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

Twenty-four patients with histologically proven metastatic malignant melanoma were included in a phase II trial of recombinant IL-2 (rIL-2, RU 49637). Twenty million international units (IU)/m2/day were given by continuous intravenous infusion on days 1 to 5, 15 to 18, and 29 to 31, and then monthly for 5 days until disease progression or major intolerance developed. All patients were evaluable for response and toxicity. Toxicity was consistent with one case of myocardial ischemia, 13 cases of grade III and IV hypotension, and 15 cases of proven sepsis. There were 8 objective responses: 4 of them were of short duration as they were observed on day 31 only. An activation of the immune system was detected in all patients. It was demonstrated by an increase in lymphocyte populations, especially in activated NK cells. A tendency for higher numbers of cytotoxic cells was found in patients with objective tumor responses. These results indicate a role for rIL-2 RU 49637 in treating patients with metastatic malignant melanoma. However, further trials are required to determine its optimal dosage and schedule of administration.
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PMID:IL-2 phase II trial in metastatic melanoma: analysis of clinical and immunological parameters. 130 93

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

The growth of immunogenic tumours stimulates the generation of tumour-sensitized, but not functional, pre-effector T cells in the draining lymph nodes. These pre-effector cells can mature into effector cells upon in-vitro stimulation with anti-CD3 and IL-2. In the current study, using a defined, poorly immunogenic tumour, B16-BL6 melanoma, the pre-effector cell response was not evident during progressive tumour growth but was elicited by vaccination with irradiated tumour cells admixed with Corynebacterium parvum. After anti-CD3/IL-2 activation, these cells were capable of mediating the regression of established pulmonary metastases. The efficacy of the vaccine depended on the doses of both tumour cells and the adjuvant. While higher numbers of tumour cells were more effective, an optimal dose (12.5 micrograms) of C. parvum was required. The dose of irradiation was not a critical factor. After vaccination, kinetic studies revealed that the pre-effector cell response was evident 4 days later and declined after 14 days. These observations illustrate the potential role of active immunization in the cellular therapy of cancer.
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PMID:A novel role for autologous tumour cell vaccination in the immunotherapy of the poorly immunogenic B16-BL6 melanoma. 134 Dec 52

Melanoma represents the single best example of a human tumor that has been shown to elicit specific T-cell reactivity. The responsiveness of some patients with metastatic melanoma to treatment with the prototypic T-cell growth factor (TCGF), interleukin-2 (IL-2), indicates that T cells play a role in antitumor immunity. Interleukin-4 (IL-4), another TCGF that has been administered clinically to humans, was not associated with tumor response in our trials conducted at the Surgery Branch of the National Cancer Institute. Combination trials of IL-2 with IL-4 have shown no increase in responsiveness of melanoma or other tumors when compared to IL-2 alone. However, enhanced expansion of tumor-infiltrating lymphocytes (TILs) in vitro has been observed with combinations of low-dose IL-2 and IL-4. We have begun a study evaluating the trafficking of such expanded lymphocytes following their adoptive transfer in association with systemic administration of IL-2 and IL-4. We have established several TIL cultures from fresh tumor samples, maintained them in long-term culture, and marked them with the neomycin phosphotransferase gene using the LNL6 retroviral vector. Such TILs appear to demonstrate no notable alterations in phenotype or cytolytic activity when compared to their nontransduced counterparts. In addition to IL-2 and IL-4, there are a variety of other novel TCGFs that are now available for evaluation in preclinical and clinical trials. IL-7 induces proliferation and lymphokine-activated killer (LAK) cell activity from human peripheral blood mononuclear cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Use of T-cell growth factors (interleukins 2, 4, 7, 10, and 12) in the evaluation of T-cell reactivity to melanoma. 135 3

