Immunotherapy of Melanoma: Current Status and Prospects for the Future

As one of the most immunogenic human malignancies, melanoma has served as a prototype for the development of immunotherapy against human cancer in a number of treatment modalities over the past two decades. These studies have included augmentation of host immunity with lymphokines and other biological response modifiers, lymphokine-activated killer cells, and cytotoxic T-cells; active immunotherapy using purified antigens, tumor cell vaccines, and anti-id antibodies; and passive immunotherapy with monoclonal antibodies. The results of these investigations are discussed as well as the prospect for future treatments of melanoma incorporating immunotherapeutic techniques. A report on a recent trial of gene therapy of human melanoma performed by Dr. Steven Rosenberg is also presented.     

Linking Cellular Metabolism to Epigenetics in Melanoma

Melanoma originates from epidermal melanocytes and is the most malignant form of skin cancer,with an increasing incidence worldwide.In addition to the known pat...     

Tissue Distribution of a Melanoma-Associated Antigen Immunogenic in Patients with Melanoma as Analyzed by Polyclonal Antibodies to Recombinant Peptide Antigen

This study aimed to detect in vivo expression of human melanoma-associated antigen D-1, which was identified by screening an expression cDNA library constructed from mRNA extracted from cultured melanoma cells with sera from patients with melanoma. The tissue distribution of D-1 antigen was then analyzed. Murine anti-D-1 recombinant peptide polyclonal antibodies were raised by immunization of in vitro synthesized D-1 peptide against Balb/c mice and applied immunohistochemically on paraffin-embedded tissue specimens. D-1 antigen was found to be restrictedly expressed on melanoma cells, but not on normal melanocytes, adjacent keratinocytes, fibroblasts, lymphocytes and adnexal structures of skin. The reactivities of anti-D-1 antibodies did not correlate with histogenesis of the lesions, their ability to produce melanin, and/or their primary or metastatic nature. There was no positive reactivity of anti-D-1 antibodies with other skin tumors, including squamous cell carcinoma, basal cell epithelioma, seborrheic keratosis, and nevus cell nevus. Further, cytoplasmic expression of D-1 antigen in melanoma cells was observed only in a certain subgroup of patients with melanoma. This indicates that the cell surface expression of D-1 peptide requires specific transporting proteins, such as HLA molecules.     

Nodular Melanoma in 62 Japanese Patients: Influence of Initial Surgical Treatment on Local Recurrence and Prognosis

The incidence of malignant melanoma is much lower in Japanese than in Caucasians, and the commonest type of melanoma in Japanese is acral lentiginous melanoma (ALM). In contrast to the improved prognosis noted in ALM, it is now of increasing concern that there is a rise in both the frequency and mortality of nodular melanoma. During the 25 years from 1970 to 1994, we observed 190 patients with melanoma, including 62 nodular melanomas and 96 ALM, at the Department of Dermatology, Tohoku University Hospital, Sendai, Japan. We retrospectively reviewed the recurrence and survival rates of nodular melanoma observed. The proportion of nodular melanoma, once comprising only 24% of all melanomas, showed a sharp increase to 40% after 1982. The anatomical sites of the primary tumor were the hands and feet (29%), extremities excluding hands and feet (27%), head and neck (23%), and trunk (21%). Comparison of the stages of nodular melanoma when diagnosed showed that the proportion of stage III remained highest throughout the whole period, but that of stage II melanomas increased after 1982. After treatment, local recurrence occurred far more frequently in nodular melanoma (19%) than in ALM (1%). The prognosis of nodular melanoma was also less favorable than that of ALM, although it slightly improved after 1982; the 5-year survival rates before and after 1982 were 34 and 50%, respectively. Twenty-eight patients with nodular melanoma had underwent simple excision or incisional biopsy of the primary tumor at another institution and were later referred to us for further intensive care or for the treatment of local recurrence and/or metastases. The rate of local recurrence of melanoma in such referred patients was higher than that in those who underwent an initial excision with wide margins in our hospital. Concurrently, the prognosis in the former group was significantly lower than that in the latter group; the 5-year survival rate for the group of narrow initial margin was 22% in contrast to that of wide margin (56%). Combination therapy including initial surgical excision with wide margins as well as the careful follow-up apparently result in a better outcome for the Japanese patients with nodular melanoma.     

