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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The National Biotherapy Study Group (NBSG) conducted a broad phase II trial using interleukin-2 (IL-2) by continuous infusion and alpha interferon (IFN) subcutaneously in 267 patients with a variety of advanced cancers, including 29 with breast cancer, 89 with renal cancer, and 69 with melanoma. IL-2 [18 million international units (MIU)/m2] was given by continuous infusion for 108 hours with 3 mu/m2 subcutaneous IFN every other day during the IL-2 infusion. The patients were treated for 1 week followed by a 2-week rest. After two cycles of treatment, patients were evaluated for response. Of the 237 patients evaluable for response, 20 (8%) had a complete or partial response and 128 (54%) were stable. Therefore, 62% of the evaluable patients were nonprogressive during the first 90 days of IL-2/IFN therapy. The objective response rate was 11% in melanoma, 7% in renal cancer, 14% in breast cancer, and 3% in patients with a variety of malignancies for an overall response rate of 7% in these patients with advanced cancer. The patients were treated on a general medical ward and tolerated treatment well with fatigue and fever being nearly universal. Dyspnea, pruritus, chills, and elevated creatinines were frequent but less common. This combination biotherapy regimen has minimal activity in a variety of advanced cancers and must be compared with the best existing chemotherapy for each cancer type in randomized, prospective trials.
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PMID:Combination biotherapy utilizing interleukin-2 and alpha interferon in patients with advanced cancer: a National Biotherapy Study Group Trial. 162 72

There is a theoretical basis for the synergy of interleukin-2 (IL-2) with other cytokines. We have investigated sequential treatment with IL-2 and alpha interferon. 1 of 22 patients with metastatic renal cell carcinoma had a partial response and one a minimal response to continuous infusion IL-2 but none of the 9 patients with melanoma responded. 16 of 17 patients with renal cell cancer, and 8 with melanoma, were then treated with alpha interferon. 2 patients with renal cell cancer responded to alpha interferon with sustained remissions of 30 and 40 months; both had responded to IL-2. The investigation of combination therapy with other cytokines is suggested, by these unusually long responses to alpha interferon.
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PMID:Sequential interleukin-2 and alpha interferon for renal cell carcinoma and melanoma. 162 71

22 cancer patients entered a randomised phase Ib trial comparing the effects of low-dose recombinant interleukin-2 (300 micrograms/m2, approximately equivalent to 6.4 x 10(6) cetus units or 38 x 10(6) U per day) given continuously by intravenous or subcutaneous infusion. At 48 h after two 5-day courses, median lymphocyte levels (x 10(9)/l) were 6.0 (387% increase) in the subcutaneous arm (n = 9) and 5.9 (369% increase) in the intravenous arm (n = 8). Liver and renal toxicity were similar in the two groups. One minor response lasting 4 months occurred in 12 renal cancer/melanoma patients receiving subcutaneous treatment and one durable complete remission continuing at 30 months and one minor response lasting 10 months occurred in 6 renal cancer/melanoma patients receiving intravenous treatment.
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PMID:Phase I study comparing continuous infusion of recombinant interleukin-2 by subcutaneous or intravenous administration. 162 72

The antitumor effects of recombinant interleukin-2 (rIL-2) and mismatched double-stranded RNA (dsRNA) were assessed in tissue culture and in a nude mouse model. Mismatched dsRNA did not show a direct antiproliferative effect against the human malignant melanoma cell line, BRO, in tissue culture. However, treatment of the BRO cells with up to 1000 units/ml rIL-2 in culture showed a slight increase in growth rate. Combined rIL-2/mismatched dsRNA treatment also demonstrated a similar slight enhancement of growth. Nude mice bearing subcutaneous tumors were treated by intraperitoneal injection of low doses (5000-20,000 units) of rIL-2 and mismatched dsRNA (500 micrograms). The in vivo tumor growth was significantly inhibited by the combined treatments (P less than 0.05) and survival was significantly increased (P less than 0.05). Measurement of cytotoxicity using splenocytes from treated animals showed significant augmentation of lytic activity against natural killer (NK)-sensitive YAC-1 cells in all rIL-2/mismatched dsRNA treatment groups, compared to the individual treatments or controls (P less than 0.05). Cytotoxicity of the splenocytes against the NK-resistant BRO cells was also augmented in animals treated with mismatched dsRNA and the highest rIL-2 dose utilized here (P less than 0.01). Renal, liver, and hematological toxicity was evaluated by measurement of blood urea nitrogen, creatinine, serum asparrtate aminotransferase, and a complete blood count with differential. There were no significant differences in these parameters in any of the treatment groups. Similarly, no differences in weight of the animals was seen in any treatment group. These results indicate that the combination of low-dose rIL-2 and mismatched dsRNA can potentiate host-mediated antitumor effects, yielding increased survival, without significant toxicity.
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PMID:Antitumor effects of interleukin-2 and mismatched double-stranded RNA, individually and in combination, against a human malignant melanoma xenograft. 163 50

