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)

Systemic effects on T-cell-mediated antitumor immunity, on expression of T-cell adhesion/homing receptors, and on the promotion of T-cell infiltration of neoplastic tissue may represent key steps for the efficacy of immunological therapies of cancer. In this study, we investigated whether these processes can be promoted by s.c. administration of low-dose (0.5 microg/kg) recombinant human interleukin-12 (rHuIL-12) to metastatic melanoma patients. A striking burst of HLA-restricted CTL precursors (CTLp) directed to autologous tumor was documented in peripheral blood by a high-efficiency limiting dilution analysis technique within a few days after rHuIL-12 injection. A similar burst in peripheral CTLp frequency was observed even when looking at response to a single tumor-derived peptide, as documented by an increase in Melan-A/Mart-1(27-35)-specific CTLp in two HLA-A*0201+ patients by limiting dilution analysis and by staining peripheral blood lymphocytes (PBLs) with HLA-A*0201-melanoma antigen-A/melanoma antigen recognized by T cells (Melan-A/Mart)-1 tetrameric complexes. The CTLp burst was associated, in PBLs, with enhanced expression of T-cell adhesion/homing receptors CD11a/CD18, CD49d, CD44, and with increased proportion of cutaneous lymphocyte antigen (CLA)-positive T cells. This was matched by a marked increase, in serum, of soluble forms of the endothelial cell adhesion molecules E-selectin, vascular cell adhesion molecules (VCAM)-1 and intercellular adhesion molecules (ICAM)-1. Infiltration of neoplastic tissue by CDS+ T cells with a memory and cytolytic phenotype was found by immunohistochemistry in eight of eight posttreatment metastatic lesions but not in five of five pretreatment metastatic lesions from three patients. Increased tumor necrosis and/or fibrosis were also found in several posttherapy lesions of two of three patients in comparison with pretherapy metastases. These results provide the first evidence that rHuIL-12 can boost the frequency of circulating antitumor CTLp in tumor patients, enhances expression of ligand receptor pairs contributing to the lymphocyte function-associated antigen-1/ICAM-1, very late antigen-4/VCAM-1, and CLA/E-selectin adhesion pathways, and promotes infiltration of neoplastic lesions by CD8+ memory T cells in a clinical setting.
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PMID:Peripheral burst of tumor-specific cytotoxic T lymphocytes and infiltration of metastatic lesions by memory CD8+ T cells in melanoma patients receiving interleukin 12. 1091 69

The First International Symposium on Melanoma and Other Cutaneous Malignancies, held in New York City on 23-25 April 2004, brought together researchers and clinicians from all over the world to discuss recent advances in the prevention, treatment and diagnosis of melanoma and other cutaneous malignancies. Discussion topics included primary and secondary prevention; advances in surgical therapy, including sentinel and elective lymph node dissection; the biology and pathogenesis of melanoma, including pathways of drug resistance; genomic analysis of melanoma, serum and tumour cell markers; with point and counterpoint sessions debating therapeutic controversies. The role of vaccines in the management of melanoma was discussed, including cell vaccines, dendritic cell-based vaccination and present research to improve the generation of melanoma vaccine-specific immunity. Adjuvant immunotherapy with high-dose IFN-alpha and an ongoing trial with biochemotherapy were debated. In addition, the role of chemotherapy and novel targeted agents in metastatic melanoma were discussed. Among the emerging agents and therapeutic targets presented were Bcl-2 antisense therapy, RAF kinases, heat-shock proteins, thalidomide and newer immunomodulatory drugs, cytotoxic T lymphocyte antigen-4 antibody and topical imiquimod. The symposium also provided an overview of existing and emerging agents and modalities in the management of patients with cutaneous T cell lymphomas, ocular melanoma and melanoma involving brain metastases. Sessions also included case-based learning and devoted ample time to providing 'how to' information for practising physicians.
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PMID:First International Symposium on Melanoma and Other Cutaneous Malignancies. 1533 20

Breaking immune tolerance against tumor self-antigens is presently an area of intense research in the design of cancer therapies. One possible method to enhance immune system activation against tumor antigens is by blocking the inhibitory co-stimulatory signals mediated by cytotoxic T lymphocyte antigen 4, (CTLA-4) expressed on activated T cells. The fully human monoclonal antibodies that are directed against human CTLA-4, ipilimumab (Medarex/Bristol-Myers Squibb) and CP-675,206 (Pfizer/Abgenix, now Amgen), have demonstrated activity against metastatic melanoma, hormone refractory prostate cancer and other malignancies. They have also uncovered unusual immune-related adverse events manifesting as self-limiting inflammatory reactions of the bowel, skin and pituitary. This article reviews preclinical development and data generated from Phase I, II and III studies with regard to the end points reported and immune-related adverse events.
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PMID:Update on anti-CTLA-4 antibodies in clinical trials. 1769 22

