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

Thirty tumour specimens, among which were 17 melanomas, were cultured with recombinant interleukin-2 (IL-2) in order to produce tumour-infiltrating lymphocytes (TIL). In the melanomas, three categories of TIL were characterised. The first, containing mostly CD3+ and CD8+ cells, lysed only autologous tumour cells; the second, containing mostly CD3+ and CD4+ cells, lysed both autologous tumour cells and allogeneic cells lines; the third, with mixed phenotype although cytotoxic for K562 targets, did not kill melanoma cells. The optimal conditions for a good development of TIL were established: we found that the lymph node or cutaneous origin of the tumour was unimportant, a 2 h enzymatic treatment was optimum and that TIL grew well in AIM V serum free medium. Therefore the easiness and the reproducibility of the TIL cultures from melanoma tumour samples allows the rapid development of therapeutic trials in metastatic melanoma.
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PMID:Phenotypic and functional analysis of tumour-infiltrating lymphocytes from patients with melanoma and other metastatic cancers. 159 Oct 49

Systemic chemotherapy for the treatment of metastatic melanoma remains disappointing. Nor new single agent has demonstrated promising results. The combination of cisplatin, decarbazine, carmustine, and tamoxifen appears to be one of the most active regimens with an overall response rate approaching 50%. In some patients, responses have been durable and exceed 3 years. Sequential small phase II trials suggest that tamoxifen is an important component in this combination. The efficacy of the combination of hormonal and chemotherapy, however, needs to be corroborated in a large multicenter phase II trial. In addition, further laboratory and clinical studies are needed to evaluate the role of tamoxifen. Biological response modifiers, such as interleukin-2 and alpha-interferon, have limited activity as single agents, but in combination with cytotoxic agents show some promise and merit further evaluation. Future research should focus on the development of more effective agents, and on the use of aggressive adjuvant and neoadjuvant chemotherapy in high-risk patients with locally advanced disease.
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PMID:Chemotherapy for advanced malignant melanoma. 159 69

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.
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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

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

Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells results in significant tumor regression in patients with advanced cancer. We have investigated the kinetics of circulating erythroid (BFU-E) and granulocytic-macrophage (CFU-GM) progenitors after IL-2 therapy in 11 cancer patients, mainly affected by metastatic melanoma and renal cell carcinoma. Administration of IL-2 from day 1 through day 5 constantly induced a dramatic decrease of the number of circulating BFU-E and CFU-GM, which then showed a striking rebound (up to values fourfold and sevenfold higher, respectively, than the pretherapy levels) on discontinuation of IL-2, ie, from day 5 through day 10. A similar kinetic pattern was observed during and after the second cycle of IL-2 administration. 3[H]-thymidine killing experiments showed that the cycling activity of the progenitors was virtually unmodified in the rebound phases. To explore the mechanism(s) underlying this kinetic pattern, we have analyzed the plasma concentration of several hematopoietic growth factors, including IL-1 beta, IL-3, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and erythropoietin (Ep). No modifications in the levels of IL-3, GM-CSF, or IL-1 beta were observed, whereas a pronounced increase of IL-6 and G-CSF concentration was monitored, starting at day 3 and peaking at day 5 of treatment (a parallel, but modest, increase of Ep level was also observed). The elevation of IL-6 and G-CSF concentration is directly correlated with and may, at least in part, underlie the subsequent rebound of circulating hematopoietic progenitors. Furthermore, the increase in IL-4 level observed at day 10 of therapy may mediate the eosinophilia gradually starting at this stage of treatment.
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PMID:Adoptive immunotherapy with high-dose interleukin-2: kinetics of circulating progenitors correlate with interleukin-6, granulocyte colony-stimulating factor level. 170 62

Twenty patients with biopsy-proven metastatic malignant melanoma, previously treated with interleukin-2 (IL-2), received combination chemotherapy for progressive disease. Treatment included carmustine, cisplatin, dacarbazine, and tamoxifen (BCDT). Nausea was the most common toxicity (100%) and usually was mild. Persistent thrombocytopenia was the most frequent toxicity limiting further treatment. Eleven patients (55%) had an objective partial response, three patients (15%) had a minor response, and six patients (30%) had no change or progressive disease in response to this treatment. These results were comparable to the high response rates (21 of 40, 53%) achieved with BCDT in previously untreated patients with melanoma. It was concluded that prior therapy using IL-2 does not significantly alter the response rate of metastatic melanoma to BCDT, thus suggesting that immunomodulators (e.g., IL-2) and chemotherapeutic agents are not cross-resistant treatments.
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PMID:Effective chemotherapy for melanoma after treatment with interleukin-2. 172 71

