黑色素瘤抗原基因与肿瘤免疫治疗

黑色素瘤抗原基因(MAGE)表达产物是一种肿瘤特异性抗原，只在肿瘤、睾丸和胎盘组织中表达，在其他正常组织不表达，其发现有助于肿瘤的早期诊断和微小转移灶的检测。细胞毒性T淋巴细胞(CTL)通过识别由MAGE基因编码的抗原而杀伤肿瘤细胞。MAGE抗原为基础的免疫治疗在黑色素瘤和某些实体瘤的治疗中取得良好疗效，在肿瘤治疗中有着广阔前景。     

黑色素瘤抗原A家族与肝细胞癌

黑色素瘤抗原A (MAGE-A)是一组肿瘤相关性抗原,主要表达于以黑色素瘤为主的多种恶性肿瘤组织中.肝细胞癌(HCC)是发生于肝脏的上皮性恶性肿瘤,患病率高,寻找有效的诊断和治疗方法成为极其迫切的任务.目前已证实MAGE-A基因在HCC组织中高表达,对HCC诊治及预后判断具有重要意义.     

黑色素瘤抗原基因与肿瘤免疫治疗

黑色素瘤抗原基因(MAGE)表达产物是一种肿瘤特异性抗原,只在肿瘤、睾丸和胎盘组织中表达,在其他正常组织不表达,其发现有助于肿瘤的早期诊断和微小转移灶的检测.细胞毒性T淋巴细胞(CTL)通过识别由MAGE基因编码的抗原而杀伤肿瘤细胞.MAGE抗原为基础的免疫治疗在黑色素瘤和某些实体瘤的治疗中取得良好疗效,在肿瘤治疗中有着广阔前景.     

黑色素瘤抗原家族

20世纪90年代以来，人们对肿瘤抗原的性质、结构、表位以及利用肿瘤抗原对肿瘤进行治疗等方面有了深入的认识，特别值得关注的是黑色素抗原（MAGE）的研究。MAGE基因主要表达于以黑色素瘤为主的恶性肿瘤组织中，人们可以利用MAGE及其产物的特异性，针对肿瘤进行治疗。     

黑色素瘤抗原与肺癌的免疫治疗

随着分子生物学及基因工程技术的出现及应用 ,肿瘤疫苗的研究已成为主动性免疫治疗的重要手段之一。黑色素瘤抗原 (MAGE)为肿瘤特异性CTL所能识别的抗原 ,该类抗原上特定的肽段可与相应的HLAⅠ类分子结合 ,引起强烈的CTL反应。由于大多数肺癌高表达MAGE ,因而应用MAGE抗原肽对肺癌患者进行免疫治疗 ,可能具有广阔的应用前景。     

黑色素瘤免疫治疗研究进展

黑色素瘤是皮肤癌中最具侵袭性的恶性肿瘤。近20年,世界范围发病率急剧上升,每年以3．1％的速度增加。我国发病率较低,但近年来增长加快,每年新发病例约2万例。     

黑色素瘤抗原与肺癌的免疫治疗

随着分子生物学及基因工程技术的出现及应用，肿瘤疫苗的研究已成为主动性免疫治疗的重要手段之一。黑色素瘤抗原（MAGE）为肿瘤特异性CTL所能识别的抗原，该类抗原上特定的肽段可与相应的HLAI类分子结构，引起强烈的CTL反应。由于大多数肺癌高表达MAGE，因而应用MAGE抗原肽对肺癌患者进行免疫治疗，可能具有广阔的应用前景。     

黑色素瘤抗原家族

20世纪90年代以来,人们对肿瘤抗原的性质、结构、表位以及利用肿瘤抗原对肿瘤进行治疗等方面有了深入的认识,特别值得关注的是黑色素抗原(MAGE)的研究。MAGE基因主要表达于以黑色素瘤为主的恶性肿瘤组织中,人们可以利用MAGE及其产物的特异性,针对肿瘤进行治疗。     

黑色素瘤抗原泛素连接酶的研究进展

黑色素瘤抗原（melanoma-associated antigen gene, MAGE）被视为一种肿瘤标志物和免疫治疗的热门对象。研究发现MAGE联合E3-RING泛素连接酶形成MAGE-RING连接酶复合体（MAGE-RING ligases, MRLs）,成为泛素化的调控因子,从而调控连接酶的活性、底物的特异性和亚细胞定位。该文就MRLs的结构、活化机制和转录功能作一综述。     

细胞因子治疗恶性黑色素瘤实验研究进展

白细胞介素(IL)、粒-巨噬细胞集落刺激因子(GM-CSF)、干扰素(IFN)等细胞因子能够促进机体的免疫反应,对恶性黑色素瘤(MM)的发生和发展有一定的抑制作用,其实验研究进展为临床应用提供了重要理论依据.     

