Clinical Benefit from Ipilimumab Therapy in Melanoma Patients may be Associated with Serum CTLA4 Levels

Leung, Anna M.; Lee, Agnes Fermin; Ozao‐Choy, Junko; Ramos, Romela Irene; Hamid, Omid; O’Day, Steven; Shin-Sim, Myung; Morton, Donald L.; Faries, Mark B.; Sieling, Peter A.; Lee, Delphine J.

doi:10.3389/fonc.2014.00110

Cited by 52 publications

(40 citation statements)

References 28 publications

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“…Four of these markers showed significant correlations to OS. Soluble CTLA-4 correlated to both response and OS ( 40 ), whereas soluble LAG3 did not ( 13 , 26 ).…”

Section: Resultsmentioning

confidence: 99%

Biomarkers for Response of Melanoma Patients to Immune Checkpoint Inhibitors: A Systematic Review

et al. 2017

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BackgroundImmune checkpoint inhibitors (ICIs), targeting CTLA-4 or PD-1 molecules, have shown impressive therapeutic results. However, only 20–40% of advanced melanoma patients have durable responses to ICI, and these positive effects must be balanced against severe off-target immune toxicity and high costs. This urges the development of predictive biomarkers for ICI response to select patients with likely clinical benefit from treatment. Although many candidate biomarkers exist, a systematic overview of biomarkers and their usefulness is lacking.ObjectivesHere, we systematically review the current literature of clinical data of ICI treatment to provide an overview of candidate predictive biomarkers for ICI in melanoma patients.MethodsTo identify studies on biomarkers for clinical response or survival to ICI therapy in melanoma patients, we performed a systematic search in OVID MEDLINE and retrieved 429 publications, of which 67 met the eligibility criteria.ResultsBlood and genomic biomarkers were mainly studied for CTLA-4 ICI, while tumor tissue markers were analyzed for both CTLA-4 and PD-1 ICI. Blood cytology and soluble factors correlated more frequently to overall survival (OS) than to response, indicating their prognostic rather than predictive nature. Systemic T-cell response and regulation markers correlated to response, but progression-free survival or OS were not analyzed. Tumor tissue analyses revealed response correlations with mutational load, neoantigen load, immune-related gene expression, and CD8+ T-cell infiltration at the invasive margin. The predictive value of PD-L1 varied, possibly due to the influence of T-cell infiltration on tumor PD-L1 expression. Genomic biomarker studies addressed CTLA-4 and other immune-related genes.ConclusionThis review outlines all published biomarkers for ICI therapy and highlights potential candidate markers for future research. To date, PD-L1 is the best studied biomarker for PD-1 ICI response. The most promising candidate predictive biomarkers for ICI response have not yet been identified. Variations in outcome parameters, statistical power, and analyses hampered summary of the results. Further investigation of biomarkers in larger patient cohorts using standardized objectives and outcome measures is recommended.

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“…Four of these markers showed significant correlations to OS. Soluble CTLA-4 correlated to both response and OS ( 40 ), whereas soluble LAG3 did not ( 13 , 26 ).…”

Section: Resultsmentioning

confidence: 99%

Biomarkers for Response of Melanoma Patients to Immune Checkpoint Inhibitors: A Systematic Review

et al. 2017

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“…This is corroborated by the direct correlation of sCTLA‐4 levels in serum of stage 4 metastatic melanoma patients and the efficacy of ipilimumab in them. It was found that, at least in a small cohort of patients, those with higher serum sCTLA‐4 levels exhibited better response and improved survival after treatment with ipilimumab . Additionally, these can also be used as therapeutic end point markers to study the efficacy of not only such immunotherapeutic treatment but after chemotherapeutic intervention as well.…”

Section: Conclusion: Importance Of Soluble Immune Checkpoint Moleculementioning

confidence: 99%

“…It was found that, at least in a small cohort of patients, those with higher serum sCTLA-4 levels exhibited better response and improved survival after treatment with ipilimumab. 161 Additionally, these can also be used as therapeutic end point markers to study the efficacy of not only such immunotherapeutic treatment but after chemotherapeutic intervention as well. Also, since the levels of these soluble markers vary in patients and healthy people, it will be interesting to investigate them as very early markers of tumor development, or even screen individuals with specific lifestyles or genetic or metabolic susceptibility for earlier intervention, much before any physical indication of disease development.…”

