Role of Immune Checkpoint Inhibitors or Targeted Therapy in the Treatment of Patients with Melanoma Volume II

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: 20 September 2024 | Viewed by 10567

Special Issue Editors


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Guest Editor
Department of Oncology, Aarhus University Hospital, DK-8200 Aarhus, Denmark
Interests: cancer immunology; innate immune system; melanoma; immunotherapy; biomarkers for immunotherapy
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Guest Editor
Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, DK-2730 Herlev, Denmark
Interests: melanoma

Special Issue Information

Dear Colleagues,

This collection is the second edition of the Special Issue “Role of Immune Checkpoint Inhibitors in the Treatment of Patients with Melanoma” (https://www.mdpi.com/journal/cancers/special_issues/melanoma_immunotherapy).

The past few years have brought revolutionary new treatments to melanoma patients, including checkpoint inhibitors and targeted therapy for both patients receiving adjuvant treatment as well as treatment for metastatic disease. Melanoma has become a model disease for developing new immunotherapies, and new drugs are constantly under development. We are very much in need of more knowledge about biomarkers to select the right patient for the right treatment, to become more effective at treating the immune-mediated adverse events in these patients, and to overcome immune resistance. We need to examine the effect of these new treatment strategies in all subgroups of melanoma patients, including ocular and mucosal melanoma, and we need to explore treatment combinations, as well as real-life benefits.

Dr. Henrik Schmidt
Dr. Eva Ellebæk
Guest Editors

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Published Papers (6 papers)

