Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of metastatic malignant melanoma with recombinant interleukin-2 (rIL-2) represents one of the earliest attempts at systemic immunomodulation as a therapy for cancer. Initial reports showed objective response rates with single-agent rIL-2 therapy in the range of 15% to 20% with some durable responses; however, the overall response rates were lower than originally anticipated. In addition, in contrast to animal models, it appears that coadministration of lymphokine-activated killer (LAK) cells, generated ex vivo with rIL-2, does not enhance the response rates achieved with single-agent rIL-2. Despite a multitude of studies with various rIL-2 regimens, with and without coadministration of LAK cells or tumor-infiltrating lymphocytes, the optimum dose and treatment schedule for rIL-2-based therapy in metastatic melanoma remains a topic of controversy. To date, there are also no clear immunologic parameters that can predict biologic response to rIL-2-based therapy.
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PMID:Treatment of malignant melanoma with interleukin-2. 912 32

Biochemotherapy, which uses recombinant interferon alpha (rIFN-alpha) and recombinant interleukin-2 (rIL-2) in combination with chemotherapy is a promising therapy for metastatic malignant melanoma. Various biochemotherapy regimens have produced overall objective response rates of > 50% and durable complete remission (CR) in approximately 10%-of treated patients. One such biochemotherapy regimen, consisting of sequential administration of cisplatin, vinblastine, and dacarbazine (CVD regimen) followed by rIFN-alpha and rIL-2, has produced a response rate of 60% and a CR rate of 20% in the most recent cohort of 62 patients treated at The University of Texas M.D. Anderson Cancer Center. The duration of partial responses with this and similar regimens typically averages 6 to 9 months; however, more than half of the CRs achieved with this regimen have been durable for 3+ to 5+ years. This has raised the possibility of long-term survival in approximately 10% of patients with metastatic melanoma. If confirmed, this will represent a significant advance in the treatment of metastatic melanoma.
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PMID:Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alpha and chemotherapy. 912 33

The prognosis for most patients with metastatic melanoma is poor, as the median survival is only 7 months. Phase II trials of chemoimmunotherapy have, however, reported response rates of 40% to 70% and prolonged disease-free survival in small subgroups of patients. Most chemoimmunotherapy trials have used high doses of recombinant interleukin-2 (rIL-2) and recombinant interferon alpha (rIFN-alpha) that produce significant toxicity and require prolonged hospitalization to manage side effects. To develop a treatment regimen for metastatic melanoma that would minimize costly hospitalization, we initiated a phase II trial of outpatient chemoimmunotherapy. Patients were treated with monthly cycles of intravenous carmustine, dacarbazine, cisplatin, and tamoxifen plus self-administered subcutaneous rIL-2 and rIFN-alpha as outpatients. To date, 32 patients have received 94 cycles of therapy. The most common toxicity was nausea and vomiting. Hospitalization for the management of toxicity was required in only seven cycles (7%). Thirty patients have been assessed for clinical response. The overall response rate was 43% (13% complete and 30% partial response). This phase II trial has established a tolerable regimen of outpatient chemoimmunotherapy, which has shown significant antitumor activity.
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PMID:Outpatient chemoimmunotherapy for the treatment of metastatic melanoma. 912 34

Metastatic malignant melanoma remains a frustrating and almost invariably fatal disease. Nonetheless, both cytotoxic chemotherapy and immunotherapy agents have shown activity against this disease, and an occasional patient will experience long-term benefit from therapy. Regimens involving various combinations of chemotherapy, the addition of either tamoxifen or interferon alfa have shown promise in phase III trials, but as yet no agent has proven to be superior to single agent dacarbazine alone. Immunotherapy with high-dose interleukin-2, has produced durable complete responses in a small percentage of patients, and combinations of cisplatin-based chemotherapy and interleukin-2-based immunotherapy have produced responses in approximately 50% of patients with 10% durable complete responses. These encouraging results have prompted the design and initiation of several phase III trials comparing various combination biochemotherapy regimens to either chemotherapy or immunotherapy alone. Several new cytotoxic and biologic agents including specific vaccines have recently been investigated, which may add to the therapeutic armamentarium. This article reviews the promising new developments in the treatment of metastatic melanoma, and it places them within in the context of established treatment approaches for this disease.
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PMID:The treatment of metastatic melanoma with chemotherapy and biologics. 916 97