We investigated the efficacy of human melanoma-specific cytotoxic T-cells (CTLs) in treating experimental human melanoma metastases in a nude mouse model of adoptive immunotherapy. Hepatic metastases were generated by the intrasplenic injection of 1.5 x 10(6) human melanoma cells. Animals were then randomized to receive saline, interleukin-2 only, or CTLs and interleukin-2. CTLs were effective when administered 3 or 7 days after generation of hepatic metastases, with 96 and 88% of animals disease-free, respectively, when examined at one month. Interleukin-2 alone was not effective. In addition, CTLs were effective when as few as 2.5 x 10(6) T-cells were adoptively transferred. Only 33% of the animals were tumor-free when CTLs were administered on day 10, and CTLs were not effective when given at day 14. Human CTLs that were not cytotoxic for the tumor line used in vivo, when tested in a 51Cr assay, were also not effective in the model of immunotherapy. This suggests that the tumor-specific CTLs maintain their specificity in vivo, and eliminates a nonspecific inflammation directed against the human CTLs as a possible cause of the antitumor effect. These studies lay the foundation for clinical trials of CTLs in the adoptive immunotherapy of patients with metastatic melanoma.
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PMID:Human xenograft-nude mouse model of adoptive immunotherapy with human melanoma-specific cytotoxic T-cells. 172 11

We investigated the immunological properties of interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes (TIL), which were used for adoptive therapy of renal cell carcinoma (RCC) (seven patients) by focusing on natural killer (NK) cells, and metastatic melanoma (six patients) by focusing on cytotoxic T lymphocytes. TIL from five of seven cases proliferated well in culture with AIM-V serum-free medium and 1000 U/ml rIL-2 in 3-L gas permeable bags, whereas TIL from two RCCs exhibited delayed proliferation. Proliferation of CD3-CD56+ NK cells with major histocompatibility complex-nonrestricted cytotoxicity in RCC-TIL (n = 6, mean = 651-fold, ranging from 39- to 3450-fold) for the first 2-4 weeks was 63 times higher than that of noncytotoxic CD3+ T cells (n = 6, 10.3-fold ranging from 0.8 to 35-fold). Thereafter, CD3+ T cells predominantly proliferated, and proliferation of CD3+ T cells (n = 5, 743-fold) for 5-6 weeks were 24 times higher than that of CD3-CD56+ NK cells (n = 5, 31-fold). Significant numbers of RCC-TIL became adherent to the surfaces of the bags several weeks after initiation of culture. These adherent TIL consisted of more CD3-CD56+ NK cells and exhibited higher cytotoxicity than did nonadherent TIL. Adherent RCC-TIL produced interferon (IFN)-gamma, while nonadherent TIL did not. These results suggest that initially cytotoxic CD3-CD56+ NK cells and, later, noncytotoxic CD3+ T cells proliferated in culture of RCC-TIL for adoptive therapy. These noncytotoxic TIL were primarily transferred to RCC patients, who also received cyclophosphamide, IL-2, and IFN-alpha. In contrast to RCC-TIL, IL-2-activated melanoma TIL consisting of all CD3+ T cells displayed modest levels of cytotoxicity, primarily restricted to autologous melanoma cells in all cases tested. The cytotoxic melanoma TIL were adoptively transferred to melanoma patients. Three of seven RCC patients responded to the adoptive therapy.
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PMID:Study of tumor-infiltrating lymphocytes for adoptive therapy of renal cell carcinoma (RCC) and metastatic melanoma: sequential proliferation of cytotoxic natural killer and noncytotoxic T cells in RCC. 179 Jan 39

A patient receiving adoptive immunotherapy with recombinant interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells for metastatic melanoma developed acute renal insufficiency out of proportion to the decrease in her renal perfusion after 4 days of receiving IL-2. On the 8th day of IL-2 and the 3rd day of LAK cell infusion she expired suddenly from an acute intra-abdominal hemorrhage due to rupture of a metastasis. Postmortem examination of the kidneys showed an interstitial infiltrate consisting largely of lymphocytes and concomitant tubulitis. Immunoperoxidase staining of the infiltrating cells with a panel of lymphocyte-specific monoclonal antibodies showed the majority of cells to be T lymphocytes (70-75%), with a more focal infiltrate of B lymphocytes (25-30%) and rare monocytes, granulocytes and natural killer cells. This patient represents the first reported case of acute interstitial nephritis associated with IL-2 immunotherapy. Our finding is consistent with the hypothesis that the acute renal failure that accompanies this therapy may sometimes be due to intrinsic renal disease as well as the usual pre-renal failure. Nephritis may be caused by IL-2-mediated effects on lymphocytes, resulting in renal parenchymal infiltration.
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PMID:Interstitial nephritis in a patient receiving adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells. 181 16


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