Changes in Immunological Parameters after Combination Adjuvant Therapy with Intravenous DTIC,ACNU, and VCR,and Local Injection of IFN-β (DAV + IFN-β Therapy) into Malignant Melanoma

Combination adjuvant therapy with intravenous dimethyl triazeno imidazole carboxamide (DTIC), 1-[4-amino-2-methyl-5-pyrimidinyl]-methyl-3-[2-chloroethyl]-3-nitrosourea hydrochloride (ACNU) and vincristine (VCR) and local injection of interferon-β (IFN-β) (DAV + IFN-β therapy) has been widely applied to treat malignant melanoma, and its therapeutic effect is accepted in Japan. Natural killer (NK) activity, CD4+ and CD8+ T cell counts, CD4/CD8 ratio, and white blood cell counts were analyzed before and after DAV + IFN-β therapy in order to validate its efficacy. After DAV + IFN-β therapy, the CD4/CD8 ratio was elevated; however, numbers of both CD4+ and CD8+ T cells and NK activity were consecutively depressed. Peripheral lymphocytes were also decreased, possibly by myelosuppression due to the DAV therapy. The posttreatment suppression of NK activity appeared in spite of the administration of IFN-β. It is suggested that a more effective adjuvant immunomodulator should be introduced to improve the therapeutic effect of the combination adjuvant chemotherapy in malignant melanoma.     

Local recurrence in melanoma in situ: influence of sex,age, site of involvement and therapeutic modalities

BACKGROUND: Melanoma in situ (MIS) occurs on various body sites, in various age groups, and is managed by a variety of treatment modalities. Despite early treatment, recurrences may be encountered. OBJECTIVES: To evaluate the influence of sex, age, body site and treatment modalities on recurrence rate in MIS. Methods Histologically confirmed cases of MIS from our dermatopathological database (n = 1351) from 1990 to 2000 were statistically analysed with respect to epidemiological characteristics, treatment modalities and outcome. Treatment modalities of the included MIS were evaluated by searching for data in the medical records and histopathological data sheets. RESULTS: There was a predominance of female patients (60.8%), and of involvement of the head and neck (53.4%). Total excision was performed in 95.9% of all patients; the remainder received cryotherapy, laser therapy or radiotherapy. In 265 patients, no data on definitive treatment were available. Alternatives to total excision were particularly performed in patients with advanced age and with lesions localized on the face. The mean +/- SD 5-year recurrence rate was 6.8 +/- 1.3% for surgically removed lesions, but was 31.3 +/- 8.5% for lesions treated by other modalities (log rank test: P < 0.0001). In a multivariate approach, mode of therapy and site of involvement, but not age, were significant prognostic variables (Cox proportional hazard model: P < 0.01). CONCLUSIONS: In MIS, treatment modalities other than surgical excision may be used in certain situations, but carry a significantly increased risk of local recurrence.     

