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Advances in Immunotherapy of Melanoma
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Advances in Immunotherapy of Melanoma

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 8537

Special Issue Editor

Dr. Anand Rotte

E-Mail Website
Guest Editor
Clinical and Regulatory Affairs, Arcellx, Gaithersburg, MD, USA
Interests: clinical research; clinical development (early and late); immunotherapy; melanoma; oxidative stress; type 2 diabetes and neuropathic pain
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metastatic melanoma is a serious type of skin cancer that arises due to the uncontrolled proliferation of melanocytes. It has very poor prognosis and low 5-year survival rates. Until recently, only a handful of treatment options were available for metastatic melanoma patients, which changed dramatically with the introduction of immune checkpoint blockers. The approval of ipilimumab, a monoclonal antibody targeting CTLA-4 receptors on T-cells in 2011, followed by the approval of anti-PD-1 antibodies, including nivolumab and pembrolizumab in 2014, resulted in significant improvement in the survival of metastatic melanoma patients and laid the foundation for immunotherapy of other types of cancer. A combination of CTLA-4 and PD-1 blockers was later approved for metastatic melanoma and the drugs were also approved as monotherapy for surgically resected high-risk melanoma patients. While the impact of immunotherapy on melanoma management has been huge, a significant proportion of patients do not respond to immunotherapy and/or develop serious immune-related adverse events. Research is ongoing to identify novel molecules that can be safely combined with approved drugs to improve the efficacy of the treatment. The current Special Issue aims to publish cutting-edge research, including both preclinical and clinical studies on the treatment of melanoma using immunotherapy. Original studies, as well as review articles, will be considered for the Special Issue. We hope that both academic and industry-based researchers working on immunotherapy of melanoma will find this platform useful and look forward to receiving exceptional submissions.

Dr. Anand Rotte
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immunotherapy
  • melanoma
  • oxidative stress
  • immune checkpoint blockers
  • CTLA-4
  • PD-1
  • melanocytes
  • monoclonal antibody

Published Papers (5 papers)

