肛管直肠恶性黑色素瘤免疫检查点抑制剂治疗一例

恶性黑色素瘤(malignant melanoma,MM)是一种常见的恶性肿瘤,死亡率高,预后差.我国恶性黑色素瘤发病率的年增长率约为3％～5％,每年约有2万例新发病例 [1].恶性黑色素瘤根据发病部位和发病原因分为慢性阳光损伤型(chronic sun-damaged,CSD)、非慢性阳光损伤型(non-chroni...     

免疫检查点抑制剂在肝癌中的应用现状及进展

原发性肝癌是我国常见的恶性肿瘤之一,其发病率位居我国癌症发病率的第4位.肝癌进展迅速且隐匿性强,患者确诊时往往已处于中晚期,错过最佳治疗时机.2007年以来,索拉菲尼的问世标志着肝癌靶向治疗时代的来临,但机体的耐药性和药物不良反应限制了其使用.近年来,免疫检查点的发现则为中晚期肝癌患者提供了新的治疗选择,免疫检查点抑制...     

免疫检查点抑制剂治疗黑色素瘤相关不良反应及其管理策略

近年来,免疫检查点抑制剂(ICI)在黑色素瘤治疗中取得了显著的成效,但是T细胞功能的活化也引起了一系列免疫相关不良反应(ir AE)。不同于传统化疗的不良反应,ir AE有着独特的临床表现和处理要求。虽然ir AE的发生和管理逐渐得到临床医生的重视,但一些常见ir AE的发生机制、临床表现、诊断和鉴别及其综合监测管理仍需进一步总结和归纳,以便提高临床医生工作水平和临床试验设计质量。而且不同ir AE的发生机制、糖皮质激素的治疗影响、原有自身免疫疾病患者的治疗风险等问题仍存在争议。本文阐述ICI治疗黑色素瘤引起的ir AE相关临床表现特点和诊疗管理措施,旨在对ir AE管理策略和研究方向提出具有指导意义的意见。     

免疫检查点抑制剂的联合治疗在胰腺癌中的研究进展

胰腺癌的恶性程度极高,发现时通常已至晚期,中位生存时间极短,严重威胁人类生命健康.并且与其他癌种相比,近些年取得的治疗进展也十分有限.免疫检查点抑制剂(Immune checkpoint inhibitors,ICIs)作为近几年的新兴药物已在多个肿瘤中获得了令人振奋的治疗效果,但是在胰腺癌中却遭遇了滑铁卢.胰腺癌对I...     

T-VEC联合依匹木单抗治疗晚期恶性黑色素瘤的多中心随机Ⅱ期临床试验的5年随访结果解读

摘 要：溶瘤病毒联合免疫检查点抑制剂方案一直是恶性黑色素瘤治疗的研究热点。一项多中心、开放标签的随机Ⅰb/Ⅱ期临床试验（NCT01740297）对比了溶瘤病毒talimogene laherparepvec（T-VEC）联合依匹木单抗对比依匹木单抗单药在不可切除的ⅢB~ⅣM1c期恶性黑色素瘤患者中的疗效和安全性。该研究的Ⅱ期于2013年8月至2021年3月在美国、法国和德国的33个中心进行，筛选入组198例患者，以1∶1的比例随机接受T-VEC联合依匹木单抗或依匹木单抗单药治疗。主要研究终点是根据免疫相关应答标准评估的客观缓解率(objective response rate，ORR)，关键次要终点包括持久反应率(durable response rate，DRR)、反应持续时间(duration of response，DOR)、无进展生存期(progression-free survival，PFS)、总生存期(overall survival，OS)和安全性。与依匹木单抗单药相比，联合用药组显著性改善了患者的ORR（35.7% vs 16.0%；OR=2.9，95%CI：1.5~5.7，P=0.003）。两组的DRR分别为33.7%和13.0%（P=0.001）。在达到客观缓解的患者中，联合用药组的中位DOR为69.2个月（95%CI：38.5~NA)，单药组尚未达到。联合用药组的中位PFS为13.5个月，单药组为6.4个月（HR=0.78，95%CI：0.55~1.09，P=0.14）。联合用药组的5年OS率为54.7%，单药组为48.4%。5年随访中未发现新的安全性事件。这是首个达到主要研究终点的溶瘤病毒联合免疫检查点抑制剂的随机对照研究。5年随访数据提示T-VEC联合依匹木单抗能安全有效地改善晚期恶性黑色素瘤患者的治疗有效率，但从长期生存角度，联合用药并未给患者带来具有统计学差异的生存获益。     

