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)

The expression of gamma/delta T cell antigen receptors (TcR) in T cell lines or clones derived from tumor-infiltrating lymphocytes (TIL) from patients with solid tumors was investigated. gamma/delta TcR T cell lines were derived from TIL from patients with Wilms tumor, sarcoma or metastatic melanoma by stimulation with autologous tumor cells alone and recombinant interleukin 2 and they exhibited nonspecific cytotoxicity against autologous and allogeneic tumor cells, or cells of the K562 or the MEL21 tumor cell lines. Two T cell lines were derived from a patient with Wilms tumor. One of them expressed a non-disulfide-linked gamma/delta TcR using the 60-kDa gamma chain, whereas, the other expressed a disulfide-linked gamma/delta TcR. A T cell line was derived from a patient with sarcoma and expressed a disulfide-linked gamma/delta TcR, whereas, a T cell line derived from a patient with melanoma expressed a non-disulfide-linked gamma chain of 62 kDa. Several T cell clones were developed from patients with metastatic melanoma or Wilms tumor and expressed either disulfide- or non-disulfide-linked gamma/delta TcR. Northern analysis of RNA from certain of these clones revealed a full-length gamma chain transcript, whereas, the alpha or beta chain transcripts were either absent or truncated. These T cell clones exhibited nonspecific cytotoxicity. Both disulfide- and non-disulfide-linked TIL T cell lines and clones expressed the delta TCS1 determinant. gamma/delta TcR+ cells in freshly prepared TIL from these patients were present in low proportions (less than 5%) and their delta TCS1/delta 1 ratios were within the range observed in the peripheral blood of normal donors. These results demonstrate that both disulfide- and non-disulfide-linked gamma/delta TcR are expressed on T cell lines and clones derived from TIL from solid tumors. Non-disulfide-linked gamma/delta TcR using the 56-66-kDa gamma chain are frequently found on TIL-derived T cell lines and clones. These 56-66-kDa gamma chains are rarely expressed on T cell lines or clones derived from peripheral blood lymphocytes of normal donors.
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PMID:Gamma/delta T cell antigen receptors expressed on tumor-infiltrating lymphocytes from patients with solid tumors. 131 72

The administration of anti-melanoma murine monoclonal antibody (MAB) 16.C8 (IgG2a) to nude mice bearing established human melanoma lung or liver metastases resulted in a significant inhibition of tumour growth. A total dose of 2 mg of affinity purified 16.C8 caused complete inhibition of tumour growth in 89 and 100% of animals in the liver and lung model, respectively. In contrast, a significant tumour growth was found in most control animals which received an irrelevant IgG2a MAB or 2% human serum albumin in Hanks Balanced Salt Solution (HBSS). The MAB was most effective when treatment was started on day 1 or 4 following tumour inoculation. When the 16.C8 MAB treatment was delayed 7 or 14 days, 33 and 67% of 16.C8 treated animals, respectively, developed tumours. The MAB-mediated anti-tumour activity appeared to be dose dependent, and the effect of a suboptimal dose was potentiated by the concomitant administration of recombinant interleukin 2 (rIL-2). Recombinant IL-2 alone in a similar dose did not elicit comparable anti-tumour activity. Moreover, the MAB 16.C8 inhibited tumour growth in irradiated animals which may suggest the involvement of host-radioresistant cellular elements in the 16.C8 antibody-mediated anti-tumour activities in nude mice. These results suggest that MAB 16.C8 alone or combined with rIL-2 may prove useful in the immunotherapy of metastatic melanoma.
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PMID:Inhibition of the growth of human melanoma metastases in nude mice by melanoma-specific murine monoclonal antibody. 134 Dec 42

