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

The clinical and immune modulatory effects of interleukin-2 (IL-2) and interferon (INF) alfa-2a were examined in a phase II study in patients with metastatic renal cell carcinoma (six patients) and melanoma (eight patients). Treatment consisted in IL-2 3 MU/m2 continuous infusion days 1-4 and INF alfa-2a 6 MU/m2 subcutaneously day 1 and 4, both given on alternate weeks. Tumour response was assessed after four cycles of treatment or earlier, if necessary. Patients with stable disease or response were to be continued for another nine cycles or up to disease progression. The 14 patients received a total of 60 cycles of treatment. Major toxicities (WHO Grade III/IV) were fever, capillary leak syndrome with hypotension, nausea and vomiting, erythema with pruritus, leuco- and thrombopenia and sepsis with staphylococcus aureus. Five of 14 patients (36%) developed a self limiting autoimmune thyroiditis with HLA-DR expression on thyrocytes. Long term treatment toxicity was moderate with an average weight loss of 5% and an average fall in Karnofsky index of 10% compared to baseline. No responses were seen in renal cell carcinoma, two patients with melanoma had a partial and two a minor response with a duration of 1-7 months. Serial measurements of immune modulatory parameters showed a functional response to treatment with an increase of NK- and LAK-activity during the first two cycles, followed by a plateau and decrease during the third and fourth cycles. These findings were paralleled by a successive decline in treatment induced INF gamma response. These findings suggest, that alternative weekly treatment with IL-2 and INF alfa-2a results in an exhaustion of lytic capacity of NK- and LAK-cells and an attenuation of secondary cytokine release.
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PMID:Clinical and immune modulatory effects of alternative weekly interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma and melanoma. 199 8

Two patients with metastasizing melanoma and diffuse melanosis have previously been reported to excrete large quantities of trichochromes in the urine. The present study describes 2 further melanoma patients with diffuse melanosis and trichochromuria. The hair of one of the patients which had been red in childhood and turned brown in adult age returned to red with the appearance of melanosis. Normal excretion of a methylated melanocytic metabolite, 6-hydroxy-5-methoxyindole-2-carboxylic acid, was observed in this patient, possibly indicating exhaustion of the methylating system. The other patients excreted large quantities of 6-hydroxy-5-methoxyindole-2-carboxylic acid. Both patients showed highly increased excretion of 5-S-cysteinyldopa. Both patients with melanosis exhibited fine electrone-dense granules in lysosomes of dermal histiocytes. The findings support the concept that trichochromes or similar pigments in dermal histiocytes are responsible for diffuse melanosis in melanoma patients.
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PMID:Trichochromuria in melanosis of melanoma. 243 64

In an attempt to better define the immunological reactivity of patients with malignant melanoma, the electrophoretic mobility of lymphocytes and their reactivity were studied in poly-L-lysine agglutination and in nucleolar test. Blood samples were examined before treatment and repeatedly after surgical removal of the tumor. A microagglutination test induced by poly-L-lysine was used for the detection of sensitized lymphocytes in peripheral blood of melanoma patients. The number of positive results was increasing with the progression of the disease. After incubation with poly-L-lysine the electrophoretic mobility of lymphocytes was changed in melanoma patients. The nucleolar test was used for the study of quantitative and morphological changes of the nucleoli in lymphocytes. Elevated values of the nucleolar coefficient and an increased number of active nucleoli provided evidence on the higher immunological reactivity of melanoma patients. The decline in the number of lymphocytes with ring-shaped nucleoli, signaling immunologic exhaustion, are of prognostic value. Lymphocytes were assayed also for the presence of receptors for sheep erythrocytes (E active and total rosettes) and C3d component of complement (EAC rosettes). The reported findings may be used to advantage in evaluating the immunological reactivity of melanoma patients.
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PMID:[Immunologic parameters in patients with malignant melanoma]. 262 50