免疫检查点抑制剂和靶向药物辅助治疗可切除黑素瘤疗效的网状Meta分析

目的通过贝叶斯网状Meta分析评估免疫检查点抑制剂和靶向药物对可切除黑素瘤的治疗效果。方法通过PubMed、Embase和Cochrane数据库检索可切除黑素瘤辅助治疗的随机对照试验。基于风险比,应用贝叶斯固定效应模型对无复发生存期进行网状Meta分析来评估相对治疗效果。通过StataSE 15和OpenBUGS 3.2.3软件对数据进行综合分析。结果共纳入6篇文章,包括5587例患者和7种治疗方法。其中Ⅲ期亚组5019例,存在溃疡亚组2085例,不存在溃疡亚组2629例,BRAF突变亚组2054例;7种治疗分别为手术+观察或安慰剂、手术+dabrafenib联合trametinib辅助治疗、手术+nivolumab辅助治疗、手术+ipilimumab辅助治疗、手术+pembrolizumab辅助治疗、手术+bevacizumab辅助治疗以及手术+vemurafenib辅助治疗。在网状Meta分析中,dabrafenib联合trametinib(HR 0.47,95%CI 0.39~0.57)、nivolumab(HR 0.49,95%CI 0.36~0.65)和pembrolizumab(HR 0.57,95%CI 0.43~0.75)辅助治疗在改善无复发生存期上明显比单纯手术治疗更有效;Ⅲ期和存在溃疡的可切除黑素瘤患者亚组分析结果与上述网状Meta分析相同。不存在溃疡的可切除黑素瘤亚组分析中,vemurafenib(HR 0.48,95%CI 0.29~0.79)、dabrafenib联合trametinib(HR 0.48,95%CI 0.33~0.70)和nivolumab(HR 0.50,95%CI 0.31~0.79)辅助治疗较单纯手术治疗可显著延长患者的无复发生存期,但pembrolizumab(HR 0.69,95%CI 0.45~1.06)并没有比单纯手术治疗效果更好。在BRAF突变的黑素瘤亚组分析中,与单纯手术相比,bevacizumab(HR 0.60,95%CI 0.43~0.85)、dabrafenib联合trametinib(HR 0.47,95%CI 0.38~0.57)、pembrolizumab(HR 0.59,95%CI 0.38~0.92)和vemurafenib(HR 0.65,95%CI 0.50~0.85)辅助治疗均能明显延长患者的无复发生存期。采用网状Meta分析对各种辅助治疗进行排序,dabrafenib联合trametinib在网状Meta分析中以及Ⅲ期亚组、存在溃疡亚组和BRAF突变亚组中排第一的可能性最大,而不存在溃疡的亚组分析中,vemurafenib排第一的可能性最大。结论对于存在溃疡或BRAF突变的可切除黑素瘤患者,dabrafenib联合trametinib是最佳辅助治疗;对于BRAF突变状态未知或野生型的可切除黑素瘤患者,nivolumab是最佳辅助治疗。     

Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: Japanese subgroup analysis from the phase 3 CheckMate 238 study

The multinational phase 3 CheckMate 238 trial compared adjuvant therapy with nivolumab versus ipilimumab among patients with resected stage III or IV melanoma (N = 906). In this Japanese subgroup analysis of CheckMate 238 (n = 28; nivolumab, n = 18; ipilimumab, n = 10), both the 12‐ and 18‐month recurrence‐free survival rates were 56% for nivolumab and 30% for ipilimumab (hazard ratio, 0.66; 97.56% confidence interval, 0.19–2.24; P = 0.4390). No new safety signals were reported for Japanese patients. Results were consistent with those from the CheckMate 238 global population, indicating that nivolumab has the potential to be a treatment option for Japanese patients with resected melanoma who are at high risk of recurrence.     

Frequency of Trauma,Physical Stress,and Occupation in Acral Melanoma: Analysis of 313 Acral Melanoma Patients in Korea

BackgroundTraumatic events are thought to be a cause of acral melanoma. However, little is known about the role of mechanical trauma or physical stress in the development of acral melanoma.ObjectiveIn our study, we evaluated the frequency of trauma, physical stress, and occupation in patients with acral melanoma and aimed to identify any pathological correlates of these factors.MethodsWe conducted a retrospective study of 313 acral melanoma patients from Chonnam National University Hospital. We mapped melanoma-developed anatomical sites of acral areas and assessed patients'' history of trauma, physical stress, and occupation.ResultsAmong the 313 acral melanoma patients, many reported a traumatic event (84 of 313; 26.8%) or physical stress (91 of 313; 29.1%) before the melanoma developed. The most common anatomical sites in these patients were on the borders of the foot (136 of 313; 43.5%). Trauma was more commonly associated with the fingernails and toenails than other sites. The frequency of each type of physical stress depended on the site of the lesion. Farmer and fisherman were the most common occupations (130 of 313; 41.5%) of the acral melanoma patients.ConclusionOur results demonstrate that traumatic events, physical stress, and certain occupations are common in acral melanomas. Further studies are needed to establish whether these are risk factors for acral melanomas.     

