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)

Patients with metastatic melanoma were immunized with an immunodominant peptide derived from the gp100 melanoma-melanocyte differentiation Ag that was modified to increase binding to HLA-A+0201. A total of 10 of 11 patients who received the g209-2M peptide alone developed precursors reactive with the native g209 peptide, compared with only 5 of 16 patients who received g209-2M peptide plus IL-2 (p2 = 0.005). Peptide reactivity closely correlated with the recognition of HLA-A+0201 melanoma cells (p < 0. 001). The decrease in immune reactivity when peptide was administered with IL-2 appeared specific for the immunizing peptide, since reactivity to an influenza peptide resulting from prior exposure was not affected. Preexisting antitumor precursors did not decrease when peptide plus IL-2 was administered. The administration of GM-CSF or IL-12 also resulted in a decrease in circulating precursors compared with the administration of peptide alone, though not as great a decrease as that seen with IL-2. Immunization with peptide plus IL-2 did, however, appear to have clinical impact since 6 of the 16 patients (38%) that received peptide plus IL-2 had objective cancer regressions. It thus appeared possible that immunization with peptide plus IL-2 resulted in sequestering or apoptotic destruction of newly activated immune cells at the tumor site. These represent the first detailed studies of the impact of immunization with tumor peptides in conjunction with a variety of cytokines in patients with metastatic cancer.
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PMID:Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine. 1041 76

The aim of this study was to evaluate the toxicity and efficacy of a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with metastatic melanoma. Consecutive patients with metastatic melanoma were enrolled in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon 3 MU subcutaneously three times a week and tamoxifen 20 mg orally were given throughout. Ninety-two patients were included in this study. Patient characteristics in the three groups were well balanced. The three regimens were delivered on an outpatient basis without major toxicity. The toxicities that did occur consisted primarily of flu-like symptoms in the IL-2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No grade IV toxicities were encountered and no treatment-related deaths occurred. The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The median duration of response was 6 months and the median survival was 11 months. According to this phase II randomized trial polychemoimmunotherapy with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has a response rate of 13%.
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PMID:Multi-institutional phase II randomized trial of integrated therapy with cisplatin, dacarbazine, vindesine, subcutaneous interleukin-2, interferon alpha2a and tamoxifen in metastatic melanoma. BREMIM (Biological Response Modifiers in Melanoma). 1059 17

Frequencies of vaccine-responsive T-lymphocyte precursors in peripheral blood mononuclear cells (PBMC) prior to and after administration of peptide-based vaccines in patients with cancer can be measured by limiting-dilution assays (LDA) or by ELISPOT assays. We have used a modified version of the ELISPOT assay to monitor changes in the frequency of gamma interferon (IFN-gamma)-producing T cells in a population of lymphocytes responding to a relevant peptide or a nonspecific stimulator, such as phorbol myristate acetate-ionomycin. Prior to its use for monitoring of patient samples, the assay was validated and found to be comparable to the LDA performed in parallel, using tumor-reactive cytolytic T-lymphocyte (CTL) lines. The sensitivity of the ELISPOT assay was found to be 1/100,000 cells, with an interassay coefficient of variation of 15%, indicating that it could be reliably used for monitoring of changes in the frequency of IFN-gamma-secreting responder cells in noncultured or cultured lymphocyte populations. To establish that the assay is able to detect the T-cell precursor cells responsive to the vaccine, we used CD8(+) T-cell populations positively selected from PBMC of HLA-A2(+) patients with metastatic melanoma, who were treated with dendritic cell-based vaccines containing gp100, MELAN-A/MART-1, tyrosinase, and influenza virus matrix peptides. The frequency of peptide-specific responder T cells ranged from 0 to 1/2,600 before vaccination and increased by at least 1 log unit after vaccination in two patients, one of whom had a clinical response to the vaccine. However, no increases in the frequency of peptide-responsive T cells were observed in noncultured PBMC or PBMC cultured in the presence of the relevant peptides after the melanoma patients enrolled in another trial were treated with the intramuscular peptide vaccine plus MF59 adjuvant. Thus, while the ELISPOT assay was found to be readily applicable to assessments of frequencies of CTL precursors of established CTL lines and ex vivo-amplified PBMC, its usefulness for monitoring of fresh PBMC in patients with cancer was limited. In many of these patients antitumor effector T cells are present at frequencies of lower than 1/100,000 in the peripheral circulation. Serial monitoring of such patients may require prior ex vivo amplification of specific precursor cells.
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PMID:Evaluation of the modified ELISPOT assay for gamma interferon production in cancer patients receiving antitumor vaccines. 1070 85

