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Immunotherapy of Melanoma: Challenges and Solutions
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Immunotherapy of Melanoma: Challenges and Solutions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 June 2021) | Viewed by 31855

Special Issue Editor

Dr. Ali Jazirehi

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Guest Editor
Department of Biological Sciences, College of Natural and Social Sciences, California State University, Los Angeles (CSULA), Los Angeles, CA, USA
Interests: melanoma; non-Hodgkin’s lymphoma; Immunotherapy; chimeric antigen receptor; signal transduction; apoptosis; resistance; sensitization; targeted therapy

Special Issue Information

Dear Colleagues,

The development of novel therapeutic approaches and the optimization of existing therapies has great potential in the clinical therapy and basic science research of melanoma. Immunotherapy, which is intended to modulate the host immune response against tumor cells, has dramatically improved the prognosis for malignant melanoma patients and is now considered a cornerstone in the treatment of this disease. The clinical application of immunotherapy is broad; it can be used in an adjuvant setting, after complete surgical excision of malignant lesions in patients with a high risk of disease relapse, as well as in the treatment of patients with advanced (unresectable or metastatic) stages of the disease.

Different clinical trials, such as those employing Adoptive Cell Therapy (ACT) using MART-1 T cell receptor (TCR)-engineered T lymphocytes or monoclonal antibodies directed against CTLA-4 or PD-1/PD-L1 pathways, have produced dramatic clinical responses in a subset of patients with metastatic melanoma; however, these responses were all transient. The underlying molecular mechanisms of melanoma resistance to apoptosis induced by immune-mediated therapies remains elusive. The design of novel molecular strategies to overcome resistance or to improve the efficacy of these therapies is an active area of research that requires further scrutiny. 

This Special Issue of IJMS “Immunotherapy for Melanoma: Challenges and Solutions” will focus on the discussion of various types of immunotherapeutic treatment modalities, the delineation of the detailed moelcular basis of these approaches, understanding the potential limitations of these approaches, the proposition of strategies to curb adverse side effects, deciphering the molecular mechanisms of resistance to immune-based approaches, and suggestions for improving the efficacy of immunotherapy in the treatment of advanced malignant melanoma. Identification of the molecular targets of immunotherapy and patient immunoprofiling may lead to the discovery of biomarkers related to the treatment response. The discovery of biomarkers of resistance/sensitivity to immune-based therapeutic modalities and the ability to modify their expression profiles to favor a proapoptotic intracellular milieu will undoubtedly assist in the design of molecular targeted strategies to overcome inherrent or acquired immune resistance of metastatic melanoma tumor cells. This information will collectively assist us in developing more effective management and treatment strategies for this deadly disease.

Dr. Ali Jazirehi
Guest Editor

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Keywords

  • CTLA-4
  • IL-2
  • immunotherapy
  • interferon
  • ipilimumab
  • melanoma
  • nivolumab
  • anti-PD-1
  • pembrolizumab
  • talimogene
  • laherparepvec
  • T cell receptor
  • adoptive cell transfer
  • melanoma
  • monoclonal antobodies
  • targetd therapy
  • apoptosis
  • resistance

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Published Papers (6 papers)