Metastatic melanoma remains a disease with few effective treatments. The anti-tumor immune response has long been felt to be important in the prognosis of melanoma, and much work has focused on harnessing the immune system to fight this disease. Tumor-specific vaccines, immunomodulatory cytokines and non-specific immunostimulants (such as Bacille Calmette Guerin/BCG) have all been investigated. A new strategy has been identified involving cytotoxic T-lymphocyte antigen-4 (CTLA4). This molecule is expressed on the surface of activated T-lymphocytes and exerts a suppressive effect on the induction of immune responses after interaction between T-cell receptor (TCR) and human lymphocyte antigen (HLA) molecules on the antigen-presenting cell (APC). Work in animal models demonstrated that antibody-mediated blockade of this target could lead to anti-tumor responses. Two fully human monoclonal antibodies, ipilimumab (MDX-010) and tremelimumab (CP-675, 206; formerly known as ticilimumab), are in clinical development. Both have demonstrated hints of clinical activity in metastatic melanoma. Both also have a toxicity profile consistent with their mechanism of action, involving inactivation of a normal immunosuppressive homeostatic mechanism: development of auto-immune breakthrough events (IBE). These include inflammatory bowel disease (IBD), uveitis, dermatitis, arthritis, and others. Generally, these events have been easily managed by cessation of therapy and intravenous or topical steroid therapy and supportive care in most patients, although colectomy had been required in several severe cases and there have been several deaths. Interestingly, patients who develop IBE seem to have the greatest likelihood of clinical benefit, but it is unclear whether clinical benefit and IBE are dissociable events. Other than IBE, no other pharmacodynamic measure has been able to predict response, although certain autoimmune antibody titers may have promise in this regard. Further research will confirm the clinical benefit of these agents alone and in combination with other agents, further define the safety profile and protocols for toxicity management, and identify pharmacodynamic parameters predicting clinical benefit and toxicity.
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PMID:The role of the CTLA4 blockade in the treatment of malignant melanoma. 1802 52

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell mediated immune responses and is the target of new anti-tumor immunotherapy strategies. Ipilimumab is a fully human, antagonistic monoclonal antibody directed against CTLA-4. Results from preclinical and early clinical trials support current phase II/III testing of ipilimumab as first- and second-line therapy for metastatic melanoma. Ipilimumab promotes durable objective responses and/or stable disease in patients with metastatic melanoma. Adverse events are medically manageable, largely immune-related, and presumably linked to the drug's mechanism of action. As more patients are treated with ipilimumab, it is becoming clear that the kinetics of responses are heterogeneous and significantly different from those of chemotherapy and other immunotherapy. Though objective response or stable disease is observed within 'conventional' time frames, responses have been observed weeks to months after therapy initiation. Response or stable disease may be preceded by apparent early disease progression, or may occur simultaneously with different progressing lesions within the same patient (a 'mixed' response). It is likely that the unique kinetics of response is a result of the time required to enhance and maintain an anti-tumor immune response to ipilimumab therapy. Consequently, patients may benefit from continued ipilimumab treatment through clinically known relevant disease progression or non-response during the full induction dosing schedule (12 weeks), without additional therapies. Understanding the kinetics of response to ipilimumab will help clinicians to manage patients who may benefit from treatment. In this article, several cases that illustrate the kinetics of response to ipilimumab are discussed.
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PMID:The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. 1819 18

A novel approach for cancer immunotherapy is to augment T-cell-mediated immunity by blocking inhibitory signals that suppress T-cell function. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T-cell activation. CTLA-4 blockade using anti-CTLA-4 monoclonal antibodies (mAbs) potentiates the T-cell response against tumors, and preliminary data on these agents demonstrate good efficacy and tolerability in the treatment of patients with metastatic melanoma and other cancers. This paper will review data from studies with anti-CTLA-4 mAbs to date, discuss some of the key clinical considerations emerging from early clinical trials with this therapeutic strategy, and provide an overview of ongoing and planned clinical trials for anti-CTLA-4 mAb therapy in metastatic melanoma and other cancers.
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PMID:CTLA-4: negative regulator of the immune response and a target for cancer therapy. 1846 42

