Melanoma is a cancer that arises from melanocytes, specialized pigmented cells that are found predominantly in the skin. The incidence of melanoma is rising steadily in western populations--the number of cases worldwide has doubled in the past 20 years. In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat and does not respond to current therapies. Recent discoveries in cell signalling have provided greater understanding of the biology that underlies melanoma, and these advances are being exploited to provide targeted drugs and new therapeutic approaches.

Melanoma biology and new targeted therapy

It has been more than three decades since the first monoclonal antibody was approved by the United States Food and Drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically evolved. Current antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeutic antibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top ten bestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and $300 billion by 2025. Thus, the market for therapeutic antibody drugs has experienced explosive growth as new drugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but there is still significant growth potential. This review summarizes the latest market trends and outlines the preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation. Finally, future applications and perspectives are also discussed.

/pdf/development-of-therapeutic-antibodies-for-the-treatment-of-4g7fs3ndpf.pdf

Development of therapeutic antibodies for the treatment of diseases

Importance Immune-related adverse events (irAEs) have been associated with the efficacy of PD-1 (programmed cell death protein 1) inhibitors in patients with melanoma, but whether such an association exists for non–small-cell lung cancer (NSCLC) has remained unknown. Objective To evaluate the relation of irAEs to nivolumab efficacy in NSCLC. Design, Setting, and Participants In this study based on landmark and multivariable analyses, a total of 134 patients with advanced or recurrent NSCLC who were treated with nivolumab in the second-line setting or later between December 2015 and August 2016 were identified from a review of medical records from multiple institutions, including a university hospital and community hospitals. Data were updated as of December 31, 2016. Exposures The absence or presence of any irAE before the landmark date. Main Outcomes and Measures Kaplan-Meier curves of progression-free survival (PFS) according to the development of irAEs in 6-week landmark analysis were evaluated with the log-rank test as a preplanned primary objective. Overall survival (OS) was similarly evaluated. Multivariable analysis of both PFS and OS was performed with Cox proportional hazard regression models. Results In a cohort of 134 patients (median [range] age, 68 [33-85] years; 90 men [67%], 44 women [33%]), irAEs were observed in 69 of the 134 study patients (51%), including 12 patients (9%) with such events of grade 3 or 4, and 24 patients (18%) requiring systemic corticosteroid therapy. In 6-week landmark analysis, median PFS was 9.2 months (95% CI, 4.4 to not reached [NR]) and 4.8 months (95% CI, 3.0 to 7.5) ( P  = .04) whereas median OS was NR (95% CI, 12.3 to NR) and 11.1 months (95% CI, 9.6 to NR) ( P  = .01) for patients with or without irAEs, respectively. Multivariable analysis also revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.525 (95% CI, 0.287 to 0.937; P  = .03) for PFS and 0.282 (95% CI, 0.101 to 0.667; P  = .003) for OS. Conclusions and Relevance Development of irAEs was associated with survival outcome of nivolumab treatment in patients with advanced or recurrent NSCLC. Further studies are needed to confirm our findings.

Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer.

The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy.

Therapeutic vaccines for cancer: an overview of clinical trials

Skin cancer is less common in persons with skin of color than in light-skinned Caucasians but is often associated with greater morbidity and mortality. Thus, it is crucial that physicians become familiar with skin cancer in persons of color so as to maximize the likelihood of early detection of these tumors. In dark-skinned ethnic groups, squamous cell carcinoma is most common; squamous cell carcinoma and melanoma usually occur on nonsun-exposed sites; and ultraviolet radiation is not an important etiologic factor for skin cancer with the exception of basal cell carcinoma. Races of intermediate pigmentation, such as Hispanics and Asians, share epidemiologic and clinical features of dark-skinned ethnic groups and Caucasians. Skin cancers pose a significant risk in skin of color and clinicians should focus on preventive measures in these groups such as regular skin exams, self-examination, public education, and screening programs. Learning objective At the completion of this learning activity, participants should be familiar with the epidemiology and unique clinical features of skin cancer in skin of color and be aware of strategies to prevent skin cancer in skin of color.

