Novel Approaches to Treatment of Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy

Niezgoda, Anna; Niezgoda, Piotr; Czajkowski, Rafał

doi:10.1155/2015/851387

Cited by 127 publications

(114 citation statements)

References 72 publications

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“…Following the discovery of the expression of CTLA-4 on the surface of T-cells, certain functions of CTLA-4 have been hypothesized, including competition with the costimulatory molecule CD28 on CD4 + /CD25 -T-cells for binding to the CD80 and CD86 ligands on antigen presenting cells (APCs), as well as the direct inhibition of APCs and CD4 + /CD25 -T-cells by CTLA-4 and CD80/86 interactions (12). Currently, two types of human anti-CTLA-4 mAbs, ipilimumab and tremelimumab, are being used in the treatment of metastatic melanoma and metastatic mesothelioma (13,14). However, the precise role of CTLA-4 in Tregs during cancer immunotherapy remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of antitumor immunity by combination of anti-CTLA-4 antibody and radioimmunotherapy through the suppression of Tregs

et al. 2017

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Abstract. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is expressed during cluster of differentiation (CD)4 + T-cell activation and terminates immune responses by interrupting CD28-enhanced activation. In addition, CTLA-4 is known to be constitutively expressed in regulatory T-cells (Tregs) and to contribute to immune suppression by enhancing the suppressive function of Tregs. However, the molecular mechanisms underlying CTLA-4-mediated Treg suppression remains incompletely understood. Furthermore, it is uncertain whether the in vivo immune suppressive functions of CTLA-4 are mediated only by a reduction in the level of conventional T-cell activity, or enhancement of Treg function. The present study demonstrated that combination therapy with an anti-CTLA-4 monoclonal antibody and dendritic cell-mediated radioimmunotherapy (IR/DC) was able to promote an antitumor response and influence Treg function in a mouse model of lung cancer. Cell surface markers, including CTLA-4, CD25 and CD4, were analyzed using flow cytometry, and T-cell activities were measured using ELISPOT and cytotoxicity assays. It was revealed that anti-CTLA-4 combined treatment with IR/DC immunotherapy may execute a more powerful and effective anti-tumor immunity through the inhibition of Treg function. IntroductionIn previous studies, the anti-cytotoxic T lymphocyte antigen (CTLA)-4 antibody was able to enhance the activity of conventional T-cells through the blockade of CTLA-4, which competes with the costimulatory molecule cluster of differentiation (CD) 28 to bind to the ligands CD80 and CD86 on dendritic cells (DCs) (1,2). However, the mechanism by which CTLA-4 influences the suppressive effect of regulatory T-cells (Tregs) in vivo remains unclear. Although studies have reported that transgenic CTLA-4 enhanced Treg function and anti-CTLA-4 antibodies induced autoimmune colitis through the suppression of Tregs in a mouse model, the presence of anti-CTLA4 antibodies did not affect the suppressive effect of Treg on CD4 + CD25 -T-cells in mouse gastritis (3,4). Therefore, investigation into the role of CTLA-4 in cancer immunotherapy is required. The present study assessed the inhibition of CTLA-4 using an anti-CTLA-4 monoclonal antibody (mAb), in order to determine whether this inhibition was able to increase the level of antitumor immunity induced by dendritic cell-mediated radioimmunotherapy (IR/DC) in a mouse model in vivo. Since malignant cells may exhibit acquired tolerance to tumor-specific antigens and Tregs may be involved in the survival of tumor cells through the suppression of antitumor immunity (5,6), the present study hypothesized that blocking CTLA-4 may break the tolerance and induce antitumor immunity through the inhibition of Tregs. Materials and methods Mice and cancer cell lines.A total of seventy-five male C57BL/6 mice aged 6 weeks and weighing 18-22 g were purchased from Central Lab., Animal Inc. (Seoul, Korea) and the animal experiments were approved by the Dongnam Institute of Radiological and Medical Sciences Institutional A...

