scholarly journals miRNAs as Key Players in the Management of Cutaneous Melanoma

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 415 ◽  
Author(s):  
Celeste Lorusso ◽  
Simona De Summa ◽  
Rosamaria Pinto ◽  
Katia Danza ◽  
Stefania Tommasi
Keyword(s):  
Biological Networks ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Mirna Gene ◽  
Progression Free Survival ◽  
Extracellular Vesicle ◽  
Resistance Mechanisms ◽  
Melanoma Patients ◽  
New Biomarkers

The number of treatment options for melanoma patients has grown in the past few years, leading to considerable improvements in both overall and progression-free survival. Targeted therapies and immune checkpoint inhibitors have opened a new era in the management of melanoma patients. Despite the clinical advances, further research efforts are needed to identify other “druggable” targets and new biomarkers to improve the stratification of melanoma patients who could really benefit from targeted and immunotherapies. To this end, many studies have focused on the role of microRNAs (miRNAs) that are small non-coding RNAs (18-25 nucleotides in length), which post-transcriptionally regulate the expression of their targets. In cancer, they can behave either as oncogenes or oncosuppressive genes and play a central role in many intracellular pathways involved in proliferation and invasion. Given their modulating activity on the transcriptional landscape, their biological role is under investigation to study resistance mechanisms. They are able to mediate the communication between tumor cells and their microenvironment and regulate tumor immunity through direct regulation of the genes involved in immune activation or suppression. To date, a very promising miRNA-based strategy is to use them as prognosis and diagnosis biomarkers both as cell-free miRNAs and extracellular-vesicle miRNAs. However, miRNAs have a complex role since they target different genes in different cellular conditions. Thus, the ultimate aim of studies has been to recapitulate their role in melanoma in biological networks that account for miRNA/gene expression and mutational state. In this review, we will provide an overview of current scientific knowledge regarding the oncogenic or oncosuppressive role of miRNAs in melanoma and their use as biomarkers, with respect to approved therapies for melanoma treatment.

scholarly journals Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 304
Author(s):  
Marta Araujo-Castro ◽  
Eider Pascual-Corrales ◽  
Javier Molina-Cerrillo ◽  
Teresa Alonso-Gordoa
Keyword(s):  
Adrenocortical Carcinoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Mechanisms Of Resistance ◽  
Response Efficacy ◽  
Predictors Of Response ◽  
Primary Endpoints ◽  
Tumor Mutational Burden

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

scholarly journals CEACAM1: Expression and Role in Melanocyte Transformation

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Gabriela Turcu ◽  
Roxana Ioana Nedelcu ◽  
Daniela Adriana Ion ◽  
Alice Brînzea ◽  
Mirela Daniela Cioplea ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Adhesion Molecule ◽  
Checkpoint Inhibitors ◽  
Advanced Melanoma ◽  
Melanoma Treatment ◽  
Melanoma Patients ◽  
New Biomarkers ◽  
Cell Adhesion Molecule 1

Metastases represent the main cause of death in melanoma patients. Despite the current optimized targeted therapy or immune checkpoint inhibitors the treatment of metastatic melanoma is unsatisfactory. Because of the poor prognosis of advanced melanoma there is an urgent need to identify new biomarkers to differentiate melanoma cells from normal melanocytes, to stratify patients according to their risk, and to identify subgroups of patients that require close follow-up or more aggressive therapy. Furthermore, melanoma progression has been associated with the dysregulation of cell adhesion molecules. We have reviewed the literature and have discussed the important role of the expression of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) in the development of melanoma. Thus, novel insights into CEACAM1 may lead to promising strategies in melanoma treatment, in monitoring melanoma patients, in assessing the response to immunotherapy, and in completing the standard immunohistochemical panel used in melanoma examination.

scholarly journals Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients

2021 ◽  
Author(s):  
Maaike Biewenga ◽  
Monique K. van der Kooij ◽  
Michel W. J. M. Wouters ◽  
Maureen J. B. Aarts ◽  
Franchette W. P. J. van den Berkmortel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Liver Metastasis ◽  
Combination Therapy ◽  
Real World ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Negative Effect ◽  
Melanoma Patients

Abstract Background Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort. Methods Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3–4 hepatitis and outcome. Results 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44). Conclusion Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.

scholarly journals Update on the role of pembrolizumab in patients with unresectable or metastatic colorectal cancer

2021 ◽  
Vol 14 ◽  
pp. 175628482110244
Author(s):  
Vanessa Wookey ◽  
Axel Grothey
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Cancer Type ◽  
Cancer Therapies ◽  
Multiple Cancer ◽  
Multiple Treatment