免疫检查点抑制剂联合治疗实体瘤的疗效和安全性的Meta分析

目的:旨在评价免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合治疗在实体瘤患者中的安全性和有效性,为临床实践提供参考依据。方法:计算机检索 PubMed,EMBASE,Cochrane Library数据库和ClinicalTrials.gov网站符合条件的随机对照试验（randomized controlled trials,RCTs）。根据PICOS（患者类型,干预,对照,结果和研究设计）原则确定纳入标准。结果:包含6 616名患者的17项随机对照试验纳入此项Meta分析。结果显示,ICI联合治疗可显著改善实体瘤患者的总体反应率（overall response rate,ORR）［RR=1.56（95％CI 1.24,1.96）,P=0.000 1］,延长无进展生存期（progression free survival,PFS）［HR=0.69（95％CI 0.59,0.81）,P<0.000 01］和总生存期（overall survival,OS）［HR=0.76（95％CI 0.67,0.87）,P<0.000 1］。亚组分析结果表明,接受ICI联合治疗的黑色素瘤患者的OS［HR=0.64（95％CI 0.58,0.72）,P<0.000 01］显著延长,但小细胞肺癌（small cell lung cancer,SCLC）［HR=0.94（95％CI 0.82,1.08）,P=0.40］和非小细胞肺癌（non-small cell lung cancer,NSCLC）［HR=0.92（95％CI 0.79,1.07）,P=0.26］患者OS无显著改善。此外,ICI联合治疗可增加疲劳、皮疹、腹泻和转氨酶升高等不良反应发生风险。结论:本研究结果表明,ICI联合治疗在未来的临床实践和研究设计中极具前景。ICI联合治疗在恶性黑色素瘤患者中有临床应用价值。然而,目前的研究结果暂不支持ICI联合治疗在NSCLC和SCLC患者中大规模临床应用。     

光疗联合免疫检查点抑制剂治疗肿瘤的研究进展

基于纳米粒子的光疗主要包括光动力疗法（PDT）和光热疗法（PTT）。近年来,光疗联合免疫检查点抑制剂（ICI）的疗 法显示出治疗恶性肿瘤的巨大潜力。这种联合疗法结合了抗体介导的靶向给药和激光激活的一系列生物/物理机制,能准确诱导 癌细胞快速死亡,同时避免损伤周围正常组织,ICI与光疗联合应用能产生协同效应,从而提高治疗效果,减少肿瘤复发和转移。 目前,这种联合疗法已在临床前研究中显示出潜力,可用于大部分常见的恶性肿瘤,如肺癌、乳腺癌、食管癌等的治疗,但面临着 激光穿透不足、不良反应等问题。未来研究需要优化治疗方案,提高其安全性和有效性。     

放疗联合免疫检查点抑制剂在食管癌中的应用

摘 要：近年来以免疫检查点抑制剂为代表的免疫治疗作为一种新兴的治疗方法，使食管癌的治疗步入了新的阶段。既往研究表明免疫治疗可以提高晚期转移性食管癌患者的生存率，且免疫检查点抑制剂与放射治疗相结合可更好地发挥局部治疗作用，放疗联合免疫检查点抑制剂应用于围手术期、局部晚期和晚期食管癌的各项临床研究取得了可观的成效。全文对近年来放疗联合免疫检查点抑制剂在食管癌中的应用进行综述。     

免疫检查点抑制剂联合治疗在小细胞肺癌中的研究进展

小细胞肺癌(small cell lung cancer，SCLC)以其恶性程度高、易转移、易复发、易耐药等特点成为预后差的难治性癌症，故极大地限制了新型治疗方法和药物的出现。免疫检查点抑制剂（immune checkpoint inhibitor, ICI)的问世打破了SCLC几十年来所依赖的依托泊苷联合铂类的传统治疗模式，具有显著的治疗效果和广阔的应用前景。同时，ICI单药治疗效果不佳的问题也浮出水面。因此，ICI与不同机制的ICI、传统化疗药物、放射治疗、靶向药物、以及多种治疗方案联合应用方案应运而出，以达到发挥协同作用、优势互补、降低不良反应等目的。本文对ICI单药或联合治疗SCLC的现有进展、不足以及未来的发展方向进行了阐述，以期对临床工作和研究有所启示。     

