Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1522102 (Melanoma)
 7,698 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanoma represents the single best example of a human tumor that has been shown to elicit specific T-cell reactivity. The responsiveness of some patients with metastatic melanoma to treatment with the prototypic T-cell growth factor (TCGF), interleukin-2 (IL-2), indicates that T cells play a role in antitumor immunity. Interleukin-4 (IL-4), another TCGF that has been administered clinically to humans, was not associated with tumor response in our trials conducted at the Surgery Branch of the National Cancer Institute. Combination trials of IL-2 with IL-4 have shown no increase in responsiveness of melanoma or other tumors when compared to IL-2 alone. However, enhanced expansion of tumor-infiltrating lymphocytes (TILs) in vitro has been observed with combinations of low-dose IL-2 and IL-4. We have begun a study evaluating the trafficking of such expanded lymphocytes following their adoptive transfer in association with systemic administration of IL-2 and IL-4. We have established several TIL cultures from fresh tumor samples, maintained them in long-term culture, and marked them with the neomycin phosphotransferase gene using the LNL6 retroviral vector. Such TILs appear to demonstrate no notable alterations in phenotype or cytolytic activity when compared to their nontransduced counterparts. In addition to IL-2 and IL-4, there are a variety of other novel TCGFs that are now available for evaluation in preclinical and clinical trials. IL-7 induces proliferation and lymphokine-activated killer (LAK) cell activity from human peripheral blood mononuclear cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma. 135 3

Chemoresistant melanoma cells are known to be susceptible in vitro to lymphokine activated killer (LAK) cells. To obtain a high LAK/tumour cell ratio in vivo and avoid systemic toxicity due to interleukin-2 (IL-2), we used IL-2 plus LAK cells in the treatment of in transit melanoma metastases of the limbs by isolation perfusion (IP). In vivo immunological modifications induced by this immunotherapeutic approach were also analysed. Six patients previously treated with IP in extracorporeal circulation with tumour cytotoxic drugs and presently relapsing or not responding, were submitted to locoregional adoptive therapy consisting of 5 days systemic administration of IL-2 (Proleukin, EuroCetus) (9-12 x 10(6) IU/m2/day c.i.). Autologous LAK cells were derived from leukapheresis and subsequent in vitro stimulation with IL-2; LAK cells were then given along with IL-2 (120-2400 IU/ml of perfusion priming) to the affected limb by IP. In addition, 7-16 x 10(9) LAK cells were administered by systemic infusion the day after together with IL-2 (9-12 x 10(6) IU/m2/day) by c.i. for 5 days. All patients concluded the treatment without major toxicity. The analysis of circulating lymphocytes obtained from extracorporeal circuit at different times revealed rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. Clinical responses included four partial and one complete response; another patient had stable disease. All patients are presently alive. Follow-up after IP ranges from 8 to 22 months.
Melanoma Res 1992 Nov
PMID:Treatment of recurrent in transit metastases from cutaneous melanoma by isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine activated killer cells. A pilot study. 149 Jan 14

Electrotherapy with direct current (DC) was performed on two murine tumor models, fibrosarcoma SA-1 and melanoma B16. Three Pt/Ir cathodes were inserted directly into the subcutaneous tumors and two anodes subcutaneously in the vicinity of the tumor. Significant tumor growth delay was achieved after electrotherapy and was dependent on DC intensity (0.6, 1.0, 1.4 and 1.8 mA). Melanoma B16 tumors were more sensitive to electrotherapy than SA-1 tumors. In order to enhance the antitumor effect of electrotherapy, combined treatment with interleukin-2 (IL-2) was performed. When both therapies were combined significant tumor growth delay and also higher curability rate was achieved. The results imply that electrotherapy can be an effective antitumor therapy and that the effects can be enhanced with additional IL-2 therapy.
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PMID:Anti-tumor effect of electrotherapy alone or in combination with interleukin-2 in mice with sarcoma and melanoma tumors. 152 6

Extracellular products from melanoma cells may play an important role in the pathogenesis of metastatic melanoma. Studies were designed to evaluate the effect of vaccination with formalinized extracellular antigens (FECA) of murine melanoma cells (MMM B16-F10) on survival and immune response of C57BL/6 mice. The cellular immune response was evaluated by assessing interleukin-2 (IL-2) production and natural killer cell activity, whereas the humoral immune response was examined by measuring the production of specific antibodies to extracellular antigens (ECA). IL-2 production by the splenocytes from immunized animals was significantly higher (4.7 U/ml and 3.7 U/ml) than that of controls (1.38 U/ml). The splenocytes from immunized mice revealed significantly higher natural killer cell activity. Similarly, immunized animals responded by producing specific antibodies against the extracellular melanoma antigens as detected by ELISA. The peak production of antibodies against ECA was observed on the 21st day post-immunization. These results suggest that FECA are immunogenic and may enhance active cellular and humoral anti-melanoma immunity.
Melanoma Res 1992 May
PMID:Induction of interleukin-2, natural killer cell activity and anti-melanoma antibodies resulting from immunization of mice with formalinized extracellular antigens (FECA) of murine melanoma. 164 24

