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)

Artificially enforced expression of CD80 (B7-1) and CD86 (B7-2) on tumor cells renders them more immunogenic by triggering the CD28 receptor on T cells. The enigma is that such B7s interact with much higher affinity with CTLA-4 (CD152), an inhibitory receptor expressed by activated T cells. We show that unmutated CD80 is spontaneously expressed at low levels by mouse colon carcinoma cell lines and other transplantable tumor cell lines of various tissue origins. Silencing of CD80 by interfering RNA led to loss of tumorigenicity of CT26 colon carcinoma in immunocompetent mice, but not in immunodeficient Rag-/- mice. CT26 tumor cells bind CTLA-4Ig, but much more faintly with a similar CD28Ig chimeric protein, thus providing an explanation for the dominant inhibitory effects on tumor immunity displayed by CD80 at that expression level. Interestingly, CD80-negative tumor cell lines such as MC38 colon carcinoma and B16 melanoma express CD80 at dim levels during in vivo growth in syngeneic mice. Therefore, low CD80 surface expression seems to give an advantage to cancer cells against the immune system. Our findings are similar with the inhibitory role described for the dim CD80 expression on immature dendritic cells, providing an explanation for the low levels of CD80 expression described in various human malignancies.
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PMID:Low surface expression of B7-1 (CD80) is an immunoescape mechanism of colon carcinoma. 1648 51

In the last decade the incidence of melanoma has been rising. Despite this, survival remains substantially constant because early diagnosis of thin lesions has increased. By contrast, metastatic melanoma continues to have a poor prognosis and it still represents a challenge for oncologists. Response rates with single agent dacarbazine range from 10% to 25% with median survival of 8 months. The advent of new drugs with specific mechanisms of action could help to improve the poor results of traditional therapies. In this review, we focused on the novel agents that entered clinical trials in melanoma patients. We show the results of some clinical trials with target-oriented drugs in melanoma patients. Moreover pre-clinical data and rationale for use in melanoma was explained. Trials with protein-kinase inhibitors, anti-CTLA-4 agents, pro-apoptotic oligonucleotides and anti-angiogenic agents were reviewed. Combinations with chemotherapeutic agents, immunotherapy and vaccine therapy were also analyzed.
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PMID:Targeted therapies in melanoma. 1700 14

Tremelimumab (CP-675,206) is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) in clinical development for patients with cancer. Blocking the CTLA-4 negative costimulatory receptor with the antagonistic antibody tremelimumab results in immune activation. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumor regressions. Its IgG(2) isotype minimizes the possibility of cytotoxic effects on activated T lymphocytes and cytokine release syndrome. Preclinical testing in vitro and in large animal models predicted the target concentrations of circulating antibody in humans necessary for a pharmacodynamic effect. Phase I clinical trials provided evidence of dose- or exposure-related effects consistent with the anticipated mechanism of action. Further clinical development has led to two ongoing registration trials in patients with metastatic melanoma: a phase III randomized trial of tremelimumab versus dacarbazine or temozolomide in previously untreated patients with advanced melanoma and a phase II trial of tremelimumab in previously treated patients with advanced melanoma.
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PMID:Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. 1767 18

There has been a long fascination with immunizing against cancer in general and against melanoma in particular. The earliest melanoma vaccines were formulated from autologous or allogeneic melanoma cells. Subsequently, molecularly defined vaccines made from proteins, peptides, or gangliosides were developed and, recently, DNA-based vaccines are currently being tested. Randomized trials using allogeneic melanoma cells/lysates or gangliosides have not demonstrated a clinical benefit, although in some trials, clinical benefit was seen in large subsets. On the other hand, some clinical trials indicated that vaccine therapy could be associated with a poorer survival. There are several mechanisms now identified by which melanoma cells can avoid detection by T cells, such as loss of expression of antigen or human leukocyte antigen (HLA) molecules, and tumor vascular adhesion molecules. Also, mediators of immune tolerance are now well-characterized such as regulatory T cells and inhibitory cytokines secreted by melanoma cells. Future approaches for immunizing against melanoma will have to incorporate strategies to overcome these barriers. Strategies being tested include depletion of regulatory T cells, immunization in the setting of lymphopenia, and blockade of T-cell inhibitory molecules such as CTLA-4. Once a relevant clinical response can be induced, it should be possible to develop validated immunoassays that will direct future melanoma vaccine development.
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PMID:Melanoma vaccines. 1808 75

