Proliferative and/or cytotoxic activity of lymphocyte clones to autologous human melanoma

Fossati, Giuseppe; Anichini, Andrea; Squarcina, Paola; Mazzocchi, Arabella; Parmiani, Giorgio

doi:10.1002/ijc.2910420216

Cited by 17 publications

(3 citation statements)

References 32 publications

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“…In humans, the existence of tumor-directed T-helper (Th) cells has been postulated on the basis of proliferative responses to autologous tumor cells of patients' peripheral-blood lymphocytes (PBL) or isolated CD4+ lymphocytes (Vanky et al, 1982;Fossati et aL, 1984;Kuppner et al, 1987;Vose et al, 1987;Allavena et al, 1988;Radrizzani et al, 1989). Clonal analyses of such proliferative responses have also been reported (Vose and White, 1983;Roberts et al, 1986;Fossati et aL, 1988). However, CD4' phenotype and the ability to proliferate in the presence of autologous tumor cells cannot be considered as unequivocal markers of Th activity, as tumorspecific CD4' lymphocytes capable of inducing suppressive phenomena have also been described (Mukherji et al, 1989).…”

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confidence: 99%

Human allogeneic melanoma‐reactive T‐helper lymphocyte clones: Functional analysis of lymphocyte‐melanoma interactions

Radrizzani

Benedetti

Castelli

et al. 1991

Intl Journal of Cancer

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Lymphocyte clones were isolated from CD4+ peripheral-blood lymphocytes (PBL) of melanoma (Me) patient 9923 (HLA-DR7, DQw2, w6), co-cultured for 30 days with autologous accessory cells, allogeneic Me (Me 1811) (HLA-DR7, DQw1, w2), IL-1 beta (2 U/ml) and IL-2 (15 IU/ml). The 55 clones tested displayed a CD3+, CD4+, CD8-, T-cell receptor (TCR) alpha/beta+, gamma/delta- phenotype. Twenty clones were assayed for proliferation in the presence of Me 1811 and B-lymphoblastoid cell line (LCL) 1811, both expressing HLA-class-I and -II (DR7 and DQw2 shared with patient 9923), intercellular adhesion molecule-1 (ICAM-1) and lymphocyte-function-associated antigen-3 (LFA-3) molecules. Eight clones were found to be reactive to Me 1811 but not to LCL 1811. Specificity analysis of these 8 clones revealed that each of them proliferated only to Me 1811, not to other 14 Me and 12 different LCL, suggesting recognition of melanoma-associated antigen (MAA) expressed on the stimulating Me. One clone (103) was analyzed in more detail. A wider specificity analysis showed that it reacted to Me 1811 but not to 10 other Me expressing or not HLA-DR7, 5 normal melanocyte cultures (2 of them typing HLA-DR7-positive when exposed to interferon-gamma--IFN-gamma), 4 tumors other than Me and 20 different LCL. Clones did not show proliferation in the presence of autologous Me cells. Clone proliferation in response to Me 1811 was significantly inhibited by monoclonal antibodies (MAbs) directed to CD3, TCR alpha/beta, TCR beta chain V12, CD4 and HLA-DR. Moreover, following stimulation with Me 1811, clone 103 showed increased surface expression of CD25 (IL-2 receptor) and CD71 (transferrin receptor) and produced significant amounts of IL-2 and IFN-gamma. The supernatant taken from co-culture of clone 103 with Me 1811 augmented the cytotoxicity of PBL 9923 and other allogeneic PBL against K562 and Me 1811. Thus, the lymphocyte clone 103 is a CD4+ Th clone which uses its CD3/TCR alpha/beta complex to recognize an MAA in conjunction with HLA-DR7. Availability of this type of reagent may prove useful to identify and characterize MAA recognized by T lymphocytes.

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confidence: 99%

Human allogeneic melanoma‐reactive T‐helper lymphocyte clones: Functional analysis of lymphocyte‐melanoma interactions

Radrizzani

Benedetti

Castelli

et al. 1991

Intl Journal of Cancer

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“…The same symbol is used to report the results of each separate experiment in the four graphs. more specific cellular immune response [5,25,26]. Second, the development of non-specific cells occurs mainly at the beginning of the culture.…”

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confidence: 99%

Human recombinant IL-4 decreases the emergence of non-specific cytolytic cells and favours the appearance of memory cells (CD4+CD45RO+) in the IL-2-driven development of cytotoxic T lymphocytes against autologous ovarian tumour cells