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Research

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33 pages, 3063 KiB  
Article
Modern Approach to Melanoma Adjuvant Treatment with Anti-PD1 Immune Check Point Inhibitors or BRAF/MEK Targeted Therapy: Multicenter Real-World Report
by Joanna Placzke, Magdalena Rosińska, Paweł Sobczuk, Marcin Ziętek, Natasza Kempa-Kamińska, Bożena Cybulska-Stopa, Grażyna Kamińska-Winciorek, Wiesław Bal, Jacek Mackiewicz, Łukasz Galus, Manuela Las-Jankowska, Michał Jankowski, Robert Dziura, Kamil Drucis, Aneta Borkowska, Tomasz Świtaj, Paweł Rogala, Katarzyna Kozak, Anna Klimczak, Paulina Jagodzińska-Mucha, Anna Szumera-Ciećkiewicz, Hanna Koseła-Paterczyk and Piotr Rutkowskiadd Show full author list remove Hide full author list
Cancers 2023, 15(17), 4384; https://doi.org/10.3390/cancers15174384 - 1 Sep 2023
Cited by 1 | Viewed by 1609
Abstract
Background: The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. Materials and Methods: An analysis of data on 248 consecutive melanoma stage III and IV patients given adjuvant therapy in eight centers (February 2019 to January 2021) was conducted. [...] Read more.
Background: The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. Materials and Methods: An analysis of data on 248 consecutive melanoma stage III and IV patients given adjuvant therapy in eight centers (February 2019 to January 2021) was conducted. Results: The analyzed cohort comprised 147 melanoma patients given anti-PD1 (33% nivolumab, 26% pembrolizumab), and 101 (41%) were given dabrafenib plus trametinib (DT). The 2-year overall survival (OS), relapse-free survival (RFS), and distant-metastases-free survival (DMFS) rates were 86.7%, 61.4%, and 70.2%, respectively. The disease stage affected only the RFS rate; for stage IV, it was 52.2% (95% CI: 33.4–81.5%) vs. 62.5% (95% CI: 52.3–74.8%) for IIIA-D, p = 0.0033. The type of lymph node surgery before adjuvant therapy did not influence the outcomes. Completion of lymph node dissection cessation after positive SLNB did not affect the results in terms of RFS or OS. Treatment-related adverse events (TRAE) were associated with longer 24-month RFS, with a rate of 68.7% (55.5–84.9%) for TRAE vs. 56.6% (45.8–70%) without TRAE, p = 0.0031. For TRAE of grade ≥ 3, a significant decline in OS to 60.6% (26.9–100%; p = 0.004) was observed. Conclusions: Melanoma adjuvant therapy with anti-PD1 or DT outside clinical trials appears to be effective and comparable with the results of registration studies. Our data support a de-escalating surgery approach in melanoma treatment. Full article
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17 pages, 1467 KiB  
Article
Analysis of the Gut Microbiome and Dietary Habits in Metastatic Melanoma Patients with a Complete and Sustained Response to Immunotherapy
by Marin Golčić, Luka Simetić, Davorin Herceg, Krešimir Blažičević, Gordana Kenđel Jovanović, Ivan Dražić, Andrej Belančić, Nataša Skočibušić, Dora Palčevski, Igor Rubinić, Vera Vlahović-Palčevski, Tea Majnarić, Renata Dobrila-Dintinjana and Stjepko Pleština
Cancers 2023, 15(11), 3052; https://doi.org/10.3390/cancers15113052 - 4 Jun 2023
Cited by 2 | Viewed by 2029
Abstract
Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients [...] Read more.
Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients only into responders and non-responders. The aim of this study was to elucidate whether metastatic melanoma patients with complete and sustained response to immunotherapy exhibit differences in gut microbiome composition among themselves, and whether those differences were associated with specific dietary habits. Shotgun metagenomic sequencing revealed that patients who exhibited a complete response after more than 9 months of treatment (late responders) exhibited a significantly higher beta-diversity (p = 0.02), with a higher abundance of Coprococcus comes (LDA 3.548, p = 0.010), Bifidobacterium pseudocatenulatum (LDA 3.392, p = 0.024), and lower abundance of Prevotellaceae (p = 0.04) compared to early responders. Furthermore, late responders exhibited a different diet profile, with a significantly lower intake of proteins and sweets and a higher intake of flavones (p < 0.05). The research showed that metastatic melanoma patients with a complete and sustained response to immunotherapy were a heterogeneous group. Patients with a late complete response exhibited microbiome and dietary habits which were previously associated with an improved response to immunotherapy. Full article
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13 pages, 729 KiB  
Article
Better Late Than Never: The Impact of Steroidal Treatment on the Outcome of Melanoma Patients Treated with Immunotherapy
by Neta Bar-Hai, Guy Ben-Betzalel, Ronen Stoff, Shirly Grynberg, Jacob Schachter, Ronnie Shapira-Frommer and Nethanel Asher
Cancers 2023, 15(11), 3041; https://doi.org/10.3390/cancers15113041 - 3 Jun 2023
Cited by 6 | Viewed by 2580
Abstract
Background: Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients [...] Read more.
Background: Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients concerning initiation timing and dosage. Methods: A retrospective, single-center analysis of patients with advanced melanoma who underwent first-line ICI therapy during 2014–2020 was conducted. Results: Among the 415 patients, two-hundred patients (48.3%) were exposed to steroids during the first line, most of them due to irAEs (n = 169, 84.5%). Nearly a quarter of them were exposed to steroids within the first four weeks of treatment. Surprisingly, steroidal exposure was associated with better progression-free survival (PFS; HR = 0.74, p = 0.015); however, early exposure (within four weeks of treatment) resulted in a significantly shorter PFS compared to late exposure (adjusted HR 3.2, p < 0.001). Conclusions: Early exposure to corticosteroids during the priming phase of ICI therapy could impede the establishment of an effective immune response. These results suggest that caution should be exercised when considering the use of steroids for the management of early-onset irAEs. Full article
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10 pages, 2111 KiB  
Communication
Cardiovascular Immunotoxicity Associated with Immune Checkpoint Inhibitors in Metastatic Melanoma
by Jean-Matthieu L’Orphelin, Charles Dollalille, Julia Akroun, Joachim Alexandre and Anne Dompmartin
Cancers 2023, 15(7), 2170; https://doi.org/10.3390/cancers15072170 - 6 Apr 2023
Cited by 2 | Viewed by 1871
Abstract
Background: Checkpoint inhibitors, such as PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab), are widely used in metastatic melanoma, and most immune-related adverse events are known. Several cardiovascular AEs (CVAEs) associated with immune checkpoint inhibitor exposure have been reported in post-marketing surveillance studies [...] Read more.
Background: Checkpoint inhibitors, such as PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab), are widely used in metastatic melanoma, and most immune-related adverse events are known. Several cardiovascular AEs (CVAEs) associated with immune checkpoint inhibitor exposure have been reported in post-marketing surveillance studies and represent major issues for patients with melanoma during and after cancer treatment. Data on CVAES induced by immune checkpoint inhibitors in melanoma, especially incidence and risk factors, are lacking. Methods: A systematic review of the literature up to 31 August 2020 was performed in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov register according to prespecified selection criteria from inception to 7 April 2020. Statistics were performed on 3289 patients from five randomized clinical trials on melanoma. Results: Patients with melanoma treated with immune checkpoint inhibitors had a significant risk of presenting dyslipidemia (Peto OR: 4.74, 95% CI: 2.16–10.41, p < 0.01, I2 = 0%, p = 0.94). The Peto OR was numerically significant for pericarditis, myocarditis, heart failure, myocardial infarction, cerebral ischemia, high pulmonary pressure, blood high pressure, arrhythmias, endocarditis, and conduction disturbances, but the confidence interval was not significant. The risk of CVAEs was not statistically different between melanoma treated with immune checkpoint inhibitors and other tumors treated with immune checkpoint inhibitors (range of p-value from 0.13 to 0.95). No interaction between follow-up length and CVAE reporting was found. Conclusions: Our study underlines that checkpoint inhibitors used for melanoma increase CVAEs, especially dyslipidemia, which could pave the way to chronic inflammatory processes, atherosclerosis, and, finally, ischemic cardiopathy. These cardiovascular adverse events could be acute or delayed, justifying the monitoring of lipidic biology and a baseline cardiology consultation. Full article
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Review