Immunization to multiple defined tumor antigens for specific immune therapy of human cancer has thus far proven difficult. Eighteen HLA A*0201(+) patients with metastatic melanoma received injections s.c. of CD34(+)progenitor-derived autologous dendritic cells (DCs), which included Langerhans cells. DCs were pulsed with peptides derived from four melanoma antigens [(MelAgs) MelanA/MART-1, tyrosinase, MAGE-3, and gp100], as well as influenza matrix peptide (Flu-MP) and keyhole limpet hemocyanin (KLH) as control antigens. Overall immunological effects were assessed by comparing response profiles using marginal likelihood scores. DC injections were well tolerated except for progressive vitiligo in two patients. DCs induced an immune response to control antigens (KLH, Flu-MP) in 16 of 18 patients. An enhanced immune response to one or more MelAgs was seen in these same 16 patients, including 10 patients who responded to >2 MelAgs. The two patients failing to respond to both control and tumor antigens experienced rapid tumor progression. Of 17 patients with evaluable disease, 6 of 7 patients with immunity to two or less MelAgs had progressive disease 10 weeks after study entry, in contrast to tumor progression in only 1 of 10 patients with immunity to >2 MelAgs. Regression of >1 tumor metastases were observed in seven of these patients. The overall immunity to MelAgs after DC vaccination is associated with clinical outcome (P = 0.015).
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PMID:Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. 1152 40

Allovectin-7 is a gene transfer product consisting of the human leukocyte antigen HLA-B7 gene co-expressed with the beta2-microglobulin gene. Allovectin-7 is being developed as an immunotherapy approach for a variety of malignancies, with special focus on melanoma, and head and neck cancer. Efficacy results in the phase II setting appear to be promising; an 11% systemic response rate among the intent-to-treat population and 15% response rate in the evaluable population was observed in patients with refractory metastatic melanoma with disease limited to skin, lymph nodes and lung. Stable disease was seen in 19.2% of the intent-to-treat population and 25.9% of the evaluable population in the same group of patients. Treatment has been extremely well tolerated with the most common side effects including mild-to-moderate injection site reactions and flu-like symptoms, all of which resolved rapidly and decreased in incidence after the first injection. Current evaluation of the drug includes higher Allovectin-7 doses and injection of multiple tumors in metastatic melanoma patients. A phase III trial comparing Allovectin-7 plus dacarbazine versus dacarbazine in untreated patients with metastatic melanoma has been completed, and preliminary results are soon to be reported. Phase I/II data also indicate promising activity of Alovectin-7 in patients with advanced refractory head and neck squamous cell carcinoma, with 10% of 60 patients achieving partial response and 23% stable disease after one cycle of treatment. Trials of Allovectin-7 as an adjuvant treatment in earlier stages of disease evolution are planned.
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PMID:Technology evaluation: Allovectin-7, Vical. 1188 99

As biologic therapies enter the mainstream for cancer and HIV treatments, clinicians need the knowledge and expertise to safely and competently care for their patients who are undergoing these therapies. This article provides an overview of the immune system, emphasizing the elements that are affected by the biologic agent interleukin 2 (lL-2), lL-2 has been approved for use in the treatment of metastatic renal cell carcinoma and metastatic melanoma. Clinical trials currently are being conducted to determine its use in treating other cancers. The severity of side effects of lL-2 varies with the dose, route, and schedule of administration. The most common effects with all methods of administration are flu-like symptoms. Because the side effects of lL-2 are relatively predictable, clinical pathways offer practical tools for anticipating and managing the toxicities associated with lL-2 administration.
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PMID:Clinical pathways for managing patients receiving interleukin 2. 1190 16

