Immune alterations in malignant melanoma and current immunotherapy concepts

Introduction: Malignant melanoma is a highly aggressive, immunogenic tumor that has the ability to modulate the immune system to its own advantage. Patients with melanoma present numerous cellular immune defects and cytokine abnormalities, all leading to suppression of the host anti-tumor immune response. Innovative treatment strategies can be achieved through employing our knowledge of the melanoma-induced immune alterations.

Areas covered: The authors review comprehensively the immune abnormalities in individuals with melanoma, and provide a summary of currently available melanoma immunotherapy agents that are currently on the market or undergoing clinical trials.

Expert opinion: Ipilimumab, a monoclonal antibody directed against the CTLA-4, is one of the current forefront treatment strategies in malignant melanoma. Novel immunomodulating agents have shown clear activity in patients with malignant melanoma. These include anti-PD-1 and anti-PD-1 ligand antibodies that may soon become important items in the anti-melanoma armamentarium. Combinations of different immunotherapy agents, between themselves or with other agents, are currently being studied in an attempt to further enhance the antineoplastic effect in patients with malignant melanoma.     

Pembrolizumab use for the treatment of advanced melanoma

Introduction: Until recently, overall long term survival in patients with stage IV melanoma was lower than 10%. However, the treatment of melanoma has evolved rapidly over the last few years, with the advent of inhibitors of BRAF and MEK and of immunotherapeutic agents including ipilimumab, nivolumab, and pembrolizumab.

Areas covered: This is a comprehensive review of the literature on the role of pembrolizumab in melanoma. Pembrolizumab is a Programmed Death Receptor 1 (PD-1) directed monoclonal antibody which is approved by FDA and EMA for the treatment of patients with metastatic melanoma.

Expert opinion: Phase II and III trials demonstrated that pembrolizumab is superior to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. Unfortunately, prospectively validated predictive markers are lacking. Immune-related adverse events are particularly interesting and should be managed per the published guidelines. There are still many issues that remain unresolved including: when to stop treatment, biomarkers for choosing a single agent or combination therapy, the optimal schedule of ipilimumab in combination with anti-PD1 monoclonal antibodies, optimal management of adverse events, the role of immunotherapy in specific populations, the optimal sequence of immunotherapy and the BRAF/MEK inhibitor combination in patients.     

Single versus combination immunotherapy drug treatment in melanoma

ABSTRACT

Introduction: The advent of new immunotherapies for the treatment of metastatic melanoma has resulted in various novel combination strategies. Because of their distinct modes of action, different immunotherapies have been investigated in combination with one another, as well as combined with targeted therapies and other treatment modalities.

Areas covered: Anti-CTLA-4 and anti-PD-1 treatments enhance antitumor immunity through complementary and non-redundant mechanisms. The combination of the anti-CTLA-4 agent ipilimumab and the anti-PD-1 agent nivolumab has been shown to improve progression-free survival and objective response rate compared with either agent alone as monotherapy in patients with advanced melanoma. However, the combination was associated with significant toxicity, with around one-third of patients discontinuing treatment as a result. The sequential use of nivolumab and ipilimumab was associated with similar outcomes and comparable toxicity to concurrent therapy. Clinical trials assessing various combinations of immunomodulating antibodies are ongoing or planned. Ipilimumab and pembrolizumab have also been investigated in combination with the oncolytic virus, talimogene laherparepvec (T-VEC), with promising results. In addition, immunotherapies have also been combined with chemotherapy, radiotherapy and electrochemotherapy.

Expert opinion: Investigation of combination approaches represents the start of a new story that begins with melanoma treatment and expands to embrace other solid and hematological cancers.     

Toripalimab for the treatment of melanoma

ABSTRACT

Introduction

Immune therapies have dramatically changed the treatment landscape for melanoma in the past decade. Ipilimumab, nivolumab, and pembrolizumab have been approved by U.S. Food and Drug Administration for the treatment of metastatic melanoma sequentially. Toripalimab, a humanized IgG4 monoclonal antibody against programmed cell death protein-1 (PD-1), was approved by National Medical Product Administration in China in 2018 as second-line therapy for metastatic melanoma.     

Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is a highly immunogenic neoplasm, and cytokine-based immunotherapies have been used for decades with limited success. In recent years, antibody-based immunotherapies targeting immune checkpoint receptors PD-1 and CTLA-4 have demonstrated clinical efficacy in metastatic RCC (mRCC) patients, leading to FDA approval of the combination of nivolumab and ipilimumab in treatment-naïve patients with intermediate- or poor-risk disease in April 2018.

Areas covered: The pharmacodynamics and pharmacokinetics of nivolumab and ipilimumab are reviewed. Clinical safety and efficacy results from pivotal phase I and III trials of the combination of nivolumab plus ipilimumab in mRCC are summarized, and the combination is reviewed in the context of other available systemic therapies for RCC. Ongoing clinical studies involving the combination of nivolumab plus ipilimumab in RCC are discussed.

Expert opinion: The combination of nivolumab and ipilimumab has demonstrated superior efficacy for treatment-naïve patients with intermediate- and poor-risk mRCC with clear cell histology and is likely to replace anti-angiogenic therapies as the treatment-of-choice in this patient population in the United States. Development of additional combination strategies, novel trial designs, and predictive biomarkers of response will be important to further optimize therapeutic selection and clinical outcomes.     

Combined immune checkpoint inhibitors of CTLA4 and PD-1 for hepatic melanoma of unknown primary origin: A case report

BACKGROUNDMelanoma is uncommonly found in lymph nodes, subcutaneous tissue, or visceral organs without a primary lesion, where it is identified as metastatic melanoma with unknown primary (MUP). Hepatic MUP is extremely rare and has a poor prognosis. There is limited information on its pathogenesis, clinical and imaging features, and pathological findings. There are no guidelines for the use of immune checkpoint inhibitors (ICIs) in hepatic MUP, and the treatment outcome has rarely been reported.CASE SUMMARYA 42-year-old woman presented to our hospital with hepatic tumors found incidentally during a routine check-up. Contrast-enhanced abdominal com-puterized tomography showed multiple mass lesions in the liver. Pathological results revealed melanoma, which was confirmed by immunohistochemical staining for HMB-45(+), Melan-A(+), S-100(+), and SOX10(+). There was no evidence of primary cutaneous, ocular, gastrointestinal, or anal lesion on a comprehensive examination. The patient was diagnosed with hepatic MUP. She received combined antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, ipilimumab) and programmed death protein-1 (PD-1, nivolumab). She died of hepatic failure 9 mo after hepatic MUP was diagnosed. This the first case of hepatic MUP treated with combined ipilimumab and nivolumab, who showed better outcome than previous cases.CONCLUSIONCombined ICIs of PD-1 and CTLA-4 may be considered as the first-line therapy for patients with hepatic MUP.     

Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies

The use of tumor-specific monoclonal antibodies (MAbs) has revolutionize the field of cancer immunotherapy. Although treatment of malignant diseases with MAbs is promising, many patients fail to respond or relapse after an initial response. Both solid tumors and hematological malignancies develop mechanisms that enable them to evade the host immune system by usurping immune checkpoint pathways such as PD-1, PD-2, PDL-1, or PDL-2 (programmed cell death protein-1 or 2 and PD-Ligand 1 or 2), which are expressed on activated T cells and on T-regulatory, B cells, natural killers, monocytes, and dendritic cells. One of the most exciting anticancer development in recent years has been the immune checkpoint blockade therapy by using MAbs against immune checkpoint receptor and/or ligands. Anti-PD1 antibodies have been tested in clinical studies that included patients with hematological malignancies and showed remarkable efficacy in Hodgkin lymphoma (HL). In our review, we will focus on the effect of PD-1 activation on hematological malignancies and its role as a therapeutic target.

• Key messages

• The programmed death 1 (PD1) immune checkpoint is an important homeostatic mechanism of the immune system that helps in preventing autoimmunity and uncontrolled inflammation in cases of chronic infections.

• However, PD1 pathway is also operated by a wide variety of malignancies and represents one of the most important mechanisms by which tumor cells escape from the surveillance of the immune system.