Immunotherapy of melanoma

The rationale for immunotherapy of human melanoma is based on the knowledge acquired in the molecular characterization of T cell defined antigens which are recognized in vitro by patients' lymphocytes. Based on this information, active immunotherapy (vaccination) and adoptive immunotherapy trials were conducted in metastatic melanoma patients. This review highlights the most important clinical studies and discuss their limits, in terms of both immune and clinical response considering the formulation of the vaccine (cellular, peptide/protein; DNA, etc.) or the features of immune cells used in adoptive immunotherapy. This new knowledge, along with that of escape mechanisms, should allow to improve significantly the clinical response rate in the immunotherapy of melanoma.     

Revolutionizing treatment of advanced melanoma with immunotherapy

Until immunotherapy was developed, a diagnosis of metastatic melanoma was most often fatal. Programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies have been shown to work synergistically to treat metastatic disease throughout the body and brain. Today, over half of patients diagnosed with stage IV disease are alive after 3 years. In the adjuvant setting, 70% patients remain disease free with PD-1 blockade after 1 year. These treatments are generally safe and well tolerated. However, treatment-related endocrinopathies require long-term medications. With better therapies producing more durable responses, advanced cutaneous melanoma is dramatically more manageable now than ever before.     

合并自身免疫性疾病的黑色素瘤患者的免疫疗法

免疫疗法已经成为黑色素瘤治疗的重要手段.抗细胞毒T淋巴细胞相关抗原-4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抗体或程序性死亡受体-1(programmed death-1,PD-1)/程序性死亡-配体1(programmed death-ligand 1,PD-L1)抑制剂用于治疗合并自身免疫性疾病(AD)的黑色素瘤安全有效.尽管如此,当此类患者应用抗CTLA-4抗体或PD-1/PD-L1时,仍应密切观察其病情变化,以预防和避免可能出现的AD进展和免疫相关不良反应.     

74例皮肤黑色素瘤的预后及影响因素分析

目的 探讨皮肤恶性黑色素瘤的临床病理特征及预后相关因素。方法 回顾性分析南京鼓楼医院2010年1月至2016年6月收治的74例皮肤黑色素瘤患者的临床病理资料。所有入组患者均接受手术治疗,术后辅助治疗分为联合免疫治疗和未联合免疫治疗,免疫治疗方法包括细胞因子治疗和过继性免疫细胞回输疗法,未联合免疫治疗者包括术后未治疗的以及术后仅行辅助放疗或辅助化疗的患者。根据随访资料分析预后情况,并采用Cox比例风险回归模型分析影响预后的因素。结果 全组患者的中位生存期（OS）和无病生存期（DFS）分别为 32.0个月（95％CI： 20.2～43.8个月）和23.0个月（95％CI： 16.4～29.6个月）。Ⅲ期患者术后联合免疫治疗较未联合免疫治疗中位OS延长（38.0个月 vs. 10.0个月,P=0.002）。多因素分析显示,年龄、分期、淋巴结转移、原发灶溃疡和肿瘤Breslow厚度是影响皮肤黑色素瘤OS的独立因子,分期、淋巴结转移、原发灶溃疡和肿瘤Breslow厚度是影响DFS的独立因子。结论 年龄、分期、淋巴结转移、肿瘤Breslow厚度和原发灶溃疡均与皮肤恶性黑色素瘤患者的预后密切相关。Ⅲ期患者术后联合免疫治疗可延长OS。     

皮肤进展期黑色素瘤的瘤体内治疗进展

瘤体内注射指向肿瘤局部病灶内注射抗肿瘤药物,在杀灭注射部位肿瘤细胞的同时,并可能引发免疫反应,产生“旁观者”效应,对非注射病灶也发挥抗肿瘤作用。2015年10月美国食品和药物管理局审批通过黑色素瘤瘤体内注射治疗的新型药物Talimogene laherparepvec上市,用于首次手术后复发的黑色素瘤患者不可切除的皮肤、皮下和淋巴结病灶的局部治疗,引发人们对该治疗手段的极大关注。本文对以往用于皮肤进展期黑色素瘤瘤体内注射治疗的药物及其相关疗效进行综述,其中包括细胞因子、质粒及溶瘤病毒等,并对该类型药物的进一步发展提出展望。     