Conventional treatment of cancer, especially for patients with metastatic melanoma tumor, is often ineffective. Immunotherapy and recently introduced gene therapy have revolutionized the treatments of patients with metastatic melanoma tumor. Use of biological response modifiers, such as interleukins and interferons, have been found to enhance therapeutic benefits to patients with malignant melanoma. Initial studies with a high-dose interleukin-2 (IL-2) therapy have proved effective in patients with melanoma tumor, although a variety of systemic toxicities were observed. A low-dose IL-2 continuous infusion has shown a similar response in patients with melanoma tumor, but produced lesser toxicity. The low-dose IL-2 therapy has been studied with an adoptive transfer combined with either autologous lymphokine activated killer cells or autologous tumor infiltrating lymphocytes (TIL). IL-2 in combination with chemotherapeutic agents such as flavone acetic acid, dacarbazine, and cyclophosphamide have also been studied in patients with metastatic melanoma. Results have shown a moderate response in patients with metastatic melanoma. TIL therapy, however, has been shown to result in higher objective regression due to potent tumor-specific killing and tumor-specific targeting characters of the TIL. The tumor targeting nature of the TIL creates the possibility of using TIL as a vehicle to deliver gene product specifically to tumor tissue. Safety and toxicity of gene-transduced TIL were addressed by the use of neomycin-resistant, gene-transduced TIL in patients with metastatic melanoma. We also investigated the use of vaccinia oncolysate therapy by using the viral oncolysate prepared with IL-2 gene encoded vaccinia virus. Preliminary studies with murine hepatic metastases colon model have shown encouraging results.
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PMID:Prospects for gene therapy and lymphokine therapy for metastatic melanoma. 164 99

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

In this pilot study of metastatic melanoma, interleukin-2 (IL-2) and cisplatin (CDDP) chemotherapy were combined using an alternating schedule designed to explore potential synergism between these modalities. Bolus IL-2 was given at a dose of 600,000 IU/kg intravenously (IV) every 8 hours, days 1 to 5 and 15 to 19, followed by high-dose CDDP administered by two different regimens: (A) 135 to 150 mg/m2 IV bolus over 30 minutes with the chemoprotectant WR-2721 910 mg/m2 or (B) 50 mg/m2 IV over 2 hours every day for 3 days. The trial design allowed an assessment of response to each phase of therapy. Among 27 assessable patients, there were 10 (37%) overall responses, including three (11%) complete responses (CRs) with durations of 9, 16, and 30+ months. Tumor regression was noted in seven patients (partial response [PR], four; minor response [MR], three; response rate [RR], four of 27 [15%]) after IL-2 administration and in 14 patients (PR, 12; MR, two; RR, 12 of 27 [44%]) after CDDP treatment, demonstrating noncrossresistance between the components of the regimen. Major PRs (greater than 90% reduction of tumor burden) or CRs were only seen in patients responding to IL-2. Toxicity during IL-2 therapy was typical for high-dose IL-2 protocols and was reversible. Among the first 20 patients treated with CDDP regimen A, there were eight episodes of grade IV nephrotoxicity (creatinine level greater than 5.0 mg/dL), including three of six patients treated with an initial CDDP dose of 135 mg/m2. This side effect was more frequent among patients with liver metastasis (P less than .05, Fisher's exact test). No significant nephrotoxicity was noted in seven patients treated on regimen B. Although ototoxicity was frequent, minimal bone marrow and neurologic toxicity was noted. There were no treatment-related deaths. This combination showed at least additive activity against melanoma, and the more protracted CDDP schedule was well tolerated. This regimen may serve as a model for future combined immunotherapy and chemotherapy trials in metastatic melanoma.
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PMID:Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study. 165 88