• Blocking of immune checkpoints by the use of monoclonal antibodies opened a new era in the field of cancer immunotherapy. Results from clinical trials are promising, and currently, this approach has been proven effective and safe in patients with solid tumors and hematological malignancies.

     

Evaluation of the immune checkpoint factors in idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN), a single-organ autoimmune disease, is recognized by autoantibodies to podocyte proteins and identified as the most frequent cause of nephrotic syndrome in adults. T cells are important contributors in autoimmunity since they promote B–cell development, antibody production, direct inflammation, and organ tissue cytotoxicity. This study investigated the inhibitory immune checkpoint (ICP) receptors expressed on T lymphocytes and other immune cells. Thus, PBMCs from IMN patients were obtained before treatment, and the levels of ICPs such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin-3 (TIM-3) were examined at both gene and protein expression using real time PCR and Western blot tests respectively. The results illustrated that gene expression levels of ICPs reduced significantly in comparison to the control which were verified by related fold changes of protein expression sequentially. Our study revealed that CTLA-4, PD-1, TIM-3, and LAG-3 expression is impaired in IMN patients before treatment which could be a potential target for therapy.     

恶性黑色素瘤术后患者免疫检查点抑制剂辅助治疗早期疲劳发展轨迹研究

目的 免疫检查点抑制剂中的程序性细胞死亡蛋白受体1（programmed cell death protein1,PD-1）抑制剂已被用于多种晚期肿瘤的治疗中,该研究旨在识别恶性黑色素瘤术后PD-1抑制剂单药辅助治疗患者早期疲劳发展轨迹及其影响因素。 方法 采用便利抽样法,选取2020年4月—2021年12月于河南省某三级肿瘤医院和吉林省某三级甲等医院肿瘤科住院的患者作为调查对象,采用癌症疲乏量表调查患者首次PD-1抑制剂治疗后1、2、3、4周后的疲乏现状,利用组基轨迹模型识别106例PD-1抑制剂单药辅助治疗患者早期疲劳症状发展轨迹,运用多元Logistic回归分析患者早期疲劳症状发展轨迹的影响因素。 结果 识别出“疲劳缓解组”和“疲劳升高组” 2种早期疲劳发展轨迹。单因素分析结果显示,各亚组在肿瘤部位、自理能力、休息后是否缓解、伴有其他免疫相关不良事件个数方面的差异均具有统计学意义（P<0.05）。多元Logistic回归分析结果显示,早期疲劳症状休息后缓解[RR=0.026,95%CI（0.004,0.179）]、不伴有其他免疫相关不良事件[RR=0.255,95%CI（0.181,0.361）]被归属为类型2“疲劳升高组”的可能性较小。 结论 恶性黑色素瘤术后患者PD-1抑制剂辅助治疗早期疲劳发展呈现不同的变化轨迹,护士应重视疲劳症状休息后不缓解、伴有其他免疫相关不良事件患者早期疲劳症状的评估和干预。     

Heat-shock proteins-based immunotherapy for advanced melanoma in the era of target therapies and immunomodulating agents

Introduction: Heat-shock proteins (HSPs) are highly conserved, stress-induced proteins that function as chaperones, stabilizing proteins and delivering peptides. Tumor-derived HSP peptide complexes (HSPPCs) induced immunity against several malignancies in preclinical models, exhibiting activity across tumor types.

Areas covered: HSPPC-based vaccination showed clinical activity in subsets of patients with different malignancies (e.g., gastric, colorectal, pancreatic, ovarian cancer, and glioblastoma). In Phase III clinical trials for advanced melanoma and renal cell carcinoma patients, HSPPC-based vaccine demonstrated an excellent safety profile, thus emerging as a flexible tumor- and patient-specific therapeutic approach.

Expert opinion: Melanoma, renal clear cell carcinoma, and glioblastoma are among suitable targets for HSP-based treatment as demonstrated by immune responses and clinical activity observed in subsets of patients, mainly those with early stage of disease and limited tumor burden. In order to further improve clinical activity, combinations of HSPPC-based vaccines with mutation-driven therapies, antiangiogenic agents, or immunomodulating monoclonal antibodies should be tested in controlled clinical trials.     