Blockade of CCR5 in melanoma: An alternative immune checkpoint modulator

Melanoma is a deadly tumor, which in recent years has been successfully treated with immune checkpoint inhibitors as PD-1/PD-L1 and CTLA-4 inhibitors and targeted therapy as BRAF and MEK inhibitors. However, immunotherapy poses deleterious side effects and pursuit of new therapeutic targets is warranted. As knowledge of tumor immunology advances, such targets are being recognized. C-motif chemokine receptor-5 (CCR5) is a receptor found on immune cells whose effects impact the immune response both to induce inflammation and to activate suppressor cells causing an anti-inflammatory effect. CCR5 is well known as a target for HIV therapy where its blockade is efficient and safe, it is also known that its mutation CCR5delta32 is for the most part non-pathological to its carriers. In oncology, activation of the CCR5 receptor has been observed in high-stage disease and CCR5 blockade has been associated with an increased immune response. In this letter, we build up the rationale to utilize CCR5 as a therapeutic target for metastatic melanoma.     

Melanoma and melanocytic nevi in decorative tattoos: three case reports

Background: In response to the demands of style and fashion, the number of decorative tattoos has been increasing worldwide. This has been paralleled by a rising incidence of melanocytic proliferations, including melanoma. The coincidence of various dermatological diseases and skin tumors with tattoos has been documented with some frequency, but reports of melanoma associated with tattoos are exceedingly rare. To date, only 13 cases have been documented in the English language literature. The possibility of an association between melanocytic proliferations and tattoos remains an area for further study. Observations: This report presents two cases of melanocytic nevi and one of melanoma occurring in association with a decorative tattoos. Conclusions: At present, the pathogenesis of melanoma developing in a tattoo is unknown. Mere coincidence cannot be ruled out. However, trauma, ultraviolet light exposure, a photoallergic effect, or an inflammatory reaction may promote malignant transformation. Clinicians and histopathologists should be aware of the clinical and pathological features if they are to make a correct diagnosis. Varga E, Korom I, Varga J, Kohán J, Kemény L, Oláh J. Melanoma and melanocytic nevi in decorative tattoos: three case reports.     

The use of electrochemotherapy in combination with immunotherapy in the treatment of metastatic melanoma: a focused review

Electrochemotherapy (ECT) is a treatment modality that combines low-dose chemotherapy with electroporation, thereby enhancing cytotoxicity. ECT was first utilized in the treatment of metastatic head and neck cancer. Today it is used as a local treatment for the cutaneous and subcutaneous metastases of a variety of cancers, including melanoma. In addition, recent evidence indicates that ECT in combination with immunotherapy can lead to a systemic tumor response. This review aims to summarize the efficacy of ECT in the treatment of metastatic melanoma, with a specific focus on the combination of ECT with immunotherapy.     

Malignant melanoma in HIV: Epidemiology,pathogenesis, and management

People affected by immunodeficiency, and especially those infected by HIV, are burdened by a higher risk of developing malignancies. It has been estimated that the incidence of melanoma in HIV‐infected people is 2.6‐fold higher than in uninfected ones. In this group of patients, melanoma shows a more aggressive phenotype and poorer survival rates compared to HIV‐negative people. Standard guidelines of diagnosis and care do not exist yet. Studies suggest high index of suspicion and a low threshold for biopsy in HIV‐positive patients regardless of their CD4⁺ count and the use of standard surgical margins for re‐excision procedures. In case of diagnosis of melanoma in HIV‐positive patients, a thorough search for metastatic disease is recommended because of the more aggressive course of this cancer in HIV‐positive patients. Moreover, to rapidly find out any recurrence or metastatic disease after treatment, these patients need a close follow‐up, every 3 months, for the first 2 years and at least twice yearly thereafter. Although surgery remains the main therapeutic option, application of immune checkpoint‐based immunotherapy is being studied and seems to be promising. The aim of this review is to present the current knowledge and future options for melanoma diagnosis and treatment in people living with HIV.     

Melanoma screening: results of the first one-day campaign in Belgium ('Melanoma Monday')

BACKGROUND: Although the incidence of melanoma is increasing and many informative campaigns have been organized. The general population is still little informed about this tumour. AIMS: To organize a media campaign, with more relevant information and the opportunity for free skin inspections. METHODS: A 'Task Force' organized a media campaign in April 1999 and convinced 65% of the Belgian dermatologists to give up 4 h of their time to do free skin examinations for skin cancer on Monday 26 April 1999; it was called 'Melanoma Monday'. RESULTS: A total 2767 patients were screened. We found 25 melanomas and suspected 59 basal cell carcinomas. In the following 4 weeks another 141 melanomas were found. These 166 melanomas found in one month represent 15-20% of the total number of melanomas per year in Belgium. SUMMARY: A media campaign with relevant information combined with screening opportunities can lead to the early detection of melanomas in a large number of patients and can continue to alert people at risk in the following weeks.     