Cancer-testis antigen expression in primary cutaneous melanoma has independent prognostic value comparable to that of Breslow thickness, ulceration and mitotic rate

To determine the effect of Cancer-Testis Antigen (CTAg) expression on the natural history of primary cutaneous melanoma we compared its impact on prognosis with that of known prognostic factors and its relationship with other clinicopathologic characteristics.The immunohistochemical expression of three CTAgs (MAGE-A1, MAGE-A4 and NY-ESO-1) in 348 cases of stage I and stage II primary cutaneous melanoma was analysed and correlated with clinicopathologic characteristics, relapse free survival (RFS) and overall survival (OS). A Cox proportional hazards regression model was used to analyse factors which independently predicted RFS.All three CTAgs were significantly co-expressed with each other (p < 0.001). The median RFS for patients with CTAg-negative tumours and CTAg-positive tumours was 72 months and 45 months, respectively, (P = 0.008). Univariate analysis demonstrated that the impact of CTAg expression on RFS was comparable in magnitude to that of Breslow thickness, ulceration and tumour mitotic rate. Multivariate Cox regression analysis indicated that CTAg expression was a powerful independent predictor of RFS (risk ratio (RR) = 1.715, 95% confidence interval (CI) = 0.430-0.902, P = 0.010). In contrast, CTAg expression was demonstrated to have no prognostic impact on overall survival.This study demonstrates that CTAg expression in primary cutaneous melanoma is a strong independent predictor of RFS and it is comparable to other known important prognostic factors. CTAg expression has no relationship with overall survival, suggesting anti-melanoma immunity directed towards CTAg expression may contribute to the natural history of the disease. In view of these results, further investigation of the function of CTAgs and their potential use in therapeutic targeting is warranted.     

Preferentially expressed antigen of melanoma (PRAME) in the development of diagnostic and therapeutic methods for hematological malignancies

PRAME (Preferentially expressed antigen of melanoma), highly expressed in various solid tumor cells and normal testis, was first isolated as a human melanoma antigen recognized by cytotoxic T cells (CTL). This gene was also expressed in some of the hematological malignancies, including acute myelogenous leukemia (AML) and multiple myeloma. We and others have extensively evaluated the PRAME expression in various hematological malignancies and demonstrated high expression of the PRAME gene in subsets of AML, chronic myelogenous leukemia, acute lymphocytic leukemia, lymphoma and multiple myeloma. In addition, we have demonstrated that PRAME was a useful marker for detection of minimal residual disease (MRD) in patients with leukemia, particularly those leukemias in which tumor specific markers are currently unavailable. Since PRAME was first identified as a tumor antigen recognized by T cells, the possibility that PRAME is a leukemia antigen recognized by T cells was evaluated, and it was found that PRAME-positive leukemia cell lines and fresh leukemia cells were susceptible to lysis by the PRAME-specific CTL. Five CTL epitopes associated with either HLA-A ∗0201 or HLA-A ∗2402 have recently been identified. It is, therefore, an attractive strategy to apply PRAME specific immunotherapy on patients with PRAME positive leukemia in MRD condition.     

Local delivery of poxvirus vaccines for melanoma

The development of vaccines for melanoma has been accelerated by the identification of melanoma-associated antigens, a better understanding of basic immunologic principles, and the ability to construct complex vectors for immunization. The location and context in which T-cell priming occurs significantly influences the type and magnitude of immune response. Furthermore, there is a delicate balance between the generation of tumor-specific immunity and the emergence of tumor escape variants. We have focused on the direct intra-tumoral delivery of poxvirus vaccines expressing costimulatory molecules as a strategy for overcoming local immunosuppression in the treatment of established melanoma. Poxviruses provide potent danger signals and, in the presence of costimulation, local administration provides a mechanism to prime tumor-specific T-cell responses. The clinical application of this approach will likely depend on the ability to induce systemic anti-tumor immunity following local injection and we are evaluating this in current clinical trials. These studies may have important implications for the design of vaccine strategies for melanoma and other tumors.