The intrathecal immune response in neoplastic meningitis (NM) was studied by quantitation of immune parameters such as immunoglobulin G (IgG); IgM; interleukins (IL) 1, 2, 4, and 6; soluble IL-2 receptors (sIL-2R); interferon gamma (IFNy); tumor necrosis factor-alpha (TNF alpha); and three tumor markers, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and fibronectin (FN), in 47 paired cerebrospinal fluid (CSF) and serum samples from patients with NM from different carcinomas, malignant melanoma, and lymphoma. Elevated IgG and IgM indices, CSF oligoclonal Ig bands, and CSF IL-6 indicated an intrathecal immune activation in most patients with NM. Results for IL-1, IL-2, and IL-4 were always negative. sIL-2R and IFNy were detected occasionally but not associated with specific malignant neoplasms. CSF TNF alpha was detected only in NM from cases of malignant melanoma. None of the immune parameters proved useful for the differentiation of NM from autoimmune or inflammatory conditions. Immune parameters were not correlated with tumor markers CEA, AFP, or FN. Results for AFP were positive only in a case of glioblastoma. CEA was a useful and specific diagnostic parameter in carcinomatous NM. CSF FN levels frequently were elevated but are not specific for NM.
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PMID:Tumor cell dissemination triggers an intrathecal immune response in neoplastic meningitis. 137 13

Fc receptor-positive lymphocytes (FcR+) contain lymphokine-activated killer cell (LAK) precursors that in response to IL-2 develop potent antitumor cytotoxicity. These FcR+ cells are also capable of antibody-dependent cytotoxicity (ADCC), which can be detected using fresh human peripheral blood lymphocytes (PBL) directed to murine targets, however, PBL-mediated ADCC to human tumors usually is very low, requiring a stimulation of the PBL, which also can be accomplished with IL-2. Using human melanoma tumor target cells, with and without the 14G2a monoclonal antibody, we examined in parallel the role of p75 IL-2 receptor for regulation of the induction of both LAK and ADCC forms of antitumor cytotoxicity. Enrichment of FcR+ cells from fresh peripheral blood by elutriation and flow cytometry, followed by varying periods of IL-2 culture, revealed a differential kinetics of activation. ADCC was detectable after PBL exposure to IL-2 for as short as the 4 h cytotoxicity assay, while LAK activation required more than 24 h of exposure. Elimination of the FcR+ cells by magnetic bead depletion from large granular lymphocyte populations (LGL) resulted in a loss of both LAK and ADCC. Addition of antibody known to block the binding of IL-2 to the p75 molecule of the IL-2 receptor complex (Mik-beta 1) to activation cultures at zero time resulted in abrogation of both cytotoxicities. These results suggest that differentiation and maturation of the ADCC effectors occurs in response to IL-2 via the p75 molecule, as also does LAK activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor recognition and lytic competence of IL-2-activated lymphocytes: regulation of both antibody-independent and -dependent cellular cytotoxicity via P75 IL-2 receptor. 142 May 99

We have treated 18 patients with metastatic malignant melanoma (MM) with high-dose IL-2 administered by continuous iv infusion in combination with dacarbazine (DTIC), and correlated the clinical response with various hematologic and immunologic parameters. Two regimens differing in the sequence of treatment were employed, and 1-6 treatment cycles were given, depending on patient response. Two patients had a complete response (CR, 46+m, 14m), two patients a partial response (PR, 16m,6m), one a minimal response and four had a stable disease lasting 2-7 months, thus the response rate (CR+PR) was 22%. None of the following parameters, tested prior to initiation of the therapy and 1-2 days after termination of each course of IL-2, correlated with the clinical response: WBC counts (total and differential), levels of blood CD4 and CD8 T cells, NK cells, monocytes and B cells, production of IL-1 and IL-1 inhibitor by monocytes, responsiveness to 3 mitogens, NK/LAK cell activity, and serum levels of IL-1 alpha, IL-2, soluble IL-2 receptor, and TNF alpha. The only prognostic parameter was the greater increase in the level of IL-2 receptor (Tac)-bearing lymphocytes in the responding patients after 1-3 cycles of IL-2. The data suggests that non-specific immune parameters have no prognostic value for patients undergoing IL-2-based immunotherapy.
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PMID:Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response. 144 17

