Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Precursors of T cells expressing the gamma delta-T cell receptor (TCR1 cells) have been identified in a resting (IL-2 non-responsive) subpopulation of human peripheral blood mononuclear cells (PBMC). Activation of the TCR1 precursor cells into proliferating and cytotoxic cells requires two signals, viz. IL-2 and either activated T cells (autologous or allogeneic) or malignant melanoma cells (MM-170). The activation process is inhibited by 0.1 microgram/ml cyclosporine. CD3 expression on TCR1 precursor cells was low, since the precursor cells were not always adequately depleted by OKT3 plus complement. Natural killer cells were generated from the same resting subpopulation of PBMC and by the same set of activation stimuli as were the TCR1 cells, suggesting a common pathway for activation of both cell types.
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PMID:Resting (IL-2 non-responsive) precursors of human T cell receptor gamma delta-positive cells (TCR1 cells) are activated by a two signal process. 252 11

The activation of murine macrophages by recombinant human interleukin-2 (rH-IL-2) alone or in combination with recombinant human tumour necrosis factor-alpha (rH-TNF) was studied. Mouse peritoneal exudate macrophages were activated in vitro to the tumouricidal state. Macrophage treatment with rH-IL-2 alone slightly enhanced cytotoxic activity against B16 melanoma cells. Synergism was observed when macrophages were treated with rH-IL-2 and rH-TNF, either when applied sequentially or when both agents were given at the same time.
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PMID:Augmentation of recombinant interleukin-2-dependent murine macrophage-mediated tumour cytotoxicity by recombinant tumour necrosis factor-alpha. 262 58

In order to evaluate their divergent effects on binding and lysis of the NCMC, rH IFN-alpha and rH IL-2 were used for the in vitro-preincubation of normal donors' PBL, which were then tested as effector cells against K562 and the long-term cultured melanoma cell line RIMA in the SCCA. Both lymphokines significantly augmented the cytolysis of K562 without relevant influence on the conjugate formation. However, against RIMA IFN-alpha additionally amplified the binding affinity. This in keeping with the other authors' opinion that IFNs have target-specific effects at the single cell level, with the principal activation of already conjugated pre-killer cells against all the target cell lines tested. We performed a therapy-follow-up of the i.p. administration of rH IFN-gamma to patients with ovarian carcinomas in vivo. With the SCCA we detected a significant correlation of the duration of therapy with the autologous cytotoxicity in the ascitic compartment. In one case the increase of this parameter was even exponential. However, the countercurrent trend of the conjugate formation delayed and reduced the activation of the autologous total killer activity. This relative stagnation resulted in the inadequate clinical response of two patients. Moreover, we observed a discrepancy in the development of the autologous and allogeneic SCCA-parameters suggesting strong effects of the peritumorally administered IFN directly on the effusion tumor cells.
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PMID:Autologous and allogenic natural cell mediated cytotoxicity at the single cell level: divergent effects of interferons and interleukin 2 on binding and lysis. 263 34

The clinical data that have been accumulated so far suggests a significant influence of IL-2 dose and schedule on the immunobiological effects and clinical toxicities observed with this cytokine. Consequently, the series of Phase I and Phase II clinical trials conducted at the University of Texas M. D. Anderson Cancer Center in patients with advanced malignant melanoma investigating the use of IL-2 in combination with other cytokines, monoclonal antibodies, or ex vivo activated effector cells have used a common dose and schedule of IL-2 administration for which abundant immunobiological information already exists. This approach allows cross-trial comparison of experience with toxicities, immunobiological observations and clinical activity by a group of investigators within a single institution, and more rapid and valid evolution towards combination biological therapy, which preclinical data suggest will have greater activity than single agent therapy.
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PMID:Interleukin-2 alone and in combination with other cytokines in melanoma: the investigational approach at the University of Texas M.D. Anderson Cancer Center. 267 Feb 14