Colorectal cancer (CRC) is the third most common cancer type in both men and women in the USA. Most patients with CRC are diagnosed as local or regional disease. However, the survival rate for those diagnosed with metastatic disease remains disappointing, despite multiple treatment options. Cancer therapies for patients with unresectable or metastatic CRC are increasingly being driven by particular biomarkers. The development of various immune checkpoint inhibitors has revolutionized cancer therapy over the last decade by harnessing the immune system in the treatment of cancer, and the role of immunotherapy continues to expand and evolve. Pembrolizumab is an anti-programmed cell death protein 1 immune checkpoint inhibitor and has become an essential part of the standard of care in the treatment regimens for multiple cancer types. This paper reviews the increasing evidence supporting and defining the role of pembrolizumab in the treatment of patients with unresectable or metastatic CRC.

scholarly journals Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 623
Author(s):  
Brigida Anna Maiorano ◽  
Giovanni Schinzari ◽  
Davide Ciardiello ◽  
Maria Grazia Rodriquenz ◽  
Antonio Cisternino ◽  
...  
Keyword(s):  
Cancer Vaccines ◽  
Viral Vectors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Tumor Development ◽  
Resistance Mechanisms ◽  
High Morbidity ◽  
Therapeutic Vaccines ◽  
Combination Strategies ◽  
New Treatment

Background: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neoplasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. Methods: We searched PubMed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. Results: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. Conclusions: Further preclinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

scholarly journals The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

2021 ◽  
Vol 22 (14) ◽  
pp. 7511
Author(s):  
Albina Fejza ◽  
Maurizio Polano ◽  
Lucrezia Camicia ◽  
Evelina Poletto ◽  
Greta Carobolante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Effective Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Hypoxia ◽  
Melanoma Cells ◽  
Vessel Normalization ◽  
Melanoma Patients

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

The predictive value of MAP2K1/2 mutations for efficiency of immunotherapy in melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21587-e21587
Author(s):  
Ting Ye ◽  
Jieying Zhang ◽  
Xinyi Liu ◽  
Mengmei Yang ◽  
Yuhan Zhou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Predictive Value ◽  
Cox Regression ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Driver Mutations ◽  
Cox Regression Analysis ◽  
Melanoma Patients ◽  
The Impact

e21587 Background: Immunotherapies targeting immune checkpoint receptors have become the cornerstone of systemic treatment options for malignant melanoma. The response to these immunotherapies may correlate with driver mutations. MAP2K1/2 genes are mutated in approximately 10% of melanomas, however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. Methods: Six metastatic melanoma clinical cohorts treated with ICIs were included to investigate the association between clinical efficacy of immunotherapy and MAP2K1/2 mutations. Survival analyses were conducted in cohorts receiving two kinds of ICB agents, namely anti-CTLA-4 or anti-PD-1. RNA expression profiling from these cohorts and from the TCGA melanoma cohort were used to explore the potential mechanism related to immune activation. Results: In an independent anti-CTLA-4-treated cohort (n = 110), we found that MAP2K1/2 mutations are predictive of high objective response rate (17.6% vs 1.3%, p = 0.0185) and long progression-free survival [median OS, 49.2 months vs 8.3 months; hazard ratio (HR) = 0.37; 95% CI, 0.15–0.91; p = 0.0307] and overall survival (median PFS, 19.4 months vs 2.8 months; HR = 0.2; 95% CI, 0.05–0.83; p = 0.0262). This predictive value was further validated in a pooled anti-CTLA-4-treated cohort (n = 235) in terms of overall survival (median OS, 49.3 months vs 22.0 months; HR = 0.44; 95% CI, 0.22–0.91; p = 0.0255). However, no correlation between MAP2K1/2 mutations and overall survival was observed in the anti-PD-1-treated cohort (n = 285). Subgroup Cox regression analysis indicated that MAP2K-mutated patients receive less benefit from the anti-PD-1 monotherapy than from the anti-CTLA-4 treatment (median OS, 27.0 months vs 49.3 months; HR = 3.26; 95% CI, 1.18–9.02; p = 0.0225), which was contrary to the result obtained for the total population. Furthermore, transcriptome profiling analysis revealed that MAP2K-mutated tumors are enriched in CD8+ T cells, B cells, and neutrophil cells and also express high levels of CD33 and IL10, which might be the underlying mechanism for melanoma patients with MAP2K1/2-mutated benefit more from anti-CTLA-4 treatment. Conclusions: We identified mutations in MAP2K1/2 genes as the independent predictive factors for anti-CTLA-4 therapy in melanoma patients and found that anti-CTLA-4 treatment in patient harbouring MAP2K1/2 mutations might be more effective than the anti-PD-1 therapy.

scholarly journals Where does transplant fit in the age of targeted therapies?