The expression of activated ras oncogenes was found to be associated with that of tumour-specific transplantation antigens in mouse tumours, which can be cured by adoptive immunotherapy with T lymphocytes and interleukin-2 (IL-2). A similar association is here proposed to exist between RAS oncogene activation (mutation) in human melanoma and susceptibility of these tumours to the lytic action of activated lymphocytes (both lymphokine-activated killers and cytotoxic T cells) which have been used, along with IL-2, in the adoptive immunotherapy of advanced melanomas. The limited clinical response (15-25%) of melanoma patients to different immunological therapies is, therefore, considered to be due to a similar frequency of immunogenic, RAS+ melanomas. The authors thus suggest that RAS activation might be a marker of immunogenicity and that only the subset of melanoma cells expressing activated RAS will in turn possess tumour antigens which can be the target of immunotherapeutic, activated lymphocytes. It is then predicted that RAS+ melanomas will be more susceptible to adoptive immunotherapy than RAS-counterparts.
Melanoma Res 1992 Jul
PMID:Can oncogene (RAS) activation predict susceptibility of human melanoma to activated lymphocytes and, therefore, the clinical response of such neoplasms to adoptive immunotherapy? 164 31

An HLA-A2-specific cytotoxic T lymphocyte (CTL) clone (CTL49), capable of killing the HLA-A2-negative autologous melanoma (Me665/2) in a T cell receptor and MHC-independent fashion, lysed six of 16 Me665/2 tumour clones in short-term (4 and 18 hour) 51Cr-release assays. In long-term (96 hour) lytic assays, CTL49 could lyse all the 16 tumour clones. The lysis observed in the 96 hour assay could be enhanced by stimulating CTL49 with anti-CD3 monoclonal antibodies (MAb) and interleukin-2 (IL-2). Supernatants of anti-CD3- or antigen-stimulated CTL49, known to contain tumour necrosis factor (TNF) alpha and interferon (IFN)gamma, were also able to lyse all but one (665/2/51) of the tumour clones in 96 hour assays. Absence of lysis of tumour clone 2/51 by supernatants correlated with resistance of the same tumour clone to lysis by recombinant IFN-gamma plus TNF-alpha. Antibodies to TNF-alpha and, to a lesser extent, to IFN-gamma, reduced significantly the 96 hour lysis of Me2/9 and Me2/10, two of the tumour clones killed in long term but not in short term assays. Winn assays in nude mice revealed that CTL49, stimulated with anti-CD3-MAb plus IL-2, could abolish tumour cell growth when injected together with clones 2/9 or 2/10. These results indicate that intra-tumour heterogeneity for susceptibility to lysis can be overcome even by a single CTL clone providing that appropriate signals (i.e. anti-CD3-MAb and IL-2) are supplied to an effector able to mediate tumour cell lysis by multiple mechanisms.
Melanoma Res
PMID:An autologous T cell clone overcomes intra-melanoma heterogeneity for susceptibility to cell-mediated lysis by using multiple lytic mechanisms: in vitro and in vivo analysis. 184 13

Melanoma metastases were harvested from 82 patients for the purpose of growing and expanding tumor-infiltrating lymphocytes (TIL). Tumor tissue cell suspensions were incubated with interleukin-2 (IL-2), followed by repeated exposure to tumor antigen with or without OKT3 monoclonal antibody (MoAb). Initial growth success was achieved in 56 of 82 cultures (72%). Efforts were made to expand 26 of these 56 cultures for therapeutic TIL; 23 of 26 early cultures (88%) were successfully expanded for in vivo therapy. It took a mean of 78.5 +/- 25.4 days to grow sufficient TIL for treatment. Therapy included cyclophosphamide (1 g/m2) on day 1, followed by a 96-hour continuous infusion of IL-2 (18 x 10(6) IU/m2/d) on days 2 to 5, and approximately 10(11) (mean 1.49 +/- 0.93 x 10(11)) TIL on day 2. Patients who responded received monthly IL-2 as a 96-hour infusion. Median patient age was 45 years of age. Sixty-seven percent of the patients were men. Performance status was 0 to 1 in 77% of patients. Thirty-four percent of the patients had liver metastases. The usual IL-2 toxicities were seen. Response rate for 21 patients was 24% (95% confidence interval, 10% to 49%). One complete response was achieved with cells 98% CD4+; four partial responses were achieved with cells 80%, 94%, 98%, and 98% CD8+, respectively. Four of eight patients who received TIL, which had never been stimulated with OKT3, had tumor response. The authors conclude that a treatment plan for IL-2/TIL is technically difficult, costly, and effective for only a minority of patients. Overall, clinical results are not clearly superior to those obtained with other IL-2 regimens.
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PMID:Continuous interleukin-2 and tumor-infiltrating lymphocytes as treatment of advanced melanoma. A national biotherapy study group trial. 204 29