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21 pages, 1853 KiB  
Review
Adjuvant PD-1 Checkpoint Inhibition in Early Cutaneous Melanoma: Immunological Mode of Action and the Role of Ultraviolet Radiation
by Matthias Brandlmaier, Magdalena Hoellwerth, Peter Koelblinger, Roland Lang and Andrea Harrer
Cancers 2024, 16(8), 1461; https://doi.org/10.3390/cancers16081461 - 11 Apr 2024
Viewed by 607
Abstract
Melanoma ranks as the fifth most common solid cancer in adults worldwide and is responsible for a significant proportion of skin-tumor-related deaths. The advent of immune checkpoint inhibition with anti-programmed death protein-1 (PD-1) antibodies has revolutionized the adjuvant treatment of high-risk, completely resected [...] Read more.
Melanoma ranks as the fifth most common solid cancer in adults worldwide and is responsible for a significant proportion of skin-tumor-related deaths. The advent of immune checkpoint inhibition with anti-programmed death protein-1 (PD-1) antibodies has revolutionized the adjuvant treatment of high-risk, completely resected stage III/IV melanoma. However, not all patients benefit equally. Current strategies for improving outcomes involve adjuvant treatment in earlier disease stages (IIB/C) as well as perioperative treatment approaches. Interfering with T-cell exhaustion to counteract cancer immune evasion and the immunogenic nature of melanoma is key for anti-PD-1 effectiveness. Yet, the biological rationale for the efficacy of adjuvant treatment in clinically tumor-free patients remains to be fully elucidated. High-dose intermittent sun exposure (sunburn) is a well-known primary risk factor for melanomagenesis. Also, ultraviolet radiation (UVR)-induced immunosuppression may impair anti-cancer immune surveillance. In this review, we summarize the current knowledge about adjuvant anti-PD-1 blockade, including a characterization of the main cell types most likely responsible for its efficacy. In conclusion, we propose that local and systemic immunosuppression, to some extent UVR-mediated, can be restored by adjuvant anti-PD-1 therapy, consequently boosting anti-melanoma immune surveillance and the elimination of residual melanoma cell clones. Full article
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20 pages, 5344 KiB  
Review
A Review of Advanced Cutaneous Melanoma Therapies and Their Mechanisms, from Immunotherapies to Lysine Histone Methyl Transferase Inhibitors
by Renato Santos de Oliveira Filho, Daniel Arcuschin de Oliveira, Melissa Maeda Nisimoto and Luciana Cavalheiro Marti
Cancers 2023, 15(24), 5751; https://doi.org/10.3390/cancers15245751 - 8 Dec 2023
Cited by 3 | Viewed by 1372
Abstract
Advanced cutaneous melanoma is considered to be the most aggressive type of skin cancer and has variable rates of treatment response. Currently, there are some classes of immunotherapy and target therapies for its treatment. Immunotherapy can inhibit tumor growth and its recurrence by [...] Read more.
Advanced cutaneous melanoma is considered to be the most aggressive type of skin cancer and has variable rates of treatment response. Currently, there are some classes of immunotherapy and target therapies for its treatment. Immunotherapy can inhibit tumor growth and its recurrence by triggering the host’s immune system, whereas targeted therapy inhibits specific molecules or signaling pathways. However, melanoma responses to these treatments are highly heterogeneous, and patients can develop resistance. Epigenomics (DNA/histone modifications) contribute to cancer initiation and progression. Epigenetic alterations are divided into four levels of gene expression regulation: DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation. Deregulation of lysine methyltransferase enzymes is associated with tumor initiation, invasion, development of metastases, changes in the immune microenvironment, and drug resistance. The study of lysine histone methyltransferase (KMT) and nicotinamide N-methyltransferase (NNMT) inhibitors is important for understanding cancer epigenetic mechanisms and biological processes. In addition to immunotherapy and target therapy, the research and development of KMT and NNMT inhibitors is ongoing. Many studies are exploring the therapeutic implications and possible side effects of these compounds, in addition to their adjuvant potential to the approved current therapies. Importantly, as with any drug development, safety, efficacy, and specificity are crucial considerations when developing methyltransferase inhibitors for clinical applications. Thus, this review article presents the recently available therapies and those in development for advanced cutaneous melanoma therapy. Full article
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