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Immunotherapy in Melanoma: Recent Advances and Future Directions

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 28545

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Special Issue Editors

Prof. Dr. Helen Gogas

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Guest Editor

First Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Interests: melanoma; immunotherapy; targeted therapy

Dr. Dimitrios C. Ziogas

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Guest Editor

First Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
Interests: melanoma; immunotherapy; targeted therapy

Special Issue Information

Dear Colleagues,

Looking beyond the pandemic, immune-checkpoint inhibitors (ICIs) continue to offer long-term remission in melanoma, either in an adjuvant or a metastatic setting. At the same time, the development of new immunotherapeutic agents (e.g., relatlimab and bempegaldesleukin) or combinatorial regimens (e.g., immune/targeted combinations, intralesional infusions and ICIs) and the identification of intratumoral or circulating biomarkers continue to open new horizons and produce new questions for immune-mediated treatments. Issues such as the duration and the exact dose of anti-PD1/anti-PDL1 and anti-CTLA4 agents in metastatic and locoregional disease, the stage of early melanoma that should be treated with ICIs and the potential of intralesional infusions are still under consideration and an open field for debate. To this end, this Special Issue of Cancers aims to explore the constantly remodeled area of immunotherapy in melanoma management in the post-COVID-19 era and tries to recap where we are and where we are going in terms of the knowledge on immune-mediated therapies in melanoma.

We look forward to receiving your contributions.

Prof. Dr. Helen Gogas
Dr. Dimitrios C. Ziogas
Guest Editors

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Keywords

melanoma
immunotherapy
prognostic and predictive biomarkers
recurrence-free and overall survival
adjuvant/neoadjuvant immunotherapy
anti-PD1/anti-PD-L1 and anti-CTLA4 agents

Published Papers (9 papers)

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Research

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14 pages, 237 KiB

Open AccessArticle

COVID-19 in Patients with Melanoma: A Single-Institution Study

by Amalia Anastasopoulou, Panagiotis T. Diamantopoulos, Panagiotis Kouzis, Maria Saridaki, Konstantinos Sideris, Michael Samarkos and Helen Gogas

Cancers 2024, 16(1), 96; https://doi.org/10.3390/cancers16010096 - 24 Dec 2023

Viewed by 818

Abstract

We conducted a single-center, non-interventional retrospective study of melanoma patients with COVID-19 (1 March 2020 until 17 March 2023). The cohort was further divided into three groups according to the periods of SARS-CoV-2 variant dominance in Greece. We recorded demographics, comorbidities, vaccination data, cancer diagnosis/stage, types of systemic melanoma treatments, date of COVID-19 diagnosis and survival. We identified 121 patients. The vast majority (87.6%) had advanced disease (stages III or IV). A total of 80.1% of the patients were receiving immune checkpoint inhibitor-based therapies, 92.5% had asymptomatic/mild COVID-19 and 7.4% had moderate/severe/critical disease, while 83.5% contracted COVID-19 during the third period of the pandemic. Sixteen patients (13.2%) were hospitalized for COVID-19 with a median length of stay of 12 days (range: 1–55 days). Advanced age, heart failure, number of comorbidities (≤1 vs. >1), vaccination status and the time period of the infection correlated with more severe COVID-19, whereas only heart failure and time period were independently correlated with severity. The 30-day mortality rate after COVID-19 was 4.2%. With a median follow-up of 340 days post-COVID-19, 17.4% of patients were deceased. In this cohort of melanoma patients with COVID-19, the 30-day mortality rate was low. There was no association between melanoma stage, treatment receipt and type of treatment with COVID-19 severity. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

15 pages, 1724 KiB

Open AccessArticle

Adjuvant BRAF-MEK Inhibitors versus Anti PD-1 Therapy in Stage III Melanoma: A Propensity-Matched Outcome Analysis

by Melissa M. De Meza, Willeke A. M. Blokx, Johannes J. Bonenkamp, Christian U. Blank, Maureen J. B. Aarts, Franchette W. P. J. van den Berkmortel, Marye J. Boers-Sonderen, Jan Willem B. De Groot, John B. A. G. Haanen, Geke A. P. Hospers, Ellen Kapiteijn, Olivier J. Van Not, Djura Piersma, Rozemarijn S. Van Rijn, Marion Stevense-den Boer, Astrid A. M. Van der Veldt, Gerard Vreugdenhil, Alfonsus J. M. Van den Eertwegh, Karijn P. M. Suijkerbuijk and Michel W. J. M. Wouters