Dendritic cells (DC) are the directors of the immune system, capable of inducing tumour antigen-specific T- and B-cell responses. As such, they are currently applied in clinical studies in cancer patients. Early small clinical trials showed promising results, with frequent induction of anti-cancer immune reactivity and clinical responses. In recent years, additional trials have been carried out in melanoma patients, and although immunological responses are often reported, objective clinical responses remain anecdotal with objective response rates not exceeding 5-10%. Thus, DC vaccination research has now entered a stage in between 'proof of principle' and 'proof of efficacy' trials. Crucial questions to answer at this moment are why the clinical responses remain scarce and what can be done to improve the efficacy of vaccination. The answers to these questions probably lie in the preparation and administration of the DC vaccines. Predominantly, cytokine-matured DC are used in clinical studies, while from preclinical studies it is evident that DC that are activated by pathogen-associated molecules are much more potent T cell activators. For sake of easy accessibility monocyte-derived DC are often used, but are these cells also the most potent type of DC? Other yet unsettled issues include the optimal antigen-loading strategy and route of administration. In addition, trials are needed to investigate the value of manipulating tolerizing mechanisms, such as depletion of regulatory T cells or blockade of the inhibitory T cell molecule CTLA-4. These issues need to be addressed in well-designed comparative clinical studies with biological endpoints in order to determine the optimal vaccine characteristics. DC vaccination can then be put to the ultimate test of randomized clinical trials. Here, we review the immunobiology of DC with emphasis on the different aspects that are most relevant for the induction of anti-tumour responses in vivo. The different variables in preparing and administering DC vaccines are discussed in this context and the immunological and clinical results of studies with DC vaccines in melanoma patients are summarized.
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PMID:Dendritic cell vaccines in melanoma: from promise to proof? 1826 31

The immunogenicity of malignant melanomas has been recognized by the observed recruitment of tumor-specific cytotoxic T-cells (CTL), leading to the identification of several melanoma associated antigen (MAA). However, numerous strategies to treat melanoma with immunotherapy have resulted in only partial success. In this editorial, we discuss recent data related to the ability of tumors to elude immune responses. We therefore discuss different strategies to induce a clinically effective immune response. These approaches include 1) immunostimulation: including peptide/protein based vaccines, dendritic cell vaccines, and adoptive cell transfer; and 2) overcoming immunosuppression, including targeting of checkpoint molecules such as CTLA-4, circumventing the activity of Tregs, and assuring antigen expression by tumor cells (thwarting antigen silencing). Finally, we discuss recent advances in gene therapy, including adoptive therapy with engineered T cell receptors (TCRs). These issues lead to the conclusion that successful immunotherapy in malignant melanoma requires a combination of strategies aimed at both inducing immunostimulation and blocking immunosuppression.
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PMID:Strategies to overcome obstacles to successful immunotherapy of melanoma. 1883 16

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

Tumors contain variable numbers of lymphocytes, referred to as tumor infiltrating lymphocytes (TILs). In melanoma, the intensity of this lymphocytic infiltrate is believed to correlate with outcome, though there is some debate about the applicability of this finding for all melanomas. Much research has gone into classifying TILs with respect to antigen receptor structure and the antigen to which melanoma-specific T cells react. However, these studies for the most part did not immunophenotype TILs, and recent data has revealed that the composition of tumoral lymphocytes is not homogenous, but rather represents varying contributions from many lymphocytic subsets. Furthermore, the function of TILs is often compromised as a result of the accumulation of immunoregulatory cells and various tumor escape mechanisms. These recent insights stress the need to collect more data on the composition and function of TIL infiltrates before definitive conclusions about the prognostic significance of TILs can be drawn. Advances in immunology have also facilitated the development of immunotherapeutic strategies, examples of which will be discussed with a special emphasis on blocking antibodies against CTLA-4, which are prototypical immunotherapeutic agents. This flurry of novel "biological" therapies will undoubtedly complicate our already incomplete understanding of TIL immunobiology as each of these agents has the potential to uniquely distort the series of immunological events which normally occur in untreated melanoma. Therefore, considerable research is needed to better elucidate the function and prognostic significance of TILs in both untreated melanoma and tumors treated with "biological" therapy.
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PMID:Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. 1933 64

Immunotherapy is an effective treatment option for a small percentage of patients with advanced melanoma or at high risk for recurrence after resection of the primary tumor. However, a long period of unsuccessful immune modulation trials involving new cytokines, antibodies, cancer vaccines, adoptive immunotherapy, and combinations generated doubts that benefit could be extended to a larger group of patients. Renewed optimism for the therapeutic potential of immune therapy is currently driven by key advances in tumor immunobiology, including the potential to manipulate and disrupt immune activation checkpoints and tumor defense mechanisms; newer approaches to antigen presentation for immune activation; refinements to procedures for antigen-specific T-cell expansions in vitro and preparative regimens to support their expansion and activity in vivo; gene transfer to alter lymphocyte specificity and function; and the potential for discovery of improved predictive biomarkers to select patients for individual treatments. Proof of concept is provided by durable remissions observed in patients with advanced melanoma enrolled in clinical trials of anti-CTLA-4 and in new studies of adoptively transferred tumor antigen-specific lymphocytes combined with lymphocyte ablation conditioning regimens. Many agents now being developed are predicted to produce broader, more potent, and more effective antitumor immune responses.
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PMID:Betting on immunotherapy for melanoma. 1967 15


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