Targeted biologic therapies such as anti-cytotoxic T lymphocyte antigen (CTLA-4) monoclonal antibodies, either as monotherapy or in combination with chemotherapy or vaccines, have shown great promise in late-stage melanoma, which has a very poor prognosis. Melanoma is relatively resistant to both chemotherapy and radiotherapy. Blockade of CTLA-4, which inhibits T-cell proliferation, promotes stimulation of adaptive immunity and T-cell activation, resulting in eradication of tumor cells. Two human monoclonal antibodies are under investigation in melanoma. Phase II and III clinical trials are currently evaluating the efficacy and safety of ipilimumab (MDX-010, Medarex, Inc., Princeton, NJ, and Bristol-Myers Squibb, Princeton, NJ) and tremelimumab (CP-675,206; Pfizer Pharmaceuticals, New York) in melanoma. Data are available on ipilimumab, which has been explored as monotherapy and in combination with vaccines, other immunotherapies such as interleukin-2, and chemotherapies such as dacarbazine. Overall response rates range from 13% with ipilimumab plus vaccine in patients with stage IV disease to 17% and 22% with ipilimumab plus dacarbazine or interleukin-2, respectively, in patients with metastatic disease. Responses have been durable, and among those experiencing grade 3 or 4 autoimmune toxicities, even higher response rates have been seen--up to 36%. While the optimal dose of ipilimumab has yet to be established, studies also indicate that higher doses may be more effective. Importantly, the lack of an initial clinical response may not predict ultimate treatment failure, because the onset of a response may follow progressive disease or stable disease. Pending results from registration studies with ipilimumab and lessons learned from registration studies conducted with tremelimumab will help to define the role of anti-CTLA-4 blockade in the treatment of metastatic melanoma.
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PMID:Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab (MDX-010). 1900 Nov 47

Ipilimumab (MDX-010), a human anti-cytotoxic T-lymphocyte antigen (CTLA)-4 monoclonal antibody, is currently being investigated for the treatment of patients with melanoma. The most frequent toxicities observed with ipilimumab involve the gastrointestinal tract and are attributed to activation of the immune system. Constipation has been reported as a symptom in the clinical trials of anti-CTLA-4 antibody and is mostly low grade. However, it is not traditionally perceived as an immune-mediated toxicity. We report the case of a patient who developed severe refractory constipation during treatment with ipilimumab for metastatic melanoma. Biopsies of the colonic wall revealed prominent inflammatory infiltrates of mononuclear lymphocytes associated with the myenteric nervous system. There was a pathologic complete remission of melanoma. To our knowledge, this is the first clinical report of either inflammatory enteric neuropathy or constipation as an immune-related adverse event from anti-CTLA-4 antibody treatment. We discuss the pathophysiology and suggest careful monitoring of patients for development of this complication from ipilimumab therapy.
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PMID:Inflammatory enteric neuropathy with severe constipation after ipilimumab treatment for melanoma: a case report. 1923 20

Metastatic melanoma is a disease associated with poor prognosis, with a median survival reported to range from 6 to 9 months. Patients who are not candidates for surgical resection have an even worse expected survival. This is largely due to the lack of effective chemotherapeutic regimens and has led to the investigation of alternative treatment strategies including immunotherapy. Although melanoma is felt to be an immunogenic tumor and has been associated with the development of spontaneous tumor-specific immune responses in patients, the implementation of vaccine-based treatment has had limited success. Because the administration of a melanoma-specific vaccine alone has not been sufficient to generate robust and reproducible clinical responses, investigators are currently pursuing additional methods to augment antimelanoma immune responses by optimizing T-cell activation. T-cell activation requires both antigen presentation to the T-cell receptor and a second signal mediated by CD80 and CD86 on antigen-presenting cells and CD28 on the T cell. Ligand binding to CD28 on the T-cell surface leads to T-cell proliferation and expression of activating cytokines such as interleukin-2. Cytotoxic T-lymphocyte antigen-4 (CTLA-4), an inhibitory protein expressed on T cells, competes for the same ligands as CD28 and modulates T-cell activation. Because CTLA-4 has a significantly higher binding efficiency than CD28, CTLA-4 is critical in maintaining immune tolerance to self-antigens and may also limit responses to tumor antigens and vaccine therapy. CTLA-4 blockade either alone or in combination with melanoma-specific vaccines has been explored as a potential means to treat advanced stage melanoma. In this article, we review the spectrum of clinical trials involving CTLA-4 blockade and also review recent correlative studies attempting to elucidate the potential mechanisms by which CTLA-4 blockade achieves its therapeutic effects.
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PMID:Recent advances using anti-CTLA-4 for the treatment of melanoma. 1955 98

A patient with metastatic melanoma who had progressive disease after prior surgical resections, high dose interleukin-2, and anti-cytotoxic T lymphocyte antigen-4 antibody received sequential treatments with autologous tumor infiltrating lymphocytes that recognized the gp100 melanocyte differentiation antigen. Although no clinical response was seen when cells were administered alone, an objective clinical response to therapy was seen with tumor infiltrating lymphocytes administered together with a highly immunogenic fowlpox vaccine expressing a gp100: 209-217 (210M) epitope. Persistence of the transferred antigen-specific lymphocytes in the peripheral blood was observed only after adoptive cell therapy plus administration of vaccine. Cell proliferation in vitro was further stimulated by additional vaccine and interleukin-2. The patient has an ongoing partial response at 10 months after the last treatment.
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PMID:Impact of a recombinant fowlpox vaccine on the efficacy of adoptive cell therapy with tumor infiltrating lymphocytes in a patient with metastatic melanoma. 1975 47


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