Peripheral blood lymphocytes from 146 patients with metastatic melanoma undergoing interleukin 2 (IL-2)-based immunotherapy were characterized for HLA A, B, Cw, DR, DQw, and DRw specificities. Patients had been enrolled into sequential treatment protocols with either IL-2 alone (28) or in combination with tumor-infiltrating lymphocytes (TILs) (86), alpha-interferon (26), lymphokine-activated killer cells (16), radiation therapy (7), cyclophosphamide (3), tumor necrosis factor (1), and interleukin 4 (1) for a total of 168 courses of therapy. HLA phenotype was then correlated with response rate and toxicity to IL-2. We noted: (a) a significant difference in the frequency of A11 (20.5% versus 10.2%; P < 0.05) allele between melanoma patients and the North American Caucasian population; (b) a significantly higher frequency of A11 phenotype among responders (40.5%) than in the melanoma patient population (20.5%; P < 0.01), which was even more obvious among patients responding to TIL therapy (47.4% versus 22.1%; P < 0.05); within TIL patients, responders also had an increased frequency of A19 (42.1% versus 25.6%; P < 0.05); (c) a correlation between the number of TILs received and response rate (P < 0.005); and (d) an association between DR4 haplotype and decreased tolerance to IL-2 among the patients receiving TILs (P = 0.01). These results suggest that, in melanoma patients, some HLA Class I specificities may predict for a greater likelihood of response to IL-2-based therapy, while HLA Class II phenotype correlates with tolerance to the combination of TIL and IL-2 therapy.
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PMID:HLA association with response and toxicity in melanoma patients treated with interleukin 2-based immunotherapy. 142 1

Adherent lymphokine-activated killer (A-LAK) cells, selected from peripheral blood lymphocytes (PBL) of normal human donors by adherence to plastic, and cultured in the presence of interleukin 2 (IL-2), are highly enriched in CD3-CD56+ natural killer (NK) cells. These IL-2-activated NK cells proliferate extensively upon further culture in conditioned medium containing IL-2. In contrast, we previously found that with PBL of some patients with advanced cancer, the same procedure often failed to yield high enrichment of NK cells or substantial expansion in the numbers of these effector cells. To obtain sufficient numbers of A-LAK cells for adoptive immunotherapy in cancer patients, an improved method for generation of human A-LAK cells with irradiated mitogen-stimulated allogeneic PBL- or Epstein-Barr virus-transformed lymphoblastoid cell lines was introduced. In paired experiments, A-LAK cultures with feeder cells showed significantly enhanced IL-2-driven proliferation of A-LAK cells obtained from normal donors or patients with metastatic melanoma, renal cell carcinoma, and other types of solid cancers. The growth-promoting effect of feeders for A-LAK cells resulted in significantly improved expansion of CD3-CD56+ (NK) effector cells in A-LAK cultures established from normal donors. Cells in these cultures also had significantly higher levels of antitumor cytotoxicity against K562 and Daudi targets than did A-LAK cells grown in the absence of feeder cells. Enrichment in CD3-CD56+ cells and antitumor activity also occurred in patient A-LAK cultures supplemented with mitogen-stimulated feeder cells, but was not statistically significant. Overall, despite improved proliferation and CD3-CD56+ cell content of A-LAK cultures established in the presence of mitogen-activated feeder cells, only 39% (21/54) of patients tested generated A-LAK cells that would be judged acceptable for large-scale therapeutic use by criteria based on fold expansion and purity of A-LAK cells. These results suggest that in comparison to normal individuals, NK cells of many patients with advanced solid tumors are defective in their ability to respond by proliferation to IL-2 even in the presence of exogenously supplied growth factors.
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PMID:Depressed ability of patients with melanoma or renal cell carcinoma to generate adherent lymphokine-activated killer cells. 179 Jan 41

Immunotherapy with tumor-infiltrating lymphocytes (TIL) activated in the presence of recombinant interleukin 2 (IL2) in vitro and adoptively transferred to patients with metastatic melanoma or renal cell carcinoma has resulted in complete or partial responses in some cases. These results have generated a wave of optimism and expectations, which may be premature. Much has been learned about TIL biology and their functional characteristics recently, but only few clinical trials have been completed to date. In this review, therapeutic potential of human TIL is evaluated based on limited knowledge of the antitumor mechanisms involved and imperfect understanding of events which occur during systemic administration of TIL. Limitations and advantages of TIL therapy are discussed and approaches to optimizing this form of therapy which are likely to be implemented in the future are summarized.
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PMID:Cancer therapy with tumor-infiltrating lymphocytes: evaluation of potential and limitations. 181 Apr 38

