and effector killing mechanisms by T cells that were activated independently from their TCR. Non-MHC-restricted activity represents a functional status rather than a property of distinct T cell subpopulations. Thus, cytokine-induced, non-MHC-restricted T cells may be relevant in immune responses against tumors showing aberrant MHC expression through their capacities of cytokine production and direct tumor cell eradication.

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Lack of correlation between peripheral blood lymphokine‐activated killer (lak) cell function and clinical response in patients with advanced malignant melanoma receiving recombinant interleukin 2

Cited by 43 publications

References 24 publications

Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: immunological studies

Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: immunological studies

Preliminary validation of an activation assay for ex vivo activated T cells utilized in cancer immunotherapy

TCR‐independent cytokine stimulation induces non‐MHC‐restricted T cell activity and is negatively regulated by HLA class I

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