Cancers 2023, 15(2), 409; https://doi.org/10.3390/cancers15020409 - 07 Jan 2023

Cited by 3 | Viewed by 3281

Abstract

Adjuvant BRAF/MEK- and anti-PD-1 inhibition have significantly improved recurrence-free survival (RFS) compared to placebo in resected stage III BRAF-mutant melanoma. However, data beyond the clinical trial setting are limited. This study describes the toxicity and survival of patients treated with adjuvant BRAF/MEK inhibitors and compares outcomes to adjuvant anti-PD-1. For this study, stage III BRAF V600 mutant cutaneous melanoma patients treated with adjuvant BRAF/MEK-inhibition or anti-PD-1 were identified from the Dutch Melanoma Treatment Registry. BRAF/MEK- and anti-PD-1-treated patients were matched based on propensity scores, and RFS at 12 and 18 months were estimated. Between 1 July 2018 and 31 December 2021, 717 patients were identified. Of these, 114 patients with complete records were treated with BRAF/MEK therapy and 532 with anti-PD-1. Comorbidities (p = 0.04) and geographical region (p < 0.01) were associated with treatment choice. In 45.6% of BRAF/MEK-treated patients, treatment was prematurely discontinued. Grade ≥ 3 toxicity occurred in 11.5% of patients and was the most common cause of early discontinuation (71.1%). At 12 and 18 months, RFS in BRAF/MEK-treated patients was 85% and 70%, compared to 68% and 68% in matched anti-PD-1-treated patients (p = 0.03). In conclusion, comorbidities and geographical region determine the choice of adjuvant treatment in patients with resected stage III BRAF-mutant melanoma. With the currently limited follow-up, BRAF/MEK-treated patients have better RFS at 12 months than matched anti-PD-1-treated patients, but this difference is no longer observed at 18 months. Therefore, longer follow-up data are necessary to estimate long-term effectiveness. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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10 pages, 554 KiB

Open AccessArticle

Immunogenicity and Safety of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Melanoma Treated with Immunotherapy

by Panagiotis T. Diamantopoulos, Christina-Nefeli Kontandreopoulou, Aikaterini Gkoufa, Elena Solomou, Amalia Anastasopoulou, Eleni Palli, Panagiotis Kouzis, Spyros Bouros, Mihalis Samarkos, Gkikas Magiorkinis and Helen Gogas

Cancers 2022, 14(15), 3791; https://doi.org/10.3390/cancers14153791 - 04 Aug 2022

Cited by 4 | Viewed by 1770

Abstract

The BNT162b2 vaccine against SARS-CoV-2 has a proven efficacy and a favorable safety profile. In cancer patients under immunotherapy in the form of immune-checkpoint inhibitors (ICIs), the efficacy of the vaccine has not been thoroughly studied, while a theoretical concern has also been raised about triggering immune-related adverse events (irAEs) by the vaccine. We conducted a prospective, non-interventional study on the immunogenicity and safety of the BNT162b2 vaccine in patients with advanced or metastatic melanoma treated with ICIs. Blood samples were obtained 0–4 days before the first dose and 12–21 days after the second dose of the vaccine for the quantification of the SARS-CoV-2 anti-spike antibody using an ELISA and immunophenotyping of the T and myeloid cell subpopulations. The active recording of AEs for a two-month period was conducted. Forty patients were included in the study. All but one (97.3%) achieved seroconversion after two doses of the vaccine and no correlations of the antibody titers with any of the studied parameters (age, gender, stage and duration of the disease, type of ICI, previous treatment, etc.) were found. Moreover, no differences in the subpopulations of the T cells (including the T-regulatory cells) or the myeloid cells were found pre- and post-vaccination. All AEs were low-grade, while one case of arthritis exacerbation was noted. The seroconversion rate in the studied population was high and was comparable to that of healthy subjects, while no major safety issues were raised during the safety follow-up. Finally, no derangements in the subpopulations of T cells or myeloid cells were noted. This is the first study focusing on the immunogenicity, safety, and effect of anti-SARS-CoV-2 vaccines on the blood-cell immunophenotype status of patients with melanoma treated with ICIs. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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17 pages, 1679 KiB