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Research

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18 pages, 5852 KiB  
Article
The Abscopal Effect in the Era of Checkpoint Inhibitors
by Ondřej Kodet, Kristýna Němejcova, Karolína Strnadová, Andrea Havlínová, Pavel Dundr, Ivana Krajsová, Jiří Štork, Karel Smetana, Jr. and Lukáš Lacina
Int. J. Mol. Sci. 2021, 22(13), 7204; https://doi.org/10.3390/ijms22137204 - 4 Jul 2021
Cited by 23 | Viewed by 4371
Abstract
Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is [...] Read more.
Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from “ab scopus”, that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8+ T cells cannot overcome the tumour microenvironment’s suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors. Full article
(This article belongs to the Special Issue Immunotherapy of Melanoma: Challenges and Solutions)
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15 pages, 2999 KiB  
Article
Mechanistic Insights into Synergy between Melanin-Targeting Radioimmunotherapy and Immunotherapy in Experimental Melanoma
by Mackenzie E. Malo, Kevin J. H. Allen, Rubin Jiao, Connor Frank, David Rickles and Ekaterina Dadachova
Int. J. Mol. Sci. 2020, 21(22), 8721; https://doi.org/10.3390/ijms21228721 - 18 Nov 2020
Cited by 10 | Viewed by 3006
Abstract
Melanoma incidence continues to rise, and while therapeutic approaches for early stage cases are effective, metastatic melanoma continues to be associated with high mortality. Immune checkpoint blockade (ICB) has demonstrated clinical success with approved drugs in cohorts of patients with metastatic melanoma and [...] Read more.
Melanoma incidence continues to rise, and while therapeutic approaches for early stage cases are effective, metastatic melanoma continues to be associated with high mortality. Immune checkpoint blockade (ICB) has demonstrated clinical success with approved drugs in cohorts of patients with metastatic melanoma and targeted radionuclide therapy strategies showed promise in several clinical trials against various cancers including metastatic melanoma. This led our group to investigate the combination of these two treatments which could be potentially offered to patients with metastatic melanoma not responsive to ICB alone. Previously, we have demonstrated that a combination of humanized anti-melanin antibody conjugated to 213Bismuth and anti-PD-1 ICB reduced tumor growth and increased survival in the Cloudman S91 murine melanoma DBA/2 mouse model. In the current study, we sought to improve the tumoricidal effect by using the long-lived radionuclides 177Lutetium and 225Actinium. Male Cloudman S91-bearing DBA/2 mice were treated intraperitoneally with PBS (Sham), unlabeled antibody to melanin, anti-PD-1 ICB, 177Lutetium or 225Actinium RIT, or a combination of ICB and RIT. Treatment with anti-PD-1 alone or low-dose 177Lutetium RIT alone resulted in modest tumor reduction, while their combination significantly reduced tumor growth and increased survival, suggesting synergy. 225Actinium RIT, alone or in combination with ICB, showed no therapeutic benefit, suggesting that the two radionuclides with different energetic properties work in distinct ways. We did not detect an increase in tumor-infiltrating T cells in the tumor microenvironment, which suggests the involvement of alternative mechanisms that improve the effect of combination therapy beyond that observed in the single therapies. Full article
(This article belongs to the Special Issue Immunotherapy of Melanoma: Challenges and Solutions)
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Review