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Section: Discussionmentioning

confidence: 99%

Enhancement of antitumor immunity by combination of anti-CTLA-4 antibody and radioimmunotherapy through the suppression of Tregs

et al. 2017

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“…Recently, the identification of mutation in v-raf murine sarcoma viral oncogene homolg B1 (BRAF), a serine/therionine kinase as a key step in melanoma carcinogenesis has opened up new possibilities in treatment. BRAF protein inhibitors such as vemurafenib and darafenib have been approved by the US FDA for treatment of metastatic malignant melanoma and have shown good results in clinical trials [13]. Our patient was not treated with these agents due to their high costs and limited availability in our region.…”

Section: Discussionmentioning

confidence: 99%

Malignant Melanoma Presenting as Bilateral Pleural Effusion

Singh¹,

Vk²

2015

JCR

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Abstract:Malignant melanoma is a common malignancy in Western population especially in light skinned people although it is relatively uncommon in India. Pleural effusion is an unusual presentation of malignant melanoma. We present the case of a 45 year old patient who presented with chest pain and dyspnea. Computed tomography scan of chest revealed bilateral pleural effusion. Cytological examination of pleural fluid was found to contain malignant epithelial cells. Fine needle aspiration cytology of ulcero-proliferative lesion in left sole was suggestive of malignant melanoma. The patient was treated with chemical pleurodesis but he succumbed to progressive disease after six months.

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“…Another modality in melanoma treatment involves the use of immunotherapy. The immune checkpoint inhibitors, anti CTLA-4 (ipilimumab) and anti-PD1/PDL1 antibodies (pembrolizumab, lambrolizumab, nivolumab, MPDL3280) (Figure 2) have made revolutionary immunotherapeutic advances and have demonstrated clinical activity in melanoma (23, [74][75][76][77][78]. In addition to their use as monotherapies, anti-CTLA-4 and anti-PD1/PDL1 are now being combined in clinical trials, and have shown impressive response rates (Table I).…”

Section: Multimodality Treatments and Future Directionsmentioning

confidence: 99%

New Drug Combination Strategies in Melanoma: Current Status and Future DirectionsNew Drug Combination Strategies in Melanoma: Current Status and Future Directions

Najem

Krayem

Perdrix

et al. 2017

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Abstract. Melanoma is the deadliest form of skinIncidence and mortality rates for melanomas, the most common form of cancer in people aged from 25 to 29, continue to rise faster than any other cancer type. Although melanoma accounts for only a small percentage of skin cancers, it is responsible for the majority of deaths of all skin cancers (1, 2). Increased understanding of the molecular events involved in melanoma development has led to the identification of novel targets and to the development of new targeted agents. Gene alterations identified in melanoma pointed to distinct molecular subsets of tumors with direct implications in therapeutic strategies. Among these, activating BRAF mutations occur in 50-60% of melanomas (V600E substitution represents about 90% of BRAF mutations), NRAS mutations in 20-30% of melanomas (mutually exclusive with BRAF mutation), KIT mutations and/or amplification in 39% of mucosal and 36% of acral melanomas (3, 4). These mutations opened new therapeutic perspectives targeting the MAPK pathway (hyperactivated in 90% of melanomas) with V600E BRAF, MEK or RTK inhibitors (5-7).Vemurafenib and dabrafenib, specific inhibitors of the mutant BRAF (V600E), have been approved by the Food and Drug Administration (FDA) in 2011 and 2013 respectively, for the treatment of patients with unresectable or metastatic melanoma carrying the V600E mutation in BRAF. Furthermore, trametinib a selective inhibitor of MEK1/2 was approved for the same indication in 2013. The approval of these inhibitors was based on improved rates of overall and progression-free survival compared to chemotherapy in phase III clinical trials (6, 8, 9). Moreover, among new MEK inhibitors in clinical development, pimasertib and binimetinib (MEK162) have been recently reported to be particularly promising in the case of patients with mutant NRAS melanoma (10-12). Finally, the results of clinical trials evaluating RTK inhibitors sunitinib and imatinib in patients presenting mutated c-KIT have been published and showed an average response rate of 20% (7, 13).Targeting MAPK pathway in melanoma with MAPK inhibitors has shown clinical benefit. However, the short duration of response and progression-free survival in patients due to resistance or to general toxicity indicate that 5941

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Novel Approaches to Treatment of Advanced Melanoma: A Review on Targeted Therapy and Immunotherapy

Cited by 127 publications

References 72 publications

Enhancement of antitumor immunity by combination of anti-CTLA-4 antibody and radioimmunotherapy through the suppression of Tregs

Enhancement of antitumor immunity by combination of anti-CTLA-4 antibody and radioimmunotherapy through the suppression of Tregs

Malignant Melanoma Presenting as Bilateral Pleural Effusion

New Drug Combination Strategies in Melanoma: Current Status and Future DirectionsNew Drug Combination Strategies in Melanoma: Current Status and Future Directions

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