Open AccessArticle

Increased Soluble PD-1 Predicts Response to Nivolumab plus Ipilimumab in Melanoma

by Jesper Geert Pedersen, Mateo Sokac, Boe Sandahl Sørensen, Adam Andrzej Luczak, Ninna Aggerholm-Pedersen, Nicolai Juul Birkbak, Trine Heide Øllegaard and Martin Roelsgaard Jakobsen

Cancers 2022, 14(14), 3342; https://doi.org/10.3390/cancers14143342 - 09 Jul 2022

Cited by 9 | Viewed by 1862

Abstract

Background: Checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, yielding long-term survival in a considerable proportion of the patients. Yet, 40–60% of patients do not achieve a long-term benefit from such therapy, emphasizing the urgent need to identify biomarkers that can predict response to immunotherapy and guide patients for the best possible treatment. Here, we exploited an unsupervised machine learning approach to identify potential inflammatory cytokine signatures from liquid biopsies, which could predict response to immunotherapy in melanoma. Methods: We studied a cohort of 77 patients diagnosed with unresectable advanced-stage melanoma undergoing treatment with first-line nivolumab plus ipilimumab or pembrolizumab. Baseline and on-treatment plasma samples were tested for levels of PD-1, PD-L1, IFNγ, IFNβ, CCL20, CXCL5, CXCL10, IL6, IL8, IL10, MCP1, and TNFα and analyzed by Uniform Manifold Approximation and Projection (UMAP) dimension reduction method and k-means clustering analysis. Results: Interestingly, using UMAP analysis, we found that treatment-induced cytokine changes measured as a ratio between baseline and on-treatment samples correlated significantly to progression-free survival (PFS). For patients treated with nivolumab plus ipilimumab we identified a group of patients with superior PFS that were characterized by significantly higher baseline-to-on-treatment increments of PD-1, PD-L1, IFNγ, IL10, CXCL10, and TNFα compared to patients with worse PFS. Particularly, a high PD-1 increment was a strong individual predictor for superior PFS (HR = 0.13; 95% CI 0.034–0.49; p = 0.0026). In contrast, decreasing levels of IFNγ and IL6 and increasing levels of CXCL5 were associated with superior PFS in the pembrolizumab group, although none of the cytokines were individually predictors for PFS. Conclusions: In short, our study demonstrates that a high increment of PD-1 is associated with superior PFS in advanced-stage melanoma patients treated with nivolumab plus ipilimumab. In contrast, decreasing levels of IFNγ and IL6, and increasing levels of CXCL5 are associated with response to pembrolizumab. These results suggest that using serial samples to monitor changes in cytokine levels early during treatment is informative for treatment response. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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Review

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15 pages, 466 KiB

Open AccessReview

Immunotherapy in Melanoma: Recent Advancements and Future Directions

by Meghan J. Mooradian and Ryan J. Sullivan

Cancers 2023, 15(16), 4176; https://doi.org/10.3390/cancers15164176 - 19 Aug 2023

Cited by 1 | Viewed by 1514

Abstract

Immune checkpoint inhibition has fundamentally altered the treatment paradigm of resectable and unresectable melanoma, resulting in dramatic improvements in patient outcomes. With these advances, the five-year overall survival in patients with newly diagnosed unresectable disease has eclipsed 50%. Ongoing research is focused on improving outcomes further, with a considerable emphasis on preventing de novo and acquired resistance and personalizing therapeutic options. Here, we review the ongoing advancements in the treatment of malignant melanoma, focusing on novel combination strategies that aim to build upon the successes of the last decade. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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32 pages, 907 KiB

Open AccessEditor’s ChoiceReview

Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment

by Dimitrios C. Ziogas, Charalampos Theocharopoulos, Panagiotis-Petros Lialios, Dimitra Foteinou, Ioannis-Alexios Koumprentziotis, Georgios Xynos and Helen Gogas

Cancers 2023, 15(10), 2718; https://doi.org/10.3390/cancers15102718 - 11 May 2023

Cited by 10 | Viewed by 5196

Abstract

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody–drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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18 pages, 1499 KiB