The main side-effects of BCG vaccination by scarification in 511 patients with malignant melanoma since 1974 have been fatigue and exhaustion, swelling of the lymph-nodes, influenza-like symptoms, nausea and dizziness. Only in 8 patients were the side-effects more severe, requiring the cessation of treatment in some of them. One patient developed granulomatous hepatitis, another experienced a reactivation of pulmonary tuberculosis. Allergic reactions occurred in two patients. A further patient developed recurrent erysipelas in the draining areas of the scarification. In two patients we observed continuous severe joint troubles, which were not due to metastatic disease. The eighth patient developed keloids at the vaccination sites on the upper arms. One third of the patients had no side-effects. Altogether vaccinations were tolerated well by most of the patients. Nearly all of them were able to work normally.
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PMID:[Side effects of BCG immune therapy in 511 patients with malignant melanoma]. 670 81

Partial regression in cutaneous malignant melanoma has been reported by a number of observers, albeit not all, to be associated with a relatively poor prognosis; in contrast, a keratoacanthoma, which eventually regresses, does not metastasize. The Hammond effect could explain the possibly poor prognosis of the thin regressing melanoma. Hammond(W.G. Hammond et al., Cancer J., 8: 130-138, 1995) showed that the speed of biological progression to less differentiated phenotypes is directly related to the immunocompetences of the tumor hosts. If partial regression is a sign of an unusually strong immune reaction, then the melanoma that partially regresses might have a relatively poor prognosis because of the greater risk of biological progression among the surviving tumor clones. A Hammond effect is not associated with regression of a keratoacanthoma. I postulate that the growth of this tumor is accelerated, rather than restrained, by the immune reaction and that the ultimate regression of the tumor is the result, not of immune cytotoxicity, but of a rapid terminal differentiation (a reverse Hammond effect); alternatively, very rapid growth might lead to an exhaustion of growth potential before progression to clonal immortality could occur.
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PMID:The paradoxical association of regression with a poor prognosis in melanoma contrasted with a good prognosis in keratoacanthoma. 864 Jul 80

An HLA-A2-positive patient with advanced stage IV melanoma was vaccinated with dendritic cells (DCs) pulsed with melanoma antigens, whereby the rapid progression of disease stalled for a period of 10 months. Monitoring of the cellular immune response against one of the vaccinated HLA-A2-restricted epitopes demonstrated both induction and subsequent decline in the number of interferon-gamma (IFN-gamma)-producing MART-1-reactive cells present in the blood. Enumeration of reactive T cells by MART-126-35/HLA-A2 tetramer staining revealed an induction of such cells after three vaccinations and a subsequent decline that most prominent at times of rapid disease progression. However, a substantial number of reactive cells were present even when no MART-1 reactivity was detectable by functional assays. Isolation of such MART-126-35-reactive T cells by means of peptide/HLA-A2-coated magnetic beads demonstrated the persistence of a TCRVbeta14+ T-cell clone in this population over the whole observation period. Intracellular fluorescence-activated cell sorter staining of such TCRVbeta14+ T cells for IFN-gamma and interleukin-2 after maximal stimulation with phorbol 12-myristate 13-acetate/ionomycin revealed an impairment in their capacity to produce cytokines at the end of the observation period. Thus, functional changes of individual T-cell clones, e.g. clonal exhaustion, seem to be responsible for the known discrepancy between functional and phenotype assays for immune monitoring of tumour patients.
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PMID:Longitudinal analysis of MART-1/HLA-A2-reactive T cells over the course of melanoma progression. 1462 28

Tumor-infiltrating lymphocytes (TILs) develop as manifestations of the recognition and defense against malignant cells by the host immune system. TILs were literally defined as "tumor-infiltrating lymphocytes", which a posteriori locate within the tumor tissues. Although such cells can be found, they fail to control the growth of tumor. Many have proposed diverse mechanisms for dysfunction of TILs with regard to the roles of immunosurveillance against cancer. However, only a few cancer types, e.g. melanoma, have seen the benefits brought by activating these cells for immunotherapy. Functional defects of TILs have been linked to abnormalities of signaling molecules; however, there is conflicting data. The death of TILs was attributed to expression of cancer-derived FasL, PD-1 and RCAS1, and cancer-induced activation-induced cell death (AICD). Confirmed by studies using TILs and animal models, the compromise of tumor-specific immune responses was thought to result from not only mechanisms of clonal anergy but also exhaustion and/or deletion. Furthermore, functional cytotoxic CD8(+) TILs might be rendered incompetent by cancer-induced up-regulation of inhibitory NK receptors or proximal signaling abnormalities. Additionally, immune privilege was partly attributed to recruitment of regulatory T cells to the tumor sites. The failure of IL-2 signaling, which stands at the center of T cell functionalities, had been linked to the enzymatic activity of cancer-derived matrix metalloproteinases (MMPs). Finally, the exploitation of IDO expression, an important enzyme in pregnancy-related immunosuppression, by cancer cells might play a role in tumor immunity. The disparity of cancer types, origin, developmental stages and individual genetic backgrounds likely account for differences, or even contradictions, which might be the reason why immunotherapy works only on a few cancer types. Delineating the mechanisms behind functional defects of TILs can help not only boost chances of the development of a successful cure but understand the not fully identified roles played by immune system in the face of malignancies.
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PMID:Current concepts of tumor-infiltrating lymphocytes in human malignancies. 1611 67