Tumor infiltrating lymphocytes (TIL) isolated from 12 patients with metastatic malignant melanoma, renal cell carcinoma, or breast adenocarcinoma were expanded in rIL-2 for 22 to 45 days (median 33 days) and analyzed for lymphokine mRNA expression and patterns of TCR gene rearrangement. All TIL cultures were significantly enriched for T cells, with CD3+ CD8+ cells predominant in 8 of 10 cases tested, and demonstrated an oligoclonal (rather than polyclonal) pattern of TCR gene rearrangement. Nine of 12 cultures could effectively lyse the autologous targets in short term chromium release assays. IL-2 expanded-TIL expressed mRNA for TNF-alpha and TNF-beta (lymphotoxin) and, in 5 of 9 (41%) cases, granulocyte/macrophage-colony stimulating factor mRNA but not IL-1 beta or IL-2 transcripts. Cultured TIL deprived of rIL-2 for 4 days did not constitutively express mRNA for any of the lymphokines tested. One long term TIL line in culture was followed and periodically tested for lytic activity and TNF-mRNA expression. Loss of the specific cytolytic but not proliferative activity at day 85 was associated with disappearance of TNF mRNA. Profiles of lymphokine secretion may provide a useful marker for functionally characterizing different T cell subsets and may provide correlates of the in vivo anti-tumor effects of these cells when TIL are adoptively transferred into cancer-bearing patients.
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PMID:Human tumor infiltrating lymphocytes. Analysis of lymphokine mRNA expression and relevance to cancer immunotherapy. 272 37

In the current study we used the therapy of established murine leukemia to identify the lymphocyte subsets responsible for toxicity and for therapeutic efficacy of high-dose IL-2. Initial results confirmed that high-dose IL-2 induces marked proliferation of a variety of host cells, including NK cells, Lyt-2+ T cells, L3T4+ T cells, and B cells. Infusion of antibody to NK-1.1 depleted NK-1.1+ cells in vivo and greatly reduced the toxicity of IL-2, but did not decrease therapeutic efficacy. By marked contrast, depletion of host T cells, either Lyt-2+ or L3T4+, had no effect on toxicity but greatly reduced therapeutic efficacy. The requirement for host T cells for the curative effect of IL-2 gives credence to the possibility that substantial efficacy of high-dose IL-2 against established malignancy may require existent host antitumor immunity. Since the human tumors that have been shown to have the most substantial responses to IL-2 (i.e., malignant melanoma and renal cell carcinoma) are those long considered to be immunogenic in the autochthonous host, the current study predicts that for these, as well as other immunogenic human tumors, it should be possible to decrease the toxicity and thus increase the therapeutic index of IL-2 by selectively depleting NK cells in vivo.
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PMID:Toxicity and therapeutic efficacy of high-dose interleukin 2. In vivo infusion of antibody to NK-1.1 attenuates toxicity without compromising efficacy against murine leukemia. 278 32

Recombinant interleukin-2 (rIL-2) (NSC# 600664; Hoffmann-La Roche, Inc., Nutley, NJ) was studied in a phase I clinical trial in 33 patients with advanced, measureable cancer of the colon or malignant melanoma, Eastern Cooperative Oncology Group (ECOG) performance status O-1, and no prior chemotherapy or radiotherapy. The goal of the study was to identify a dose and schedule of IL-2 to generate maximal immune modulation with tolerable toxicity. Such a regimen might allow the addition of other treatment modalities and/or prolonged treatment duration in later trials. Each patient received IL-2 as a continuous 24-hour infusion once weekly for 4 weeks and then twice weekly for 4 weeks. Five treatment groups received from 10(3) U/m2 to 3 x 10(7) U/m2 per 24-hour infusion. The maximal tolerated dose was 3 x 10(7) U/m2/d twice weekly. Patients treated twice weekly at 1 x 10(7) and 3 x 10(7) U/m2/d had immune modulation in terms of lymphocytosis, eosinophilia, increased natural killer (NK) activity, and elevated numbers of peripheral blood mononuclear cells expressing CD16, OKT10/Leu-17, and Leu-19 surface markers. Endogenous generation of peripheral blood lymphokine-activated killer (LAK) activity was demonstrated by lysis of NK-resistant Daudi targets, in patients treated at 3 x 10(7) U/m2/d. Biochemical and hematological abnormalities were moderate and reversible. Clinical toxicity included hypotension, myalgia, arthralgia, stomatitis, fever, fatigue, nausea, headache, chills, diarrhea, and oliguria at high doses. Cardiovascular toxicity was tolerable for most patients and reversed after IL-2 was stopped. Two of six melanoma patients at 3 x 10(7) U/m2/d achieved partial responses by the end of the eighth week. This IL-2 schedule appears to produce potentially clinically useful immune enhancement with tolerable toxicity.
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PMID:A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions. 278 32