We have established a sensitive ELISPOT assay measuring interferon gamma (IFN gamma) release on a single-cell basis to detect influenza peptide-specific CD8+ T cells in uncultured peripheral blood mononuclear cells (PBMC). Using this method, we studied the T cell response to HLA-A1 and HLA-A2.1 binding peptide epitopes derived from the MAGE-1 and MAGE-3 proteins, from the melanoma-associated antigens tyrosinase, Melan-A/MART-1 and gp100, and from influenza proteins in stage IV melanoma patients and healthy controls. In 18 of 24 HLA-A2-positive donors (75%), but only in 9 of 25 HLA-A2-positive melanoma patients (36%) T cells reactive with the influenza matrix peptide were demonstrated (p = 0.007). T cells responding to one or several of the melanoma-associated peptides were detected in 5 of 25 HLA-A2-positive patients with metastatic melanoma. Four of these 5 patients had been treated with interleukin-2- and IFN alpha-containing therapy. Two of the 24 healthy donors had T cells reactive with the MART-1 27-35 peptide. No reactivity with the HLA-A1-binding peptides from MAGE-1 or MAGE-3 was detected in any of the HLA-A1-positive healthy controls or melanoma patients. These results show that the IFN gamma-ELISPOT assay is suitable to determine quantitatively T cells reactive with melanoma-associated and influenza peptide epitopes in uncultured PBMC. The failure to detect T cells responding to influenza in many melanoma patients with progressive disease may indicate an impairment of their T cell function.
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PMID:Analysis of the T cell response to tumor and viral peptide antigens by an IFNgamma-ELISPOT assay. 918 91

The administration of high-dose interleukin-2 (IL-2) causes tumor regression in 17-25% of patients with metastatic melanoma or renal cell carcinoma. Renal dysfunction is a common dose-limiting toxicity of IL-2 administration, limiting 26% of treatment cycles. We have conducted a prospective randomized trial to evaluate whether the prophylactic administration of low-dose dopamine (2 mg/kg/min) can minimize renal toxicity and thus affect the amount of IL-2 administered. Forty-two patients were randomly assigned to receive systemic high-dose IL-2 with standard supportive measures (group A = 21 patients) or with the addition of prophylactic dopamine (group B = 21 patients) at 2 mg/kg/min. For patients in group B, dopamine was instituted 1 h before the initiation of IL-2 administration and was discontinued 6-12 h after the maximum number of doses of IL-2 were given. There was no difference in the amount of IL-2 administered for each course of therapy for groups A and B. Despite differences in urine flow (milliliters per kilogram per day), fluid balance (liters per day), and overall weight gain, prophylactic low-dose dopamine did not significantly alter maximum plasma urea or creatinine levels in group B when compared with the control group (group A). The overall toxicity profile considering all grade 3 and 4 toxicities for patients in groups A and B was comparable. Thus, there is no evidence to support the routine use of prophylactic low-dose dopamine in patients receiving high-dose IL-2.
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PMID:A prospective randomized evaluation of the prophylactic use of low-dose dopamine in cancer patients receiving interleukin-2. 922 Mar 19

From January 1994 to July 1996 we immunized metastatic melanoma patients with HLA-A2-compatible, interleukin-2 (IL-2)-secreting, immunogenic melanoma lines in an attempt to induce a systemic reaction that might also affect distant melanoma lesions. Twelve patients (6 male and 6 female) aged from 28 to 72 years, affected with visceral and/or subcutaneous (s.c.) melanoma metastases, were treated. Two different HLA-A2+ melanoma lines were transduced with the human IL-2 gene (14932/IL-2 and 1B6/IL-2) and used as vaccine. Two groups of 4 patients each were injected s.c. with 5 x 10(7) and 15 x 10(7) irradiated 14932/IL-2 melanoma cells respectively, whereas a third group received 5 x 10(7) cells of the second line (1B6/IL-2). All patients received the vaccine on days 1, 13, 26; if no progression was evident, further immunizations were administered at monthly intervals. All patients were assessable for clinical response after at least three injections of the vaccine. In 4 cases a stabilization of disease lasting from 2 to 6 months was observed: in 2 of them a mixed type of response to treatment was noted with simultaneous evidence of regressing and non-responding lesions in the same patients. No signs of clinical response were found in the remaining patients. Nine patients died of disease between 3 and 24 months after the onset of therapy, whereas 3 were alive 3 months after the end of therapy. The local and systemic side-effects of treatment were mild. These results indicate that vaccination with cells bearing the appropriate antigens and releasing IL-2 locally can produce weak clinical responses, but also indicate that better results may be achieved through modifications of the vaccine, the schedule of immunization and/or a more appropriate selection of patients.
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PMID:Active immunization of metastatic melanoma patients with interleukin-2-transduced allogeneic melanoma cells: evaluation of efficacy and tolerability. 922 77