Although there has been initial success with some types of immunotherapy, such as adoptive cellular therapy and monoclonal antibody therapy for cancer, the experience with therapeutic cancer vaccines has been much less encouraging. Almost all randomized phase III trials testing therapeutic cancer vaccines have failed to meet their end points. There are several potential explanations for this, ranging from factors related to the clinical trial design and the vaccine itself. Perhaps the most important are host-related factors. Specifically, progression and metastases of many cancers are associated with induction of multiple cancer-specific immune-inhibitory pathways. These inhibitory pathways include induction of T-cell anergy through dendritic cell dysfunction, release of immunosuppressive cytokines, T-cell exhaustion through inhibitory T-cell signaling and T regulatory cell-mediated tumor-specific immune suppression. All of these pathways have been shown to be operational in patients with melanoma. To enhance the activity of therapeutic cancer vaccines, these immunosupressive pathways need to be addressed and reversed. A number of new immunomodulatory reagents that are able to interfere with some of these pathways are now being assessed in the clinic. Sanofi Pasteur designed a clinical trial in patients with advanced or metastatic melanoma that is intended to both induce tumor-specific T-cell responses and modulate or reverse some of the immune suppression pathways that the melanoma has induced. To accomplish this, the recently optimized ALVAC melanoma multi-antigen vaccine is administered with high doses of IFN-alpha. Clinical trial parameters have also been optimized to enhance the likelihood of inducing and documenting antitumor activity. Success with other therapeutic cancer vaccine approaches will likely require similar approaches in which promising immunogenic vaccines are integrated with biologically and clinically active immunomodulatory reagents.
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PMID:Strategies to enhance the therapeutic activity of cancer vaccines: using melanoma as a model. 1976 43

Melanoma cells can play a number of tricks to evade the host immune response. They can make themselves invisible to cells of the immune system poised to attack them, elaborate molecules that are frankly immunosuppressive, and can create a microenvironment that is hostile to cells of the immune system. Efforts are underway to institute measures that would make tumor cells more susceptible to immune attack, but these efforts have not been all that successful so far. This contribution reviews the history and the rationale of cancer vaccines, the major obstacles to peptide-based immunization, and a discussion on how to surmount them. Also included are the roles played by peripheral tolerance, low-affinity T-cell receptors, T-cell ignorance, activation-induced cell death, exhaustion of T cells and regulation of the immune response, helpless cytolytic T lymphocytes, and evasion by tumor cells.
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PMID:Obstacles to and opportunities for more effective peptide-based therapeutic immunization in human melanoma. 1988 48

Active vaccination strategies using viral vectors often give disappointing protection from tumor development, and usually require multiple immunizations. These approaches normally use viruses that cause acute infections, as they provoke potent CD8 T cell responses. Persistent virus vectors have not been used in this setting due to the perception that exhaustion of the T cell response occurs and would lead to poor anti-tumor protection. However, such exhaustion generally only occurs in high-load virus infections, whereas T cell function is intact in lower-load persistent infections. In fact, CD8 T cell responses in these infections, which are adapted for long-term immune surveillance, have properties that may make them more desirable for long-term anti-tumor immunity. In this report, we show that a persistent gammaherpesvirus vector provides superior protection against melanoma, relative to a non-persistent mutant of the same virus. These data suggest that vaccine vectors derived from persistent viruses may perform better than those from acute viruses at mediating anti-tumor protection.
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PMID:A persistent virus vector confers superior anti-tumor immunity, compared with a non-persistent vector. 1992 Nov 88


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