Open AccessReview

Cutaneous Adverse Reactions of Immunotherapy in Patients with Advanced Melanoma

by Vasiliki Nikolaou, Antonis Tsimpidakis and Alexander Stratigos

Cancers 2023, 15(7), 2084; https://doi.org/10.3390/cancers15072084 - 31 Mar 2023

Cited by 3 | Viewed by 3473

Abstract

Immune checkpoint blockers (ICBs) have been widely used during the last decade for the treatment of various tumors, including advanced and metastatic melanoma. While these agents have improved melanoma patients’ survival rates, they have also been associated with various autoimmune toxicities, with the skin being most commonly affected. The severity of cutaneous toxicity can not only negatively affect patients’ quality of life but can also limit the proper treatment of cancer. Thus, the role of the dermatologist is substantial in early detecting and promptly treating these adverse events. Maculopapular rash, psoriasiform, lichenoid dermatoses and bullous pemphigoid are the most frequent cutaneous adverse events that require immediate intervention. Other rare autoimmune toxicities, e.g., sarcoidosis, dermatomyositis or subacute lupus, have also been reported. In this review, we summarize the aspects of ICB-induced cutaneous toxicities in patients with melanoma, emphasizing their management and treatment options in clinical practice. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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18 pages, 1196 KiB

Open AccessReview

Immunotherapy in Melanoma: Recent Advances and Future Directions

by Andrew Knight, Lilit Karapetyan and John M. Kirkwood

Cancers 2023, 15(4), 1106; https://doi.org/10.3390/cancers15041106 - 09 Feb 2023

Cited by 39 | Viewed by 7352

Abstract

The use of immunotherapy in the treatment of advanced and high-risk melanoma has led to a striking improvement in outcomes. Although the incidence of melanoma has continued to rise, median survival has improved from approximately 6 months to nearly 6 years for patients with advanced inoperable stage IV disease. Recent understanding of the tumor microenvironment and its interplay with the immune system has led to the explosive development of novel immunotherapy treatments. Since the approval of the therapeutic cytokines interleukin-2 and interferon alfa-2 in the 1990s, the development of novel immune checkpoint inhibitors (ICIs), oncolytic virus therapy, and modulators of the tumor microenvironment have given way to a new era in melanoma treatment. Monoclonal antibodies directed at programmed cell death protein 1 receptor (PD-1) and its ligand (PDL-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) have provided robust activation of the adaptive immune system, restoring immune surveillance leading to host tumor recognition and destruction. Multiple other immunomodulatory therapeutics are under investigation to overcome resistance to ICI therapy, including the toll-like receptor-9 (TLR-9) and 7/8 (TLR-7/8) agonists, stimulator of interferon genes (STING) agonists, and fecal microbiota transplantation. In this review, we focus on the recent advances in immunotherapy for the treatment of melanoma and provide an update on novel therapies currently under investigation. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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Other

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30 pages, 1458 KiB

Open AccessSystematic Review

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

by Chrysoula Mytareli, Dimitrios C. Ziogas, Athina Karampela, Petros Papalexis, Vasiliki Siampanopoulou, Alexandros Lafioniatis, Olga Benopoulou, Helen Gogas and Anna Angelousi

Cancers 2023, 15(7), 2016; https://doi.org/10.3390/cancers15072016 - 28 Mar 2023

Cited by 3 | Viewed by 1846

Abstract

Immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancers, either in adjuvant or metastatic settings. Regarding safety, endocrine adverse events (AEs) are some of the most common AEs in ICI-treated patients, with thyroid dysfunction and hypophysitis being the most frequent disorders. However, there are also some rare and very rare immune-related (ir) endocrine complications (incidence between ≥1/10,000 to <1/1000 and <1/10,000, respectively, according to the established classification) that have been reported in isolated case reports, with limited data about their management. In this systematic review, we summarize all published cases with primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, lipodystrophy, osteoporosis, hypergonadotrophic hypogonadism, or Cushing disease and discuss their diagnostic and therapeutic approaches as well as the current knowledge on their pathophysiology. In these ICI-treated cancer patients, the presentation of symptoms unrelated to their underlying malignancy has led to further diagnostic tests, including hormonal profile and functional assays which subsequently confirmed endocrinopathy, while the assessment of autoantibodies was rarely available. In most of these cases, the exact pathogenesis remained unknown, and the endocrine dysfunction was permanent, requiring lifelong supplementation. Although endrocine irAEs are rare, physicians must be aware of these irAEs to recognize them on time and treat them appropriately. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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