Skin cancer in skin of color.

Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2-9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression-free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11-0.55 and 0.03-0.79; P = 0.005, and 0.047, respectively). At the 20-week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome.

Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study.

Background. A statistical investigation was conducted of Japanese melanoma patients who had been registered by the Prognosis and Statistical Investigation Committee of the Japanese Skin Cancer Society. The data were obtained from 24 main medical institutions in Japan in the period 1987 to 1996. The patients were classified into two chronological groups; group A, 535 patients registered from 1987 to 1991; and group B, 639 patients registered from 1992 to 1996. As the preliminary data for group A has been reported previously (Gann Monograph on Cancer Research 43), in this report, the survival data of group B were assessed, and compared with the data for group A. 
Methods. The data analyzed included age, sex, anatomical distribution, clinical features of primary lesions, Clark's subtype, tumor thickness, Clark's level, disease stage, and treatment. The survival rate was assessed by the Kaplan-Meier method, and the significance of differences was determined with the log-rank test. In addition, the results of a nationwide survey of various types of skin malignancies, obtained from 101 medical institutions in Japan between 1987 and 1996, were analyzed. 
Results. The nationwide survey revealed that the number of patients with malignant melanoma showed a steady increase during the period 1987–1996 in Japan. It is noteworthy that the numbers of actinic keratoses, a type of early squamous cell carcinoma in situ, showed a steep increase in recent years. Results revealed in our study of the melanoma registry for the period 1987–1996 were as follows: (1) the male-to-female ratio was 1 to 1.06, (2) the survival rate of female patients was higher than that of male patients (10-year survival in group B: female, 71.6% vs male, 55.9%), (3) the commonest site of melanoma in both sexes was the sole of the foot, (4) with respect to Clark's subtype, acral lentiginous melanoma was commonest, accounting for about half of all melanomas, (5) nodular melanoma showed the worst prognosis among the subtypes, (6) patients in stage IIIB and stage IV had an unfavorable outcome, with 10-year survivals of less than 50% and less than 10%, respectively, (7) Clark's level of invasion, as well as Breslow's tumor thickness of the primary lesions, were confirmed to be important prognostic factors, and (8) prophylactic lymph node dissection in stage II and IIIA and chemotherapy in stage IV seemed to have limited effect on the prognosis. 
Conclusion. The prognosis of advanced melanoma is poor, as it is highly resistant to chemotherapy. Thus, to improve the prognosis, early detection is mandatory, and this is possible because this neoplasm appears as a distinctive pigmented lesion on the skin.

Updated statistical data for malignant melanoma in Japan.

Metastatic and chemoresistant melanoma can be a good target of immunotherapy because it is an intractable cancer with a very poor prognosis. Previously, we tested a dendritic cell (DC)-based phase I vaccine, and confirmed that it was safe. In the present study, we performed a phase II trial of a DC vaccine for metastatic melanoma patients with mainly the HLA-A24 genotype, and investigated the efficacy of the vaccine. Twenty-four patients with metastatic melanoma were enrolled into a phase II study of DC-based immunotherapy. The group included 19 HLA-A24-positive (A*2402) patients and 3 HLA-A2-positive (A*0201) patients. The protocol for DC production was similar to that in the phase I trial. Briefly, a cocktail of 5 melanoma-associated synthetic peptides (gp100, tyrosinase, MAGE-A2, MAGE-A3 and MART-1 or MAGE-A1) restricted to HLA-A2 or A24 and KLH were used for DC pulsing. Finally, DCs were injected subcutaneously (s.c.) into the inguinal region in the dose range of 1–5×107 per shot. The DC ratio (lin-HLA-DR+) of the vaccine was 38.1±13.3% and the frequency of CD83+ DCs was 25.7±20.8%. Other parameters regarding DC processing were not different from phase I. Immune response-related parameters including the ELISPOT assay, DTH reaction to peptide or KLH, DC injection numbers were shown to be related to a good prognosis. The ELISPOT reaction was positive in 75% of the patients vaccinated. The increase of anti-melanoma antigen antibody titer before vaccination was also shown to be a prognosis factor, but that post-vaccination was not. Based on immunohistochemical analysis, CD8 and IL-17 were not involved in the prognosis. Adverse effects of more than grade III were not seen. Overall survival analysis revealed a significant survival prolongation effect in DC-given melanoma patients. These results suggest that peptide cocktail-treated DC vaccines may be a safe and effective therapy against metastatic melanoma in terms of prolongation of overall survival time.