乙酰肝素酶和基质金属蛋白酶-9蛋白在皮肤黑素瘤中的表达

目的探讨乙酰肝素酶和基质金属蛋白酶-9蛋白在皮肤黑素瘤中的表达及其意义。方法应用免疫组化S-P法检测乙酰肝素酶和基质金属蛋白酶-9蛋白在皮肤黑素瘤30例、交界痣30例及15例正常皮肤组织中的表达。结果皮肤黑素瘤中乙酰肝素酶(63.3%)和基质金属蛋白酶-9蛋白(73.3%)的阳性表达率明显高于交界痣(6.6%)和正常对照组(0)(P均<0.05),交界痣与正常对照组相比,差异无统计学意义(P>0.05)。结论乙酰肝素酶和基质金属蛋白酶-9蛋白的高表达可能与皮肤黑素瘤的发生发展有关,有望作为治疗黑素瘤的靶点。     

Clinical risk factors and prognostic significance of local recurrence in cutaneous melanoma

BACKGROUND: True local recurrence (LR) means clinically detectable regrowth of parts of the tumour which were not completely excised. In the literature the term 'LR' has been used in a vague and inconsistent manner that may include satellite and in-transit metastasis. OBJECTIVE: The aim of this study was to establish clinical, histological and surgical risk factors for the manifestation of LR and to evaluate the prognostic significance of LR. STUDY DESIGN: Data from 3960 Stage I and II melanoma patients who visited the melanoma clinic of the Department of Dermatology at the University of Tuebingen from 1980 to 1999 were documented in a prospective manner. A retrospective comparative analysis of patients with and without LR was performed. RESULTS: Of all patients 1.4% had a LR as a first recurrence and 1.7% had a LR in the course of the follow-up period. LR were most frequent after previous clinical or histological misdiagnosis and inadequate therapy. In the univariate analysis significant risk factors for LR-free survival were age, tumour surface area, locality, tumour thickness, level of invasion, histological type, associated naevus, surgery (one step vs. multiple steps) and compliance with recommended excision margins. In the multivarate analysis the factors locality (P < 0.0001), tumour thickness (P = 0.0086) and compliance with recommendations on excision margins (P = 0.014) were significant independent risk factors for the manifestation of LR. The overall survival of patients with LR as first progression did not significantly differ from the overall survival of the other patients with melanoma (P = 0.60). CONCLUSION: True LR is a rare event for which tumour locality, tumour thickness and surgery are independent risk factors. The occurrence of LR might not impair the prognosis of melanoma patients. However, in the published literature numerous definitions of 'LR', including lymphogenic metastasis, complicate comparison.     

Familial Atypical Mole Syndrome Manifesting as Polypoid Melanoma: A Case Report and Review of the Japanese Literature

A family with atypical mole syndrome which manifested as polypoid melanoma in one member is reported. A 46-year-old man presented with a polypoid tumor on his lower back, which was excised under clinical diagnosis of soft fibroma. The tumor proved to be polypoid melanoma. He was referred to our clinic, and examination revealed that he had the atypical mole syndrome phenotype. The clinicopathological screening of his first-degree relatives confirmed that his 58-year-old sister had the same phenotype. In addition to our discussion of the clinical significance of polypoid melanoma, we also attempted to elucidate the characteristics of the reported Japanese cases of melanomas with atypical moles from a survey of the literature, which revealed the following characteristics: 1) younger mean age than that of total Japanese melanoma cases, 2) sun sensitive skin, 3) unexpectedly and frequently observed familial incidence (Kraemer's D₁ and D₂), 4) frequent site of the melanoma on the trunk and none on the sole of the foot, and 5) high incidence of superficial spreading melanoma and nodular melanoma, and 6) no cases of acral lentiginous melanoma.