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16 pages, 1082 KiB  
Review
Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy
by Ali R. Jazirehi
Int. J. Mol. Sci. 2021, 22(21), 11726; https://doi.org/10.3390/ijms222111726 - 29 Oct 2021
Cited by 6 | Viewed by 2960
Abstract
Metastatic melanoma accounts for the highest number of skin cancer-related deaths. Traditional treatments are ineffective due to their inability to induce tumor regression at a high rate. Newer treatments such as immune checkpoint inhibitors (ICI), targeted therapy (BRAFi and MEKi), and T cell [...] Read more.
Metastatic melanoma accounts for the highest number of skin cancer-related deaths. Traditional treatments are ineffective due to their inability to induce tumor regression at a high rate. Newer treatments such as immune checkpoint inhibitors (ICI), targeted therapy (BRAFi and MEKi), and T cell receptor (TCR)-engineered T cells aim to increase the ability of the host immune system to recognize and eradicate tumors. ICIs inhibit negative regulatory mechanisms and boost the antitumor activity of the host’s immune system, while targeted therapy directed against aberrant signaling molecules (BRAF and MEK) will block the uncontrolled proliferation and expansion of melanomas. The basis of the TCR-engineered T cell strategy is to transduce host T cells with antigen-specific TCRα/β chains to produce high-affinity T cells for tumor-associated antigens. TCR-transgenic T cells are expanded and activated ex vivo and reinfused into patients to increase the targeting of cancer cells. While these treatments have had varyingly favorable results, their efficacy is limited due to inherent or acquired resistance. Various mechanisms explain melanoma immune-resistance, including the loss or downregulation of the MCH/peptide complex, aberrant activity of signaling pathways, and altered dynamics of apoptotic machinery. Collectively, these mechanisms confer melanoma resistance to apoptotic stimuli delivered by T cells despite a fully functional and effective antitumor immune response. Identification of biomarkers, combination treatment, and the use of CAR T cells are among the approaches that can potentially circumvent melanoma’s resistance to immunotherapy. Full article
(This article belongs to the Special Issue Immunotherapy of Melanoma: Challenges and Solutions)
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19 pages, 1158 KiB  
Review
Microbeam Radiotherapy—A Novel Therapeutic Approach to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma
by Verdiana Trappetti, Jennifer M. Fazzari, Cristian Fernandez-Palomo, Maximilian Scheidegger, Vladislav Volarevic, Olga A. Martin and Valentin G. Djonov
Int. J. Mol. Sci. 2021, 22(14), 7755; https://doi.org/10.3390/ijms22147755 - 20 Jul 2021
Cited by 30 | Viewed by 3835
Abstract
Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. [...] Read more.
Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an ‘MRT-induced immune effect’. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy. Full article
(This article belongs to the Special Issue Immunotherapy of Melanoma: Challenges and Solutions)
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23 pages, 379 KiB  
Review
Immunostimulatory Effects of Radiotherapy for Local and Systemic Control of Melanoma: A Review
by Junko Takahashi and Shinsuke Nagasawa
Int. J. Mol. Sci. 2020, 21(23), 9324; https://doi.org/10.3390/ijms21239324 - 7 Dec 2020
Cited by 21 | Viewed by 3830
Abstract
Recently, modern therapies involving immune checkpoint inhibitors, cytokines, and oncolytic virus have been developed. Because of the limited treatment effect of modern therapy alone, the immunostimulatory effect of radiotherapy attracted increasing attention. The combined use of radiotherapy and modern therapy has been examined [...] Read more.
Recently, modern therapies involving immune checkpoint inhibitors, cytokines, and oncolytic virus have been developed. Because of the limited treatment effect of modern therapy alone, the immunostimulatory effect of radiotherapy attracted increasing attention. The combined use of radiotherapy and modern therapy has been examined clinically and non-clinically, and its effectiveness has been confirmed recently. Because melanomas have high immunogenicity, better therapeutic outcomes are desired when using immunotherapy. However, sufficient therapeutic effects have not yet been achieved. Thus far, radiotherapy has been used only for local control of tumors. Although extremely rare, radiotherapy has also been reported for systemic control, i.e., abscopal effect. This is thought to be due to an antitumor immune response. Therefore, we herein summarize past information on not only the mechanism of immune effects on radiotherapy but also biomarkers reported in case reports on abscopal effects. We also reviewed the animal model suitable for evaluating abscopal effects. These results pave the way for further basic research or clinical studies on new treatment methods for melanoma. Currently, palliative radiation is administered to patients with metastatic melanoma for local control. If it is feasible to provide both systemic and local control, the treatment benefit for the patients is very large. Full article
(This article belongs to the Special Issue Immunotherapy of Melanoma: Challenges and Solutions)
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47 pages, 3109 KiB  
Review
Overcoming Immune Evasion in Melanoma
by Kevinn Eddy and Suzie Chen
Int. J. Mol. Sci. 2020, 21(23), 8984; https://doi.org/10.3390/ijms21238984 - 26 Nov 2020
Cited by 122 | Viewed by 12586
Abstract
Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is “curable” at this stage. However, after metastasis, it is difficult to treat [...] Read more.
Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is “curable” at this stage. However, after metastasis, it is difficult to treat and the five-year survival is only 25%. In recent years, a better understanding of the etiology of melanoma and its progression has made it possible for the development of targeted therapeutics, such as vemurafenib and immunotherapies, to treat advanced melanomas. In this review, we focus on the molecular mechanisms that mediate melanoma development and progression, with a special focus on the immune evasion strategies utilized by melanomas, to evade host immune surveillances. The proposed mechanism of action and the roles of immunotherapeutic agents, ipilimumab, nivolumab, pembrolizumab, and atezolizumab, adoptive T- cell therapy plus T-VEC in the treatment of advanced melanoma are discussed. In this review, we implore that a better understanding of the steps that mediate melanoma onset and progression, immune evasion strategies exploited by these tumor cells, and the identification of biomarkers to predict treatment response are critical in the design of improved strategies to improve clinical outcomes for patients with this deadly disease. Full article
(This article belongs to the Special Issue Immunotherapy of Melanoma: Challenges and Solutions)
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