/pdf/dendritic-cell-based-vaccination-in-metastatic-melanoma-4jd63gxz24.pdf

Dendritic cell-based vaccination in metastatic melanoma patients: Phase II clinical trial

Background. Eccrine spiradenoma is a well-differentiated benign tumor of the sweat glands. Malignant change arising within eccrine spiradenoma is rare.

Objective. We describe a patient with malignant eccrine spiradenoma exhibiting both carcinomatous and sarcomatous differentiation.

Methods. Case report and literature review.

Results. A 37-year-old woman noted enlargement of a left axillary tumor that had been present for 20 years. The tumor was resected and the specimen, measuring 3.0 cm × 1.5 cm, revealed an encapsulated benign eccrine spiradenoma as well as an undifferentiated carcinoma possessing both carcinomatous and sarcomatous components. A transition zone was evident between the benign eccrine spiradenoma and the undifferentiated carcinoma, suggesting that the latter had arisen from the benign tumor. The malignant areas consisted principally of undifferentiated carcinoma (70%), although squamous cell carcinoma (10%), adenocarcinoma (10%), and chondrosarcomatous (10%) components were also present. Numerous mitotic figures were noted within the areas of malignant change, suggesting that the tumor was aggressive in nature. The patient died of systemic metastases 7 months after diagnosis.

Conclusion. Although eccrine spiradenomas are usually benign, they can, on rare occasions, undergo malignant transformation. This case report describes one such occurrence of malignant transformation of a benign eccrine spiradenoma that unfortunately resulted in the patient's death from systemic metastases 7 months after diagnosis.

Malignant eccrine spiradenoma : A case report and review of the literature

Background Melanoma is an intractable cancer with a poor prognosis and increasing prevalence worldwide. Specific biomarkers for early diagnosis have yet to be found. Materials and methods Serum samples from melanoma patients and healthy volunteers were utilized for identifying melanoma marker proteins using a serological proteome approach. Specifically, G361 cell protein spots separated by 2-dimensional gel electrophoresis and transferred to a membrane were incubated with patient sera, and positive spots that reacted with more than 5 serum samples were identified using time of flight mass spectrometry. Results Only patient sera showed many spots reacted in G361 gels. A total of 13 positive spots were detected and 5 proteins were identified: eukaryotic elongation factor2 (EEF2), enolase1 (ENO1), aldolase A (ALDOA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and heterogeneous nuclear ribonucleoproteins (HNRNP) A2B1. The mRNAs of four proteins (EEF2, ENO1, ALDOA and HNRNPA2B1) were highly expressed in G361 cells compared with melanocytes. EEF2, ENO1 and ALDOA mRNAs were also frequently expressed in other melanoma cell lines. Conclusion The autoantibody-based proteomic approach was effective for investigating melanoma biomarkers. This study might contribute to the development of a diagnostic device for the early detection of cancer.

Akifumi Yamamoto

Papers

Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study.

Updated statistical data for malignant melanoma in Japan.

Dendritic cell-based vaccination in metastatic melanoma patients: Phase II clinical trial

Malignant eccrine spiradenoma : A case report and review of the literature

Identification of Melanoma Antigens Using a Serological Proteome Approach (SERPA)