Research progress and clinical application of predictive biomarker for immune checkpoint inhibitors

Introduction: Immune checkpoint inhibitors (ICIs) have emerged as epochal milestones in the ?eld of anti-cancer immunotherapy. With promising clinical effectiveness, ICIs can significantly prolong the overall survival of patients with advanced cancer of different types. Although their remarkable effectiveness has been demonstrated in clinical application, ICIs display limitations in terms of unique response patterns. Only a subset of patients exhibits objective responses, while others show rapid disease progression. Considering that there is a fair representation of both subsets of patients (responders and non-responders), clinicians ought to effectively stratify patients who will potentially benefit from ICI therapy, and optimize a strategy for patient selection.

Areas covered: In this review, the authors have summarized several key factors involved in the biomarker development of ICI therapy, such as neoantigen production and presentation, the tumor microenvironment, and alternation in specific gene signaling pathways.

Expert opinion: Considering the extreme complexity of the immune system, a single biomarker may fail to appropriately stratify patients for ICI therapy. Therefore, future biomarker research should focus on designing an integrated biomarker system that will successfully guide combination therapies to overcome resistance to immunotherapy.     

VAC/IE方案一线姑息治疗晚期成人横纹肌肉瘤的疗效及安全性分析

目的:探讨VAC/IE方案治疗晚期成人横纹肌肉瘤(RMS)的疗效及安全性。方法:选择2010年1月至2018年12月在复旦大学附属中山医院肿瘤内科接受VAC/IE方案一线姑息治疗的成人RMS患者16例,中位发病年龄31岁,分析其疗效及不良反应。结果:平均随访时间13个月。16例患者VAC/IE方案的总体有效率(ORR)达37.5%(6例)、疾病控制率达68.8%(11例),中位无进展生存时间为5.8个月,中位总生存时间为15个月。所有患者共化疗93个周期,其中,3级以上化疗不良反应主要包括中性粒细胞下降(34/93,36.6%)、恶心呕吐(27/93,29.0%)。结论:成人RMS是一种罕见的高度恶性肿瘤,总体预后差。对于晚期患者,在预防性升白细胞及止吐治疗基础上,采用VAC与IE方案交替姑息治疗有效可行。     

Results and challenges of immune checkpoint inhibitors in colorectal cancer

Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and clinical outcome has improved substantially during the last two decades with targeted therapies. The immune system has a major role in cancers, especially the CD8 + T cells specific to tumor antigens. However, tumors can escape immune response by different mechanisms including upregulation of inhibitory immune checkpoint receptors, such as well-known Programmed cell Death protein-1 (PD-1)/Programmed cell Death Ligand 1 (PD-L1) interaction, leading CD8 + T cells to a state of anergy. Immunotherapy, with the so-called immune checkpoint inhibitors (CPIs), has recently been approved in treatment of multiple cancers due to its prolonged disease control and acceptable toxicities. The recent groundbreaking success involving anti-PD-1 CPIs in metastatic CRC with deficient mismatch repair system (dMMR) is promising, with several trials ongoing. Major challenges are ahead in order to determine how, when and for which patients we should use these CPIs in CRC.

Areas covered: This review highlights some promises and challenges concerning personalized immunotherapy in CRC. First results and ongoing breakthrough trials are presented. The crucial role of biomarkers in selecting patient is also discussed.

Expert opinion: As of now, dMMR and POLE mutations (DNA polymerase ε) with ultramutator phenotype are the most powerful predictive biomarkers of CPI efficacy. The most challenging issue is pMMR mCRC and determination of how to convert a ‘nonimmunogenic’ neoplasm into an ‘immunogenic’ neoplasm, a combination of CPIs with radiation or MEK inhibitor probably being the most relevant strategy. Next-generation sequencing (NGS) assays to quantify mutational load could be more reliable predictive biomarkers of CPIs efficacy than PD-L1 expression or immune scores.     