Section: Tnf Superfamily Members In Tumor-specific Immune Response mentioning

confidence: 99%

Soluble immune checkpoint molecules: Serum markers for cancer diagnosis and prognosis

2019

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Background With the recent advances in the understanding of the interaction of the immune system with developing tumor, it has become imperative to consider the immunological parameters for both cancer diagnosis and disease prognosis. Additionally, in the era of emerging immunotherapeutic strategies in cancer, it is very important to follow the treatment outcome and also to predict the correct immunotherapeutic strategy in individual patients. There being enormous heterogeneity among tumors at different sites or between primary and metastatic tumors in the same individual, or interpatient heterogeneity, it is very important to study the tumor‐immune interaction in the tumor microenvironment and beyond. Importantly, molecular tools and markers identified for such studies must be suitable for monitoring in a noninvasive manner. Recent findings Recent studies have shown that the immune checkpoint molecules play a key role in the development and progression of tumors. In‐depth studies of these molecules have led to the development of most of the cancer immunotherapeutic reagents that are currently either in clinical use or under different phases of clinical trials. Interestingly, many of these cell surface molecules undergo alternative splicing to produce soluble isoforms, which can be tracked in the serum of patients. Conclusions Several studies demonstrate that the serum levels of these soluble isoforms could be used as noninvasive markers for cancer diagnosis and disease prognosis or to predict patient response to specific therapeutic strategies.

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“…Patients treated with either mutated BRAF or MEK inhibitors, despite initial excellent response rates, showed a rapid relapse [ 4 ]. The anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) monoclonal antibody ipilimumab, despite its effectiveness, has side effects that can be non-reversible (autoimmune responses, bowel perforation) [ 5 ]. Thus, the elucidation of the molecular mechanisms of melanoma growth and progression is urgently needed for the identification of novel targets of intervention for the prevention and therapy of this disease [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Estrogen Receptor β Agonists Differentially Affect the Growth of Human Melanoma Cell Lines

et al. 2015

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BackgroundCutaneous melanoma is an aggressive malignancy; its incidence is increasing worldwide and its prognosis remains poor. Clinical observations indicate that estrogen receptor β (ERβ) is expressed in melanoma tissues and its expression decreases with tumor progression, suggesting its tumor suppressive function. These experiments were performed to investigate the effects of ERβ activation on melanoma cell growth.Methods and ResultsProtein expression was analyzed by Western blot and immunofluorescence assays. Cell proliferation was assessed by counting the cells by hemocytometer. ERβ transcriptional activity was evaluated by gene reporter assay. Global DNA methylation was analyzed by restriction enzyme assay and ERβ isoforms were identified by qRT-PCR. We demonstrated that ERβ is expressed in a panel of human melanoma cell lines (BLM, WM115, A375, WM1552). In BLM (NRAS-mutant) cells, ERβ agonists significantly and specifically inhibited cell proliferation. ERβ activation triggered its cytoplasmic-to-nuclear translocation and transcriptional activity. Moreover, the antiproliferative activity of ERβ agonists was associated with an altered expression of G1-S transition-related proteins. In these cells, global DNA was found to be hypomethylated when compared to normal melanocytes; this DNA hypomethylation status was reverted by ERβ activation. ERβ agonists also decreased the proliferation of WM115 (BRAF V600D-mutant) cells, while they failed to reduce the growth of A375 and WM1552 (BRAF V600E-mutant) cells. Finally, we could observe that ERβ isoforms are expressed at different levels in the various cell lines. Specific oncogenic mutations or differential expression of receptor isoforms might be responsible for the different responses of cell lines to ERβ agonists.ConclusionsOur results demonstrate that ERβ is expressed in melanoma cell lines and that ERβ agonists differentially regulate the proliferation of these cells. These data confirm the notion that melanoma is a heterogeneous tumor and that genetic profiling is mandatory for the development of effective personalized therapeutic approaches for melanoma patients.

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Clinical Benefit from Ipilimumab Therapy in Melanoma Patients may be Associated with Serum CTLA4 Levels

Cited by 52 publications

References 28 publications

Biomarkers for Response of Melanoma Patients to Immune Checkpoint Inhibitors: A Systematic Review

Biomarkers for Response of Melanoma Patients to Immune Checkpoint Inhibitors: A Systematic Review

Soluble immune checkpoint molecules: Serum markers for cancer diagnosis and prognosis

Estrogen Receptor β Agonists Differentially Affect the Growth of Human Melanoma Cell Lines

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