A novel strategy for enhancing the efficacy of immunotherapy with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) in human neoplasia is presented. IL-2 and IFN-alpha are potent activators of the antitumour activity of natural killer (NK) cells but only rarely reduce the tumour burden in treated patients. Recent studies suggest that a reason why these cytokines are insufficiently effective in human cancer is that phagocytes inhibit the tumour-killing activity of NK cells at the site of the tumour. Histamine prevents the phagocyte-induced, NK cell-inhibiting signal; thus, histamine and IL-2 or histamine and IFN-alpha synergize to induce NK cell-mediated killing of human tumour cells in vitro. Further, treatment of tumour-bearing mice with histamine enhances IL-2- and IFN-alpha-induced destruction of NK cell-sensitive tumour cells in vivo. More than 50 patients with neoplastic disease have been treated with histamine, given in subcutaneous injections, together with IL-2 or IFN-alpha. The results of two pilot trials in metastatic melanoma suggest that the addition of histamine to IL-2 and IFN-alpha prolongs survival time and induces regression of tumours, such as liver melanoma, which are otherwise considered refractory to immunotherapy. The results of a trial in acute myelogenous leukaemia (AML) suggest that histamine and IL-2 protects AML patients against relapse of leukaemic disease. Histamine is well tolerated: for example, AML patients in remission have treated themselves with histamine at home without supervision for a total of > 300 weeks with only a handful of therapy-related hospital contacts. Controlled trials in melanoma and AML are under way to further investigate the putative benefit of histamine in neoplastic disease.
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PMID:Histamine in cancer immunotherapy. 923 54

A cell line (UISO-H-MEL-2) was established from the neoplastic cells of a patient with malignant melanoma during the natural course of the patient's treatment. The melanoma cells express defined MHC Class I histocompatibility determinants including determinants specified by the HLA-A2 Class I allele, along with a common melanoma-associated T-cell epitope derived from the tyrosinase gene. The gene for human interleukin-2 (IL-2) was transduced into the cells with a provirus (pZipNeoSVIL-2), packaged in GP + envAM12 cells. Integration of the IL-2 gene into genomic DNA of the transduced cells and its expression were established. The IL-2-secreting cell line (UISO-H-MEL-2-IL-2) was found to be free of recombinant retroviruses and other infectious agents. The IL-2-secreting cells will be subjected to 5000 rads X-irradiation and administered to 12 informed patients with metastatic malignant melanoma in a Phase I toxicity study. The dose of X-irradiation was sufficient to inactivate one hundred percent of the cells, but insufficient to completely inhibit IL-2 synthesis during a fourteen-day period of analysis. Patients who have failed all standard forms of treatment will become eligible for inclusion in the study if they develop metastatic melanoma, and if their tumor cells express products of the tyrosinase gene. The patients will differ with the cellular immunogen at no less than three of six MHC Class I alleles, but will share identity at the HLA-A2 Class I allele. The patient's antimelanoma immune response to the injected cells will be determined by both in vivo and in vitro parameters. Background studies performed in inbred mice indicate that X-irradiated IL-2-secreting cells that express both melanoma-associated antigens and allogeneic Class I histocompatibility antigens are more antigenic in terms of their capacity to induce an antimelanoma response than X-irradiated IL-2-secreting melanoma cells. Of significance for the future potential of this form of therapy in melanoma patients, the period of survival of mice was established melanoma treated with the IL-2-secreting allogeneic cells was significantly (P < 0.001) longer than that of untreated animals, or animals treated with X-irradiated melanoma cells. An analogous protocol was reviewed and approved by the Recombinant DNA Advisory Committee of the National Institutes of Health.
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PMID:Phase I evaluation of interleukin-2-transfected irradiated allogeneic melanoma for the treatment of metastatic melanoma: appendix 1: protocol. 932 73

An open, multicentre non-randomised study was performed to evaluate the activity and toxicity of combination chemoimmunotherapy, consisting of cisplatin, interleukin-2 and interferon-alpha, in metastatic malignant melanoma. Between March 1992 and September 1993, 28 patients with pathologically proven metastatic malignant melanoma, bidimensionally measurable disease and an Eastern Co-operative Oncology Group score < or = 1 were treated with the combination chemoimmunotherapy. The regimen consisted of cisplatin (100 mg/m2 on day 0), interleukin-2 (Proleukin, Chiron, Middlesex, U.K.) 18 x 10(6)IU/m2/d continuous intravenous infusion on days 3-7 and 17-22, with interferon-alpha (Roferon-A, Roche, Hertfordshire, U.K.) 9 x 10(6) U/d subcutaneously on days 3, 5, 7, 17, 19, 21 during the interleukin-2 infusions. The treatment cycle lasted 28 days. Among 27 assessable patients, 5 patients achieved partial responses, for an overall response rate of 18% (95% CI 6-37%). Median progression-free survival was 44 days (range 8-279) and median overall survival was 264 days (range 41-1432). Differential responses were noted in 41% of patients and responses were more frequent in non-visceral disease (skin, lymph node and soft tissue disease) (P = 0.04). These results indicate that differential responses to chemoimmunotherapy are common in patients with metastatic melanoma. This may account for the broad range of response rates reported in the literature.
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PMID:Differential responses to chemoimmunotherapy in patients with metastatic malignant melanoma. 933 79


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