The purpose of this study was to evaluate the efficacy and safety of a continuous-infusion interleukin 2 (IL-2) regimen for patients with metastatic melanoma and renal cell cancer. To investigate the contribution of adoptively transferred lymphokine-activated killer cells, patients were randomized to receive either IL-2 alone or IL-2 plus lymphokine-activated killer cells. Twenty-three patients with renal cell carcinoma and 20 with melanoma were entered into the protocol. There were no objective responses noted in the 38 assessable patients (20 with renal cell carcinoma, 18 with melanoma). Most patients demonstrated progressive disease following one 31-day cycle of weekly continuous-infusion IL-2. Grade I and II toxic reactions, including fever, rash, anorexia, and weight gain, were common and treated symptomatically. Significant in vivo stimulation of lymphokine-activated killer and natural killer cell activity was noted in most patients. This continuous-infusion IL-2 regimen with or without lymphokine-activated killer cells was ineffective in the treatment of melanoma and renal cell carcinoma.
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PMID:Randomized study of interleukin 2 (IL-2) alone vs IL-2 plus lymphokine-activated killer cells for treatment of melanoma and renal cell cancer. 185 52

T cell lines and clones with autologous tumor-specific activity have been developed in malignant melanoma by stimulating peripheral blood lymphocytes (PBL), lymph node lymphocytes or tumor-infiltrating lymphocytes (TIL) with autologous melanoma cells in the presence of recombinant interleukin 2 (rIL2). T-cell lines and clones have been developed with specific cytotoxicity and/or proliferative responses for autologous melanoma targets but not for allogeneic melanoma tumor cells, autologous normal cells or natural killer (NK)-sensitive targets. The concentration of rIL2 is critical for the generation of autologous tumor-specific T-cell lines, with low rIL2 concentrations (up to 800 IU/ml) facilitating the growth of T-cell lines with tumor-specific activity. The alpha beta T-cell receptor (TCR) and the CD3 antigen are involved in specific cytotoxicity and/or proliferative responses of these T-cell lines and clones. An oligoclonal pattern of beta-chain TCR gene rearrangements was observed on T-cell lines and clones with autologous tumor-specific cytotoxicity, suggesting that they are comprised of T cells that have undergone a clonal expansion in response to particular antigen. Autologous tumor-specific cytotoxic T cells are HLA-restricted and recognize on the melanoma tumor cells HLA Class I or possibly Class II antigens plus a tumor-specific determinant. TIL from patients with metastatic melanoma have unique characteristics in comparison with PBL and lymph node lymphocytes and they appear to contain substantial proportions of T cells that have been locally sensitized to autologous tumor cells. Single stimulation of TIL with autologous tumor cells in the presence of rIL2 is sufficient for the generation of T cell lines with autologous tumor-specific activity, whereas, multiple stimulation of PBL and lymph node lymphocytes was required to achieve the same purpose. TIL-derived T cell lines have been expanded in rIL2 in vitro by at least 1,500-fold without losing their activity. Approximately, 40% of the patients exhibited complete or partial responses to adoptive immunotherapy with melanoma TIL and rIL2.
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PMID:Human autologous tumor-specific T cells in malignant melanoma. 187 55