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 287-293 ◽  
Author(s):  
Victor A. Chow ◽  
Ajay K. Gopal
Keyword(s):  
Follicular Lymphoma ◽  
Hematopoietic Cell Transplantation ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Low Toxicity ◽  
First Recurrence ◽  
Autologous Hct

Abstract The role of hematopoietic cell transplantation (HCT) for indolent lymphoma has evolved over the last 5 years with the availability of novel low-toxicity therapies and a better understanding of the prognosis of these entities. However, despite numerous treatment options for patients with follicular lymphoma, none are thought to be curative, and many require ongoing therapy with chronic toxicity. Historical trials indicate that autologous HCT as initial consolidation leads to improved progression-free survival, but not overall survival (OS) and, thus, is not typically recommended. However, autologous HCT for chemosensitive relapse can be carried out with ∼1% early mortality risk, affording disease control lasting a median of 3 to 5 years and the potential to improve OS. These results may compare favorably in efficacy, toxicity, and cost vs multiple sequential novel therapies with shorter durations of benefit. Recent data indicate that autologous HCT in follicular lymphoma patients with early initial progression will result in more than one third being alive and without relapse at 5 years, leading to improved OS when used within a year of the first recurrence. Unlike other available therapies, allogeneic HCT has the potential to cure up to one half of those transplanted with indolent B-cell non-Hodgkin lymphoma, although the risks need to be recognized and appropriate patient and donor selection is critical to ensure the best outcomes. HCT continues to remain a viable option in the current era of multiple targeted agents.

Baseline and early change of neutrophil to lymphocyte ratio (bNLR and ΔNLR) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab: Preliminary results of the Meet-URO 15 (I-BIO-REC) study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 752-752
Author(s):  
Sara Elena Rebuzzi ◽  
Sebastiano Buti ◽  
Luca Galli ◽  
Giuseppe Procopio ◽  
Ugo De Giorgi ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Complete Blood Count ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Prognostic Role ◽  
Free Survival ◽  
The Difference ◽  
Line Of Therapy ◽  
Metastatic Sites

752 Background: Biomarkers to select mRCC patients most likely to benefit to immune-checkpoint inhibitors are still needed. The ongoing retrospective multicentre Meet-URO 15 (I-BIO-REC) study evaluates the prognostic role of peripheral blood cells in mRCC patients treated with nivolumab. Methods:The primary endpoint of the study was median overall survival (mOS) according to bNLR. Complete blood count was collected at the first four cycles of nivolumab. NLR was defined as the ratio of neutrophil to lymphocyte (cutoff = 3) and ΔNLR the difference between NLR at 2nd cycle and bNLR (median used as cutoff = 0.3). Here we reported preliminary analyses on bNLR and DNLR. Results: From May 2016 to January 2019 189 patients started nivolumab as 2nd (62%), 3rd (25%) and > 3rd (13%) line. Median age was 69 years, 67% were male and 87% had clear cell histology. Baseline IMDC group was favorable in 26%, intermediate in 63% and poor in 11%. Lymph-nodes, visceral and bone metastases were present in 55%, 92% and 37%. mOS and progression-free survival (PFS) were 30.5 months and 9.5 months. Overall response rate (ORR) and disease control rate (DCR) were 28% and 57%. bNLR was available in 162 patients: bNLR < 3 (52%) correlated with statistically significant longer PFS [11.5 vs 5.6 months; HR 1.61 (1.09-2.39), p = 0.017] and OS [NR vs 22.4 months; HR 2.61 (1.53-4.46), p < 0.001], with similar ORR (32% vs 32%) but higher DCR (66% vs 55%) compared to NLR ≥ 3. ΔNLR was available in 136 patients: ΔNLR < 0.3 (50%) correlated with statistically significant longer PFS [17.1 vs 8.5 months; HR 1.57 (1.02-2.43) p = 0.04] and OS [medians not reached; HR 1.91 (1.04-3.51) p = 0.038], with similar ORR (39% vs 32%) but higher DCR (73% vs 56%) compared to ΔNLR ≥ 0.3. Univariate and multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation between ΔNLR with PFS and OS and NLR with OS but not with PFS. Conclusions: Preliminary analyses of our study showed a prognostic role of bNLR and early ΔNLR in mRCC patients treated with nivolumab.

scholarly journals Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors

2019 ◽  
Vol 8 (4) ◽  
pp. e1568812 ◽  
Author(s):  
Arielle Elkrief ◽  
Layal El Raichani ◽  
Corentin Richard ◽  
Meriem Messaoudene ◽  
Wiam Belkaid ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Melanoma Patients
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