层级管理在进修护士培训中的应用与效果

目的探讨层级管理在进修护士培训中的应用效果。方法选取102名进修护士为对照组,采用常规培训方式;选取104名进修护士为实验组,将其分为年轻护士N1级、年轻护理骨干N2级、专业精通型护士N3级、专家型护士N4级4个层级,从组建培训师资、制订培训方案、实施培训方案进行分层级管理培训。培训结束后,比较两组进修护士的考核成绩和对进修培训的满意度。结果实验组进修护士的考核成绩及进修满意度高于对照组(P0.01)。结论对进修护士实施层级管理培训,既丰富了各级进修护士的理论知识和操作技能,又提高了实践综合能力及进修满意度,从而有利于提升护理科学化管理水平。     

胸腺肽α1对晚期非小细胞肺癌免疫功能和骨髓抑制的影响

目的观察胸腺肽α1对晚期非小细胞肺癌(NSCLC)患者细胞免疫功能和骨髓抑制的影响。方法选择90例体力状况评分1～2分晚期NSCLC患者,随机分为对照组(n=45)和实验组(n=45)。对照组进行常规化疗,实验组予常规化疗外加用胸腺肽α1针1.6mg,皮下注射,每周2次,共4周。观察比较两组化疗后免疫功能〔自然杀伤细胞(NK)、CD3+、CD4+及CD4+/CD8+T细胞的变化〕及骨髓抑制的变化。结果实验组与对照组治疗后比较,NK、CD3+、CD4+及CD4+/CD8+T细胞均明显升高,CD8+明显下降,差异均有统计学意义(t分别=2.12、3.24、3.02、2.79、3.76,P均<0.05);实验组化疗前后比较,差异均无统计学意义(t分别=0.86、1.23、1.36、1.33、1.40,P均>0.05);对照组化疗前后比较,差异亦均无统计学意义(t分别=0.89、1.21、1.19、1.13、1.43,P均>0.05)。实验组的骨髓抑制Ⅲ-Ⅳ级发生率明显低于对照组,差异有统计学意义(χ2=5.03,P<0.05)。结论胸腺肽α1能够增强晚期NSCLC化疗期间的细胞免疫功能并减少骨髓抑制风险。     

生殖专科医院进修人员的管理现状分析

目的探讨生殖专科医院进修人员的管理现状,为我院医务人员进修管理及培训工作的加强提供依据。方法选择2014年7月至2019年7月我院的进修管理系统纳入的221位进修人员,统计分析其基本情况。结果近五年进修人员数量有不同程度的波动,且2018年进修人员数量开始呈现明显的增长趋势。山东与河北为进修医师的主要来源地区,进修人员的科室来源主要为女科,职称以初级和中级为主。结论目前生殖专科医院进修人员的管理仍存在部分问题,接下来的进修管理应从进修人员的实际需求出发,加强过程管理,提高进修教育质量。     

晚期肺癌生活质量与治疗方案选择

Inrecentyears，incidenceoflungcancerisincreas－ing．Incidenceaswellasmortalityoflungcancerrankthefirsta－mongcancersinmeninChina．Itisestimatedthat６５％ofpatientswithlungcancerwereinlatestageatdiagnosis．Now，longationofsurvivaltimeandimprovementofqualityoflifereceivemoreatten－tionindesignoftreatmentproject．Managementoflungcancerfallsintosurgery，radiotherapyandchemotherapy．Hottocombineinter－disciplinarilycomprehensivetreatmentsandavoidsimpledisciplinarytreatmentswhichcancauseexcessivein…     

替吉奥治疗老年进展期胃癌临床观察

目的观察替吉奥胶囊单药治疗老年进展期胃癌的临床疗效及不良反应。方法 33例老年进展期胃癌患者,应用替吉奥胶囊口服,至少完成2个周期后评价疗效和不良反应。结果 33例患者中完全缓解(CR)1例(3%)、部分缓解(PR)12例(36.4%)、稳定(SD)6例(18.2%),总有效率RR39.4%,生活质量改善12例(36.4%),主要毒副反应为血液学毒性和消化道反应。结论替吉奥胶囊是治疗进展期胃癌安全、有效的药物,特别适宜于老年体弱的患者。