Conventional treatment for metastatic melanoma consists of surgical resection, chemotherapy, and radiation therapy. New approaches toward treatment of this disease include the development of passive and active immunotherapeutic regimens. Malignant melanoma is particularly amendable to immunotherapy since the tumor is relatively immunogenic, expressing unique cell surface protein and lipid antigens. Clinical trials investigating the benefit of active specific immunotherapy documented increased survival of invasive Stage 1 and metastatic Stage 2 melanoma patients following immunization with tumor cell vaccines and BCG. Additional trials showed that the development of specific antibodies after immunization of Stage 2 patients with a viral oncolysate was correlated with an increased survival compared to matched controls given only BCG. Passive immunotherapy approaches using either lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) administered with interleukin 2 have also resulted in regression of disease with complete or partial remissions occurring in 25% of the patients. Additional studies have focused on the generation of specific cytotoxic T lymphocytes by stimulation with autologous tumor in vivo. Future trials will evaluate the therapeutic efficacy of these specific cytologic T lymphocytes relative to LAK and TIL.
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PMID:Experimental trials of immunotherapy for malignant melanoma. 192 50

In vitro culture of metastatic melanoma fragments with 150 units of recombinant interleukin 2 resulted in the successive expansion of CD4+ and then CD8+ tumor-infiltrating lymphocytes (TIL) throughout a 2-month period. TIL cultured for 43 days and consisting of 95% CD8+ and 10% CD4+ T lymphocytes were cloned by limiting dilution (LD). Thirteen CD8+ and thirty-one CD4+ clones were obtained, indicating that the frequency of clonogenic CD8+ proliferative T lymphocytes was much lower than that of their CD4+ homologues. When LD was performed in the presence of autologous melanoma cells the frequency of CD8+ clones was increased by factor 4. The DNA from TIL of day 43 bulk culture and of six CD8+ clones was hybridized with T cell receptor (TcR) beta and gamma probes. Identical configuration of the nonfunctional gamma and functional beta TcR genes was found in "bulk culture" and cloned TIL. The CD8+ clones therefore derived from a clonal population of CD8+ cells which had expanded in vitro before the LD. All the CD8+ clones tested were strongly cytotoxic for autologous melanoma cells but did not kill autologous fibroblasts or concanavalin A blasts, or any of the 10 allogeneic tumor targets tested, including 5 melanomas, 2 breast cell lines, 1 neuroblastoma, K-562 and the Epstein-Barr virus-transformed cell line used as a feeder. Furthermore, specific killing was inhibited by monoclonal antibodies against CD3, CD8, TcR alpha/beta and against class I major histocompatibility complex antigens indicating that these cytotoxic T lymphocyte clones recognized autologous tumor cells through the TcR, in an HLA class I-restricted manner. These data show that it is feasible to obtain tumor-specific cytotoxic T lymphocytes from melanoma TIL with a simple culture technique and that a single clone could be expanded to more than 10(10) cells which should allow testing of immunotherapeutic potential of these cells by adoptive transfer into melanoma patients.
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PMID:Selective expansion of a specific anti-tumor CD8+ cytotoxic T lymphocyte clone in the bulk culture of tumor-infiltrating lymphocytes from a melanoma patient: cytotoxic activity and T cell receptor gene rearrangements. 197 94

We investigated the effects of human melanoma-specific cytotoxic T lymphocytes in treating experimental human melanoma hepatic metastases in a nude mouse model of adoptive immunotherapy. Hepatic metastases were generated by intrasplenic injection of 1.5 x 10(6) human melanoma cells. Three days after injection, animals received salt solution and interleukin 2 or interleukin 2 and cytotoxic T lymphocytes. Twenty-four of 25 control animals had developed multiple tumor nodules in the liver; 11 of 13 animals receiving only interleukin 2 also had significant tumor burdens. In striking contrast, 17 of 18 animals receiving cytotoxic T lymphocytes and interleukin 2 had no gross or histologic evidence of tumors. The remaining animal had a 2-mm nodule. Human tumor-specific cytotoxic T lymphocytes are effective in vivo in a model of adoptive immunotherapy and may prove useful in adoptive immunotherapy of humans with metastatic melanoma.
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PMID:Treatment of human melanoma hepatic metastases in nude mice with human cytotoxic T lymphocytes. 200 57


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