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15 pages, 6820 KiB  
Article
The Association of CD8+ Cytotoxic T Cells and Granzyme B+ Lymphocytes with Immunosuppressive Factors, Tumor Stage and Prognosis in Cutaneous Melanoma
by Satu Salmi, Kaisla Hälinen, Anton Lin, Sanna Suikkanen, Otto Jokelainen, Eija Rahunen, Hanna Siiskonen and Sanna Pasonen-Seppänen
Biomedicines 2022, 10(12), 3209; https://doi.org/10.3390/biomedicines10123209 - 10 Dec 2022
Cited by 1 | Viewed by 1035
Abstract
The immunosuppressive tumor microenvironment (TME) consists of suppressive cells producing a variety of immunomodulatory proteins, such as programmed death ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase (IDO). Although granzyme B (GrB) is known to convey the cytolytic activities of CD8+ cytotoxic lymphocytes, it is also [...] Read more.
The immunosuppressive tumor microenvironment (TME) consists of suppressive cells producing a variety of immunomodulatory proteins, such as programmed death ligand 1 (PD-L1) and indoleamine-2,3-dioxygenase (IDO). Although granzyme B (GrB) is known to convey the cytolytic activities of CD8+ cytotoxic lymphocytes, it is also expressed by other cells, such as regulatory T and B cells, for immunosuppressive purposes. The role of GrB+ lymphocytes in melanoma has not been examined extensively. In this study, benign, premalignant, and malignant melanocytic tumors were stained immunohistochemically for CD8 and GrB. PD-L1 was also stained from malignant samples that had accompanying clinicopathological data. The association of CD8+ and GrB+ lymphocytes with PD-L1 expression, tumor stage, prognosis, and previously analyzed immunosuppressive factors were evaluated. Our aim was to obtain a more comprehensive perception of the immunosuppressive TME in melanoma. The results show that both CD8+ and GrB+ lymphocytes were more abundant in pT4 compared to pT1 melanomas, and in lymph node metastases compared to primary melanomas. Surprisingly, a low GrB/CD8 ratio was associated with better recurrence-free survival in primary melanomas, which indicates that GrB+ lymphocytes might represent activated immunosuppressive lymphocytes rather than cytotoxic T cells. In the present study, CD8+ lymphocytes associated positively with both tumor and stromal immune cell PD-L1 and IDO expression. In addition, PD-L1+ tumor and stromal immune cells associated positively with IDO+ stromal immune and melanoma cells. The data suggest that IDO and PD-L1 seem to be key immunosuppressive factors in CD8+ lymphocyte-predominant tumors in CM. Full article
(This article belongs to the Special Issue Advances in Immunotherapy of Melanoma)
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16 pages, 1963 KiB  
Article
Inflammatory Blood Parameters as Biomarkers for Response to Immune Checkpoint Inhibition in Metastatic Melanoma Patients
by Ken Kudura, Lukas Nussbaumer, Robert Foerster and Lucas Basler
Biomedicines 2022, 10(9), 2135; https://doi.org/10.3390/biomedicines10092135 - 31 Aug 2022
Cited by 3 | Viewed by 1363
Abstract
Objectives: We aimed to investigate whether inflammatory parameters in peripheral blood at baseline and during the first six months of treatment could predict the short- and long-term outcomes of metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs). Methods: This single-center retrospective study [...] Read more.
Objectives: We aimed to investigate whether inflammatory parameters in peripheral blood at baseline and during the first six months of treatment could predict the short- and long-term outcomes of metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs). Methods: This single-center retrospective study considered patients with metastatic melanoma treated with either single or dual checkpoint inhibition. Blood sample tests were scheduled together with 18F-2-fluor-2-desoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans at baseline and at three and six months after initiation of ICI treatment. The short-term response to ICIs was assessed using FDG-PET/CT scans. The long-term response to ICIs was assessed using the overall survival OS and progression-free survival PFS as endpoints. Results: A total of 100 patients with metastatic melanoma were included (female, n = 31; male, n = 69). The median age was 68 years (interquartile range (IQR): 53–74 years). A total of 82% of the cohort displayed a disease control (DC), while 18% presented a progressive disease (PD) after six months of ICIs. Patients with DC after six months of ICIs showed a lower median of the neutrophils-to-lymphocytes ratio (NLR) toward patients with PD, with no significant prediction power of NLR neither in the short nor in the long term. The count of neutrophils at the baseline time point (TP 0) (p = 0.037) and erythrocytes three months after treatment start (TP 1) (p = 0.010) were strong predictive parameters of a DC six months after treatment start. Erythrocytes (p < 0.001) and lymphocytes (p = 0.021) were strong biomarkers predictive of a favorable OS. Erythrocytes (p = 0.013) and lymphocytes (p = 0.017) also showed a significant prediction power for a favorable PFS. Conclusions: Inflammatory blood parameters predicted the short- and long-term response to ICIs with a strong predictive power. Our results suggested the validation of inflammatory blood parameters as biomarkers that predict immunotherapies’ efficacity in metastatic melanoma patients. However, confounding factors that interfere with myelopoiesis should also be taken into consideration. Full article
(This article belongs to the Special Issue Advances in Immunotherapy of Melanoma)
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14 pages, 2687 KiB  
Article
Chrysin Induces Apoptosis and Autophagy in Human Melanoma Cells via the mTOR/S6K Pathway
by Jae-Han Lee, Eun-Seon Yoo, So-Hee Han, Gi-Hwan Jung, Eun-Ji Han, Eun-Young Choi, Su-ji Jeon, Soo-Hyun Jung, BumSeok Kim, Sung-Dae Cho, Jeong-Seok Nam, Changsun Choi, Jeong-Hwan Che and Ji-Youn Jung
Biomedicines 2022, 10(7), 1467; https://doi.org/10.3390/biomedicines10071467 - 21 Jun 2022
Cited by 2 | Viewed by 1834
Abstract
Chrysin is known to exert anti-inflammatory, antioxidant, and anticancer effects. The aim of this study was to investigate the anticancer effects of chrysin in the human melanoma cells A375SM and A375P. The results obtained demonstrated successful inhibition of the viability of these cells [...] Read more.