CTL lines were established in vitro by stimulating patient lymphocytes with autologous melanoma cells in the presence of IL-2. Resulting CTL lines lysed autologous melanoma and failed to lyse several allogeneic melanomas or K562. The mechanism of target cell recognition by autologous tumor-specific CTL was evaluated in this system, using several CTL lines: DT6, DT105, DT141, DT166, DT169, and DT179. Autologous melanoma lysis was inhibited by W6/32, mAb directed against HLA class I Ag, but not by L243, mAb directed against HLA class II Ag. CTL from DT6, DT141, DT166, DT169, and DT179 lysed fresh and cultured allogeneic melanomas, which shared the HLA-A2 Ag, but failed to lyse allogeneic melanomas, which shared B-region or C-region Ag, or shared no HLA class I Ag. CTL from DM141 lysed DM93, which shared A2 and Bw6, but failed to lyse DM105, which shared only Bw6. DM105 CTL failed to lyse allogeneic melanomas that shared HLA-A1, or that shared B or C region Ag, but they did lyse allogeneic melanoma DM49, which expressed an A region Ag that either was A10 or was serologically cross-reactive with A10. A T cell leukemia line, three EBV transformed B cell lines, and a pancreatic cancer line, all of which expressed HLA-A2, were not lysed by DM6 or DM179 CTL. Furthermore, HLA-matched nonmelanomas failed to inhibit autologous tumor lysis in cold target inhibition assays, whereas an HLA-A2+ allogeneic melanoma, DM93, inhibited autologous tumor lysis as effectively as the autologous tumor itself. HLA-A2, and possibly other HLA-A-region Ag, appear to function in HLA-restricted recognition of shared melanoma associated Ag by CTL.
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PMID:The role of HLA class I antigens in recognition of melanoma cells by tumor-specific cytotoxic T lymphocytes. Evidence for shared tumor antigens. 278 41

Serum-free supernatants from in vitro maintained gastrointestinal cancer and melanoma cell lines inhibit the generation of lymphokine (IL-2) activated killer (LAK) cells in a time and dose-related manner. Concentrations as low as 5% can inhibit the generation of LAK cytotoxicity but inhibition of proliferation is not observed until higher concentrations are included in the culture system. Inhibition is not observed with supernatants from a breast cancer cell line nor with supernatants from normal cells. There was complete concordance between the capacity of the tumour cells themselves to inhibit LAK generation and the presence of inhibitory activity in the corresponding supernatant. The inhibitory factor(s) is stable after heating to 44 and 56 degrees C. Production of the inhibitory factor(s) is sensitive to metabolic inhibitors and has a molecular weight greater than 25 kD. The inhibition of LAK cell stimulation by tumour cells may partially explain the failure of adoptively transferred LAK cells and IL-2 therapy to cause tumour regression in man.
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PMID:Suppression of the generation of lymphokine-activated killer (LAK) cells by serum-free supernatants of in vitro maintained tumour cell lines. 278 96

Tumor infiltrating lymphocytes (TIL) were grown in IL-2 from single cell tumor suspensions of 14 human melanomas resected from 12 patients. As a function of time in culture, 4 of 14 TIL cultures eventually expressed highly specific cytolytic activity against fresh autologous melanoma targets in short term chromium release assays, failing to lyse multiple allogeneic tumors or autologous normal cells. These highly specific TIL were identified as CTL by phenotype (CD3+/CD4-/CD8+/Leu7-) and by function (lysis inhibited by antibodies directed against CD3 and MHC class I molecules). Cell separation experiments using immunomagnetic beads identified a highly tumor-specific CTL subpopulation within a nonspecific TIL culture, suggesting that the lytic activity of tumor-specific CTL may be diluted by the nonspecific killer activity present in heterogeneous TIL cultures. These studies provide evidence for specific MHC-restricted human immune responses against autologous tumor in cancer-bearing patients, and may be of importance to ongoing clinical trials using TIL in the immunotherapy of advanced malignancies.
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PMID:Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. 278 62


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