Although most cultured melanoma cell lines express DR Class II molecules, many of these do not also express the DS (MB) Class II molecules as detected by a monoclonal antibody specific for DS. Cells lacking either DR or DS molecules or both could only be induced to express DR antigens in rare cases by combined incubations with azacytidine and Interleukin-2 conditioned medium, although the expression of DR molecules on fibroblasts or U937 monocytes could more easily be induced under the same culture conditions. Melanoma cells expressing DR antigens could function in antigen presentation for the histocompatibility antigens themselves and for DR specific presentation of TNP determinants to allogeneic T-cells sensitized to TNP modified lymphocytes and showing restriction in their responses to the specificity of the DR molecules expressed on the original, autologous sensitizing cells. DR positive melanoma cells could not, however, be demonstrated to function in the presentation of any of the soluble antigens tested. All DR positive melanoma cells also expressed SB antigens, but these were not detected on DR negative melanoma cells. These studies collectively indicate that the expression of Class II histocompatibility antigens on diverse cell types is subject to differential regulatory control and is associated with differences in their functional activities.
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PMID:Functional characteristics and differential expression of class II DR, DS, and SB antigens on human melanoma cell lines. 660 12

LM mouse fibroblasts (H-2k) were modified for the expression of (antibody-defined) melanoma-associated antigens (MAA) and the secretion of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) (RLBA-IL-2/IFN-gamma cells). The cell construct was tested for its immunogenic properties in C57BL/6 mice (H-2b) with B16 melanoma. The results indicated that the survival of mice injected with a mixture of B16 cells and the modified, double cytokine-secreting fibroblasts was significantly longer than that of mice injected with B16 cells and LM cells modified for the expression of MAA and the secretion of IL-2 or IFN-gamma alone (RLBA-IL-2 or RLBA-IFN-gamma cells). Both natural killer/lymphokine-activated killer (NK/LAK) cells and Lyt-2.2 + CTLs with anti-melanoma cytotoxic activities were predominant in mice immunized with the double cytokine-secreting cells. B16 melanoma cells persisted in mice treated with RLBA-IL-2 cells (B16-R3). The B16-R3 cells were resistant to anti-melanoma effector cells from mice immunized with RLBA-IL-2 cells. The recurrent melanoma cells were deficient in the expression of MHC class I determinants. Class I expression by B16-R3 cells was increased if they were incubated in medium conditioned by the growth of IFN-gamma-secreting RLBA-IL-2/IFN-gamma or RLBA-IFN-gamma cells. After incubation, the sensitivity of B16-R3 melanoma cells to immune-effector cells from mice immunized with RLBA-IL-2 cells was restored. The survival of mice bearing low MHC class I-expressing B16-R3 cells, treated RLBA-IL-2/IFN-gamma cells, was determined. The treated animals survived significantly longer than mice with B16-R3 melanoma treated with RLBA-IL-2 cells. Similar results were obtained for mice with B16-R3 melanoma treated with RLBA-IFN-gamma cells. We postulate that immunization of mice with IL-2/IFN-gamma double cytokine-secreting cells stimulated multiple anti-melanoma effector mechanisms. Analogous to the enhanced therapeutic anti-tumour effects of combination chemotherapy, it was likely that treatment with a cellular immunogen engineered to stimulate more than one effector mechanism resulted in the elimination of larger numbers of tumour cells than treatment with an immunogen that stimulated a single effector mechanism alone.
Melanoma Res 1995 Aug
PMID:Immunization with interleukin-2/interferon-gamma double cytokine-secreting allogeneic fibroblasts prolongs the survival of mice with melanoma. 749 56

The combination of chemotherapy and immunotherapy seems to improve response rate in metastatic melanoma. We investigated the effects on toxicity and immunological effects of a single dose of dacarbacin (DTIC; 850 mg/m2) or cisplatin (CDDP; 100 mg/m2) added to subsequent immunotherapy with interferon-alpha (IFN-alpha) and interleukin-2 (IL-2). Twelve patients, who did not respond to IFN-alpha/IL-2 alone were studied. Six received DTIC and IFN-alpha/IL-2, and six received CDDP and IFN-alpha/IL-2. DTIC did not add significant toxicity except for nausea. Significant thrombocytopenia was observed in two patients after CDDP. Although CDDP led to grade 3 nephrotoxicity in two patients, the IL-2-induced fluid retention was less severe than with IFN-alpha/IL-2 alone. Pharmacokinetics of IL-2 were not altered by DTIC, but higher IL-2 serum levels were found in patients with grade 3 nephrotoxicity after CDDP. The IL-2-related induction of secondary mediators (interferon-gamma, tumour necrosis factor-alpha, soluble CD25) was not impaired by chemotherapy and the induction of neopterin was significantly higher after addition of CDDP. One partial response was observed after addition of DTIC to IFN-alpha/IL-2, and one after addition of CDDP. The addition of a single dose of DTIC or CDDP to IFN-alpha/IL-2 is fairly well tolerated and does not abolish induction of secondary mediators. Randomized trials are necessary to test the clinical efficacy.
Melanoma Res 1995 Aug
PMID:Addition of dacarbazine or cisplatin to interferon-alpha/interleukin-2 in metastatic melanoma: toxicity and immunological effects. 749 66


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