Twelve autologous mixed peripheral blood (PBL) tumor cell interactions (MLTC) followed by in vitro expansion of the stimulated T cells in recombinant interleukin-2 (IL-2) were analyzed for the potential emergence of oligoclonal or monoclonal T cell populations in the PBL by Southern blot analysis of the T cell receptor (TCR) beta gene. The emergence of oligoclonal or monoclonal TCR beta gene rearranged populations was seen in 5 of the 12 cases. In 2 of these 5 cases only one dominantly rearranged band was observed. The emergence of oligoclonal or monoclonal T cell populations following stimulation with autologous melanoma cells was associated with predominant CD4 phenotype of the stimulated PBL exhibiting a varied degree of cytotoxicity toward the respective autologous melanoma cells. The evidence of emergence of monoclonal or oligoclonal T cell populations following stimulation with autologous tumor cells strongly supports the existence of T cell-mediated responses against autologous melanomas. Furthermore, cellular and molecular analyses of T cell responses in autologous mixed lymphocyte tumor cell interactions will provide valuable information on the nature of the T cell responses and on the pattern of gene segment usages by the T cells in response to the autologous tumor cells.
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PMID:Clonal expansion of T cells following in vitro stimulation with autologous melanoma cells and interleukin-2 studied by molecular analysis of a T cell receptor. 167 14

A range of potent immunoregulatory molecules termed cytokines has become available for the therapy of human melanoma. Among the cytokines, the interferons (IFN) have been examined in great depth for the therapy of melanoma. IFN are able to modulate host effector cell function, including the tumor cytolytic function of lymphocytes and monocytes. IFN also have the capacity to regulate the distribution of circulating immunoregulatory (T) lymphocytes and the expression of tumor cell surface antigens, as well as class I and II products of the major histocompatibility locus. These activities of the IFN have led to their early application for treatment of human melanoma. The empirical evidence that IFN alpha exerts clinically significant anti-tumor effects against melanoma is reviewed, and evolving status of adjuvant trials of IFN alpha and gamma is noted. New indirect host-mediated anti-tumor activities that may potentially be manifest by IFN have yet to be fully harnessed. The opportunity to obtain meaningful anti-tumor activity in advanced disease or adjuvant settings, at dose ranges below those which are toxic (conventional maximal tolerable), are at hand. The U.S. cooperative groups [Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), and South West Oncology Group (SWOG)] are studying IFN gamma in pursuit of this goal in advanced and adjuvant settings for melanoma and other tumors. The determination of the clinical role of IFN as biologic response modifiers demands equal commitment to the clinical assessment of immunobiologic mechanisms and anti-tumor effects. The immunologic assessment of IFN and a number of other cytokines is a major focus of the Pittsburgh Cancer Institute. Regional delivery of cytokines such as interleukin-2 (IL-2) may be the most appropriate and least toxic approach, given their half-life. Regional therapy by the intralesional route has yielded enhanced activity for a range of biologics, including bacillus Calmette-Guerin (BCG), IL-2, and tumor necrosis factor (TNF). Intralymphatic therapy with methanol extraction residue of BCG (MER-BCG) has been tested, and trials are now in progress with IL-2 to assess the optimal dosage by this route. It is likely that the optimal role of IFN and other cytokines will be found in combination with one another, and with different biologic modalities such as monoclonal antibodies and vaccines, to allow expansion and heightened activity of the desired effector cell populations in the host. Enhanced host toxicities, as well as anti-tumor effects, may require that special attention be devoted to optimal sequence of administration to enhance the therapeutic index.
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PMID:Role of interferons in the therapy of melanoma. 170 5


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