Chemoresistant melanoma cells are known to be susceptible in vitro to lymphokine activated killer (LAK) cells. To obtain a high LAK/tumour cell ratio in vivo and avoid systemic toxicity due to interleukin-2 (IL-2), we used IL-2 plus LAK cells in the treatment of in transit melanoma metastases of the limbs by isolation perfusion (IP). In vivo immunological modifications induced by this immunotherapeutic approach were also analysed. Six patients previously treated with IP in extracorporeal circulation with tumour cytotoxic drugs and presently relapsing or not responding, were submitted to locoregional adoptive therapy consisting of 5 days systemic administration of IL-2 (Proleukin, EuroCetus) (9-12 x 10(6) IU/m2/day c.i.). Autologous LAK cells were derived from leukapheresis and subsequent in vitro stimulation with IL-2; LAK cells were then given along with IL-2 (120-2400 IU/ml of perfusion priming) to the affected limb by IP. In addition, 7-16 x 10(9) LAK cells were administered by systemic infusion the day after together with IL-2 (9-12 x 10(6) IU/m2/day) by c.i. for 5 days. All patients concluded the treatment without major toxicity. The analysis of circulating lymphocytes obtained from extracorporeal circuit at different times revealed rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. Clinical responses included four partial and one complete response; another patient had stable disease. All patients are presently alive. Follow-up after IP ranges from 8 to 22 months.
Melanoma Res 1992 Nov
PMID:Treatment of recurrent in transit metastases from cutaneous melanoma by isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine activated killer cells. A pilot study. 149 Jan 14

We have studied the effects of interleukin-4 (IL-4) on the expansion, proliferation, phenotype, and antitumor activity of tumor-infiltrating lymphocytes (TIL) derived from human renal cell carcinoma. Cultures were obtained from three primary renal tumors and one group of tumor-invaded, regional lymph nodes. IL-4 induced a significant increase in lymphocyte expansion and proliferation, but the response was dependent on the concurrent dose of IL-2 in culture. Increased growth activity was only observed in those cultures receiving low doses (20 U/ml) of IL-2 (average increase of fold expansion of 6.5, P < 0.01) with no changes in growth activity in the high dose (1000 U/ml) cultures. The combination of low dose IL-2 and IL-4 (200 U/ml) promoted lymphocyte growth significantly better than high dose IL-2 alone, the current standard growth regimen for in vitro expansion of TIL. TIL grown in the presence of IL-4 significantly reduced the level of non-specific, non-major histocompatibility complex-restricted antitumor activity (P < 0.01 for allogeneic renal, nonrenal, and NK-sensitive K562 cells), while exhibiting no effect on the level of autologous killing. This is in contrast to previous findings of significant enhancement of autologous antitumor activity using IL-4 on tumor-specific, melanoma-derived TIL. We also evaluated the effects of irradiated autologous tumor stimulation (TIL:tumor ratio, 10:1) on TIL cultures. Addition of autologous tumor cells increased expansion and proliferation of all cultures regardless of concurrent lymphokines present in the culture media (average increase fold expansion of 2.21, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulatory effects of interleukin-4 on tumor-infiltrating lymphocytes derived from human renal cell carcinoma. 149 94

The study of specific immunity in human cancers has been hampered by the elusive distribution and heterogeneity of effector cells. In this study, we have investigated the distribution of autologous melanoma-specific cytotoxic T lymphocytes (CTLs) in 18 different distant metastases from melanomas (9 non-visceral and 9 visceral metastases). Uncultured cells from tumors were provided directly for the establishment of T-cell clones using limiting dilution analysis to avoid any possible effects of in vitro sensitization of T cells to coexisting tumor cells. Autologous tumor specific CTL clones were detected in 6 of 18 tumors (33%, 4 non-visceral and 2 visceral metastases). The majority of CTL clones (35 of 46 and 17 of 19) in 2 patients with HLA class-I A2 haplotype failed to lyse either A2+ or A2- allogeneic melanoma cells, although anti-class-I (monomorphic) MAb inhibited their cytotoxicity. The remaining 11 of 46 and 2 of 19 CTL clones showed A2-restricted cytotoxicity. Autologous tumor-specific cytotoxicity was also detected after polyclonal culture of these tumor-infiltrating lymphocytes (TILs) in 8 of 16 tumors (50%, 5 non-visceral and 3 visceral metastases). These results suggest that tumor-specific T cells exist at tumor sites in at least one-third of distant metastases of melanomas and could be induced by the addition of IL-2 in at least half of the tumors. Tumor-specific T cells were detectable more often in non-visceral than in visceral metastases.
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PMID:Distribution of autologous tumor-specific cytotoxic T lymphocytes in human metastatic melanoma. 150 Feb 28


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