The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) low-dose interleukin-2 (IL2), granulocyte-monocyte colony stimulating factor (GM-CSF) and interferon-alpha 2b (IFN alpha) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150-250 mg m(-2)) for 5 days followed by s.c. IL2 (4 MIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFN alpha (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12-30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8-42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose- and patient-dependent. Lymphocytopenia (grade 3-4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basis.
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PMID:Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFN alpha in patients with metastatic melanoma. 1261 Apr 99

Dendritic cells (DCs) can be utilized either as vectors or as targets for therapy. Patients with metastatic melanoma received CD34-DC vaccine that contains Langerhans' cells and interstitial DCs. DCs were pulsed with MART1, tyrosinase, MAGE3, gp100 and Flu-MP peptides, and KLH. DCs induced an immune response to control antigens in 16/18 patients. An enhanced immune response to 1 or more melanoma antigens (MelAgs) was seen in these 16 patients. The two patients failing to respond experienced rapid tumour progression. Six out of seven patients with immunity to two or fewer MelAgs had progressive disease 10 weeks after study entry, in contrast to tumour progression in only 1/10 patients with immunity to > two MelAgs. Since tumour immunotherapy targets autologous antigens we can learn from systemic autoimmunity such as systemic lupus erythematosus (SLE). As opposed to normal monocytes, SLE monocytes induce proliferation of allogeneic CD4+ T cells. SLE sera induce monocyte differentiation towards DCs in an IFNalpha-dependent mechanism. Spiking autologous serum with IFNalpha reproduces DC differentiation. 50% of SLE patients have high serum levels of IFNalpha, which could explain T/B lymphopenia. Yet, plasmacytoid DCs, a major IFNalpha source, are 80% decreased. pDCs and IFNalpha may play a role in SLE pathogenesis and therapy.
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PMID:Dendritic cells: controllers of the immune system and a new promise for immunotherapy. 1460 22

Between March 1999 and May 2000, 18 HLA-A*0201(+) patients with metastatic melanoma were enrolled in a phase I trial using a dendritic cell (DC) vaccine generated by culturing CD34(+) hematopoietic progenitors. This vaccine includes Langerhans cells. The DC vaccine was loaded with four melanoma peptides (MART-1/MelanA, tyrosinase, MAGE-3, and gp100), Influenza matrix peptide (Flu-MP), and keyhole limpet hemocyanin (KLH). Ten patients received eight vaccinations, one patient received six vaccinations, one patient received five vaccinations, and six patients received four vaccinations. Peptide-specific immunity was measured by IFN-gamma production and tetramer staining in blood mononuclear cells. The estimated median overall survival was 20 months (range: 2-83), and the median event-free survival was 7 months (range: 2-83). As of August 2005, four patients are alive (three patients had M1a disease and one patient had M1c disease). Three of them have had no additional therapy since trial completion; two of them had solitary lymph node metastasis, and one patient had liver metastasis. Patients who survived longer were those who mounted melanoma peptide-specific immunity to at least two melanoma peptides. The present results therefore justify the design of larger follow-up studies to assess the immunological and clinical outcomes in patients with metastatic melanoma vaccinated with peptide-pulsed CD34-derived DCs.
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PMID:Long-term outcomes in patients with metastatic melanoma vaccinated with melanoma peptide-pulsed CD34(+) progenitor-derived dendritic cells. 1633 19

Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 x 10(8) to 3 x 10(11) viral particles (vp). Intratumoral TG1024 injections in combination with dacarbazine (DTIC) were tested in metastatic melanoma in one cohort. No clinical responses were observed at doses below 3 x 10(11) vp. Six local objective responses were recorded in patients receiving 3 x 10(11) vp per treatment [five in metastatic melanoma and one in metastatic squamous cell carcinoma (SCC) of the skin], of which two were complete responses (CRs). Most of the common side effects were injection site reactions and flu-like syndrome. TG1024 dose intensification across cohorts resulted in increased serum IL-2 levels after the injection. Intratumoral TG1024 injection induced pronounced inflammation of the treated lesion, with predominant CD8(+), TIA+ lymphocytic infiltrate. Our results show that intratumoral injections of TG1024 are safe and well tolerated. The clinical activity of TG1024 observed in this study warrants further investigations.
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PMID:Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma. 1838 30


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