A phase I study of the safety and efficacy of talimogene laherparepvec in Japanese patients with advanced melanoma

Talimogene laherparepvec (T‐VEC) is approved for the treatment of unresectable melanoma in the USA, Europe, and Australia. This phase I, multicenter, open‐label, dose de‐escalation study evaluated the safety and efficacy of T‐VEC in Japanese patients with unresectable stage IIIB–IV melanoma. Eligible adult patients had histologically confirmed stage IIIB–IVM1c cutaneous melanoma, may have received prior systemic anticancer therapy, must have had ≥1 injectable lesion, serum lactate dehydrogenase ≤1.5x upper limit of normal, ECOG performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. T‐VEC was injected intralesionally (first dose, ≤4.0 ml of 10⁶ PFU/ml; after 3 weeks and then every 2 weeks thereafter, ≤4.0 ml of 10⁸ PFU/ml). Primary endpoints were dose‐limiting toxicities (DLTs) and durable response rate (DRR). Of 18 enrolled patients (72.2% female), 16 had received ≥1 prior line of therapy. Ten patients discontinued T‐VEC due to disease progression. Median (range) follow‐up was 20.0 (4–37) months. No DLTs were observed; 17 (94.4%) patients had treatment‐emergent adverse events (AEs). Fourteen (77.8%) patients had treatment‐related AEs; the most frequent were pyrexia (44.4%), malaise (16.7%), chills, decreased appetite, pruritus, and skin ulcer (11.1% each). The primary efficacy endpoint was met: 2 (11.1%) patients had a durable partial response ≥6 months. The DRR was consistent with that observed in a phase III trial of T‐VEC in non‐Asian patients. The safety profile was consistent with the patients'' underlying disease and the known safety profile of T‐VEC.     

真实世界中免疫检查点抑制剂导致免疫相关不良反应病例分析

目的:探讨免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）导致的免疫相关不良反应（immune-related adverse events,irAEs）的发生情况。方法:收集并分析2018年1月至2021年3月我院irAEs的具体情况,包括基本资料、用药情况、不良反应具体情况、治疗情况等。结果:63例irAEs,包括肺毒性3例、肝脏毒性9例、皮肤毒性23例、内分泌毒性15例、神经毒性4例、肾毒性3例、胃肠毒性1例、心脏毒性2例、血液毒性1例、眼毒性2例。男性47例,女性16例,中位发病年龄61岁,不良反应中位发生时间6.6周,17例需要大剂量糖皮质激素治疗。毒性级别1-2级49例,3-4级13例,5级1例。少见irAEs 14例,1例死于心肌炎。结论:irAEs涉及的器官或系统较多,多数在3级以下。常见不良反应预后较好。少见irAEs中,心肌炎可能导致患者死亡,需要临床予以重视。     

Talimogene laherparepvec (T-Vec) for the treatment of melanoma and other cancers

Talimogene laherparepvec (T-Vec) is the first live virus to be approved by the US Food and Drug Administration for the treatment of cancer. This engineered version of herpes simplex virus type 1 (HSV-1) is the product of decades of preclinical work aimed at identifying and modifying aspects of the viral genome involved in virulence and immunogenicity. T-Vec preferentially infects and lyses tumor cells and, in some cases, induces a systemic immune response against the tumor. These properties have translated into significant and durable clinical responses, particularly in advanced melanoma. Many unanswered questions remain, including how to augment these clinical responses and which other tumor types may respond to oncolytic therapy. Here, we review the development of T-Vec, our current understanding of its impact on the tumor immune micro-environment, and its safety and efficacy in clinical trials for melanoma and other cancers.     

Phase II study of tauromustine in disseminated malignant melanoma

Forty-seven patients with metastatic malignant melanoma took part in a phase II trial of tauromustine (TCNU), a new chlorethylnitrosourea based on the endogenous amino acid taurine. TCNU was given orally at a dosage of 130 mg/m² every fifth week. No patient had previously received cytotoxic therapy. Among 37 evaluable patients, 26 patients experienced progressive disease including seven patients with early death, five showed no change, and six partial responses, yielding an objective response rate of 16%. Responses were limited to subcutaneous, lymph node, bone and lung metastases. Median time to progression was 26 weeks for responders. The treatment schedule was well tolerated with a median dose of 88% of the predicted dose given during all cycles. Dose-limiting toxicity was thrombocytopenia. It appears that TCNU is active in disseminated malignant melanoma with a response rate similar to other nitrosoureas.     