Roth

Dupuis

Alberto

1995

Clinical and Experimental Immunology

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SUMMARYAs IL-4 and IL-6 have also been reported to promote the development ofT lymphocytes such as IL-2, we investigated their role in the development of specific cytotoxic T lymphocytes (CTL) against autologous ovarian tumours in mixed lymphocyte tumour cultures (ML TC). Peripheral blood lymphocytes (PBL) from five ovarian carcinoma (OC) patients were incubated with autologous OC cells at a PBL:OC cell ratio of 20:1 in IL-2 alone (50 Urml for the first week and 200 U/ml thereafter) or with IL-4 (100 U/ml) and/or IL-6 (5 U/m!). Neither IL-4 nor IL-6 improved lymphocyte proliferation consistently. In contrast, IL-4 reduced significantly the development of LAK activity as assayed against Daudi cell line, and decreased modestly the emergence of natural killer (NK) activity as assayed against K562. This property was not shared by IL-6. The prevention of the development of non-specific cytolytic activity (LAK and NK activities) was much stronger when the MLTC was started with IL-4 in the absence of IL-2 during the first week in culture. A concomitant drop in NKH-I expression (CD56) was observed. By inhibiting the emergence of non-specific cytotoxicity, IL-4 provided better evidence of the specific cytolytic activity directed at ovarian cells. In parallel, a significant increase in the generation of memory cells (CD4+CD45RO+) was observed with IL-4. In conclusion, in this model, IL-4 added before IL-2 decreases significantly the emergence of non-specific cytotoxic cells, and promotes the generation of memory cells. These properties may be of interest in the design of strategies aimed at obtaining tumour-specific cells for investigational and immunotherapeutic purposes.

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“…A second population of CD3+ CD4+ cells can also be established, and these TlLs, have the ability to release or activate cytokines (Fossati et al, 1988). By using labelled TILs, a substantial accumulation at the tumour site has been described for humans (Fisher et al, 1989).…”

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A phase I trial of repeated tumour-infiltrating lymphocyte (TIL) infusion in metastatic melanoma

Ravaud

Legrand²,

Delaunay³

et al. 1995

Br J Cancer

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The aim of the protocol was to evaluate the side-effects induced by repeated tumour-infiltrating lymphocyte (TIL) infusions in patients with metastatic melanoma (MM). Patients were to receive four TIL infusions at given intervals: every 3 weeks (two patients), every 2 weeks (3 patients) and weekly (4 patients). All patients were evaluated and received a total of 34 TIL infusions. The total number of TILs administered varied from 0.65 to 2.34 x 10(11) cells. TIL phenotypes were predominantly CD8+ (two patients), CD4+ (4 patients), CD4+ then CD8+ (two patients) or CD56+ (two patient). Autocytotoxicity was only observed for one culture. Six patients presented at least one WHO grade 3 side-effect: hypotension (5 patients), dyspnoea (two patients), fever (one patient), fatigue (one patient), chills (two patients), diarrhoea (one patient), agitation (one patient), locoregional pain (two patients). Hypotension was constantly seen in patients who were given TILs every week. Two cases of minor pericarditis were recorded. No objective response to treatment was observed; 1 stable disease occurred in one patient and progression in eight. However, five patients presented a partial response on a tumour site for 1-4 months. Three patients presented signs of inflammation or softening at one tumour site. Plasma tumour necrosis factor alpha (TNF-alpha) levels were increased 1.2- to 22-fold after TIL infusion. TILs could be produced in sufficient quantity to perform this study, so repetitive infusions of TIL became possible on a weekly basis. However, no objective response was observed even when TIL infusions were performed weekly. An increase in circulating TNF-alpha was noted after TIL infusion.

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Proliferative and/or cytotoxic activity of lymphocyte clones to autologous human melanoma

Cited by 17 publications

References 32 publications

Human allogeneic melanoma‐reactive T‐helper lymphocyte clones: Functional analysis of lymphocyte‐melanoma interactions

Human allogeneic melanoma‐reactive T‐helper lymphocyte clones: Functional analysis of lymphocyte‐melanoma interactions

Human recombinant IL-4 decreases the emergence of non-specific cytolytic cells and favours the appearance of memory cells (CD4+CD45RO+) in the IL-2-driven development of cytotoxic T lymphocytes against autologous ovarian tumour cells

A phase I trial of repeated tumour-infiltrating lymphocyte (TIL) infusion in metastatic melanoma

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