Chrysin is known to exert anti-inflammatory, antioxidant, and anticancer effects. The aim of this study was to investigate the anticancer effects of chrysin in the human melanoma cells A375SM and A375P. The results obtained demonstrated successful inhibition of the viability of these cells by inducing apoptosis and autophagy. This was confirmed by the level of apoptosis-related proteins: Bax and cleaved poly (ADP-ribose) polymerase both increased, and Bcl-2 decreased. Moreover, levels of LC3 and Beclin 1, both autophagy-related proteins, increased in chrysin-treated cells. Autophagic vacuoles and acidic vesicular organelles were observed in both cell lines treated with chrysin. Both cell lines showed different tendencies during chrysin-induced autophagy inhibition, indicating that autophagy has different effects depending on the cell type. In A375SM, the early autophagy inhibitor 3-methyladenine (3-MA) was unaffected; however, cell viability decreased when treated with the late autophagy inhibitor hydroxychloroquine (HCQ). In contrast, HCQ was unaffected in A375P; however, cell viability increased when treated with 3-MA. Chrysin also decreased the phosphorylation of mTOR/S6K pathway proteins, indicating that this pathway is involved in chrysin-induced apoptosis and autophagy for A375SM and A375P. However, studies to elucidate the mechanisms of autophagy and the action of chrysin in vivo are still needed. Full article
(This article belongs to the Special Issue Advances in Immunotherapy of Melanoma)
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15 pages, 1533 KiB  
Article
Outcome of Elective Checkpoint Inhibitor Discontinuation in Patients with Metastatic Melanoma Who Achieved a Complete Remission: Real-World Data
by Leanne Perez, Wolfram Samlowski and Ruby Lopez-Flores
Biomedicines 2022, 10(5), 1144; https://doi.org/10.3390/biomedicines10051144 - 16 May 2022
Cited by 8 | Viewed by 1747
Abstract
Checkpoint inhibitor therapy for metastatic melanoma has dramatically improved outcomes. Currently, 20 to 40% of treated patients achieve lengthy remissions. It is not clear whether patients in remission require ongoing therapy or if treatment can be safely discontinued. A retrospective chart review was [...] Read more.
Checkpoint inhibitor therapy for metastatic melanoma has dramatically improved outcomes. Currently, 20 to 40% of treated patients achieve lengthy remissions. It is not clear whether patients in remission require ongoing therapy or if treatment can be safely discontinued. A retrospective chart review was performed of patients who underwent elective treatment discontinuation after two negative scans three months apart. Of 132 checkpoint inhibitor-treated patients, 46 achieved a complete response (34.8%) and electively discontinued therapy. The progression-free survival was 97.5% at 1 year and 94.7% at 3 years following treatment discontinuation. The median duration of follow-up was 26 months. In total, 4 of 46 individuals (8.7%) eventually relapsed (median time to relapse: 27 months). The median disease-specific survival of the entire cohort was not reached and was 100% at 4 years from the start of therapy. Two patients eventually died, one from melanoma and the other from an unrelated illness. We have identified an elective treatment discontinuation strategy that is generalizable to a variety of checkpoint inhibitor ± targeted therapy regimens. We found that most complete remissions remained durable after elective treatment discontinuation. We hypothesize that this approach could decrease potential drug toxicities, reduce the treatment-related financial burden, and improve patients’ quality of life. Full article
(This article belongs to the Special Issue Advances in Immunotherapy of Melanoma)
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14 pages, 280 KiB  
Systematic Review
Checkpoint Inhibitors Immunotherapy in Metastatic Melanoma: When to Stop Treatment?
by Ivana De Risi, Angela Monica Sciacovelli and Michele Guida
Biomedicines 2022, 10(10), 2424; https://doi.org/10.3390/biomedicines10102424 - 28 Sep 2022
Cited by 6 | Viewed by 1548
Abstract
Background: Immune checkpoint inhibition (ICI) has significantly improved the survival of metastatic melanoma (MM) with a significant proportion of patients obtaining long-lasting responses. However, ICI also exposes patients to new, heavy, and sometimes irreversible toxicities. Thus, identifying the minimal amount of treatment time [...] Read more.
Background: Immune checkpoint inhibition (ICI) has significantly improved the survival of metastatic melanoma (MM) with a significant proportion of patients obtaining long-lasting responses. However, ICI also exposes patients to new, heavy, and sometimes irreversible toxicities. Thus, identifying the minimal amount of treatment time is extremely urgent. Methods: We researched English peer-reviewed literature from electronic databases (MEDLINE and PubMed) until July 2022 with the aim of evaluating the clinical outcomes after the cessation of ICI therapy due to elective study plans, clinician–patient sharing, and adverse events. Results: Although most of the data are from retrospective studies, considering that most patients with major responses maintain it after treatment cessation, it is proposed that for complete response (CR)/near CR, a further six months of therapy after best response may be considered enough. For partial response (PR) or stable disease (SD), treatment must be continued for at least 2 years and, in some cases, indefinitely, based on residual disease, the patient’s will, and the toxic profile. Of note, in spite of the best response, 25–30% of patients relapsed, and, when retreated, responded far less than in front-line treatment. Conclusions: Most of the data being from retrospective and heterogeneous experiences, their grade of evidence is limited and no consensus has been reached on the optimal treatment duration. Controlled prospective studies are needed. Full article
(This article belongs to the Special Issue Advances in Immunotherapy of Melanoma)
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