Phase II study of recombinant alpha-interferon in malignant melanoma

Ninety-seven evaluable patients with measurable, advanced, malignant melanoma were treated with recombinant alpha interferon in a cooperative phase II efficacy trial, whose primary objective was to estimate the response rate. Interferon (rIFN alpha-2a, Roferon-A) was injected subcutaneously daily for 70 days. Dose was escalated in four steps from three million units to 36 million units over ten days. Eight patients responded objectively and six patients (6%) had a complete response. The median duration of complete response was 11 months. Patients achieving complete response had only cutaneous, nodal, or pulmonary disease; some had extensive prior therapy; some could tolerate no more than three million units per day. Few patients could tolerate the target dose of 36 million units daily for 70 days. Limiting toxicity was primarily fatigue. Interferon in tolerable doses is effective in a small subset of patients with melanoma. Comparison of published trials of dacarbazine and recombinant alpha interferon indicates the two drugs have similar activity.     

Value of sentinel lymph node study in malignant melanoma

The sentinel lymph node (SLN) is the first station of the lymph drainage of a primitive lesion and is therefore the most likely to harbor metastasis. Isotopic tracers or dyes can be used to detect the SLN. SLN biopsy reduces morbidity and the cost of unnecessary lymphadenectomies in patients with clinically non-metastasized melanoma and improves staging of SLN located outside the usual drainage area. We studied 115 patients with the diagnoses of cutaneous malignant melanoma with a Breslow of 0.75 mm. To map the lymphatic drainage areas, all patients underwent lymphoscintigraphy prior to surgery with intradermal injection of Technetium 99m sulfur colloid around the biopsy scar. Twenty minutes before surgery, 1 cc of isosulfan blue (1% lymphazurin) was also injected. Dye was used in the intraoperative search for SLN in nine patients and both dye and a gamma probe (Navigator; USSC, Norwalk, CT) were used in 106. The SLN was identified in 113 patients (98%). The SLN was infiltrated in 14 patients (12.4%) and the SLN was the only node involved in 14 of them (78.6%). Selective lymphadenectomy in melanoma is associated with a low rate of morbidity and reduces the rate of unnecessary complete lymphadenectomies in patients with intermediate-risk cutaneous melanoma while allowing for appropriate staging according to current recommendations.     

Phase II study of m-AMSA in advances malignant melanoma

A phase II study of methanesulfonamide, N-(4-(9 acridinylamino)-3-methoxyphenyl)-(m-AMSA) was undertaken by the Eastern Cooperative Oncology Group. Thirty-five evaluable patients were studied, 18 of whom had had no prior therapy and eight of whom had been treated only one cytotoxic drug. Thirty-one of these patients were ECOG performance status 2 or better. The dose of m-AMSA employed in this study was 40 mg/M2 as an I.V. infusion over 20 minutes daily for 3 days, repeated every 3 weeks. Leukopenia was found to be dose-limiting; thrombocytopenia and anemia were also observed. Other prominent toxicities included anorexia, nausea, and vomiting. No cardiovascular toxicity was observed in this study, but none of the patients had received prior anthracycline therapy. Only one partial response of measurable disease was observed, all other patients had progressive disease on m-AMSA therapy. No significant clinical activity of m-AMSA against malignant melanoma was demonstrated in this very favorable group of patients.     

黑素瘤免疫治疗的研究进展

黑素瘤是起源于黑素细胞或其母细胞的恶性肿瘤,对放化疗不敏感,一旦远处转移,难以控制,预后极差。黑素瘤因存在很强的免疫源性,一直是生物治疗的研究热点。以往研究发现,LAK、TIL等过继性细胞以及黑素瘤抗原相关免疫瘤苗等都有一定的治疗效果。近年来随着免疫编辑学说的提出,新一代肿瘤免疫治疗方案,如抗CTLA4抗体、针对肿瘤抗原的IgG抗体、Toll样受体9激动剂、白喉毒素/IL2融合蛋白等开展了一系列临床试验,并取得了可喜的进步。