免疫检查点抑制剂在消化系统恶性肿瘤治疗中的应用

[摘要] 消化系统肿瘤是人类常见的恶性肿瘤,其中胃癌、结直肠癌、胰腺癌的发病率和病死率均较高。免疫治疗作为一种新的治疗方法,正逐步成为多种肿瘤的有效治疗策略之一。CTLA-4 和PD-1 是通过不同机制负调控T细胞活化的关键免疫检查点分子。针对这些免疫检查点抑制剂,已经显示出临床疗效,并已获美国FDA批准用于多种实体瘤的治疗。其中,纳武单抗在延长晚期肝癌患者生存期方面超过了索拉非尼,派姆单抗在PD-L1 阳性晚期食管癌有效率可达30%,纳武单抗与伊匹单抗联合治疗dMMR/MSI-H晚期结直肠癌的客观缓解率达到55%。本文就近年来免疫检查点抑制剂在消化系统肿瘤治疗中的研究进展进行综述。     

免疫检测点抑制剂特殊安全性问题的认识及处理

近几年,美国食品药品管理局（FDA）相继批准了抗细胞毒T淋巴细胞相关抗原4（CTLA-4）和抗程序性死亡受体1（PD-1）两种免疫检测点抑制剂（ICBs）用于黑色素瘤和非小细胞肺癌的治疗。研究发现,ICBs在多种肿瘤亚型的治疗中均有效,包括小细胞肺癌、肾细胞癌、尿道上皮癌、头颈鳞状细胞癌、胃癌、肝细胞癌、卵巢癌、三阴性乳腺癌以及错配修复缺陷型直肠癌等。这些以免疫系统为靶点的药物疗效显著,但同时伴随一定的免疫相关不良事件（irAEs）或者免疫异常毒性的发生,如何管理这些毒副作用尚没有成熟的方法。本综述将对目前国内外关于ICBs免疫异常毒性的管理相关经验进行总结,以期能够给临床医师在肿瘤患者的免疫异常毒性管理工作中提供一些参考。     

PD-1/PD-L1和CTLA-4免疫检查点抑制剂在小细胞肺癌中的临床研究进展

小细胞肺癌(SCLC)属于高度恶性神经内分泌癌,早期即易发生转移,确诊时60％～70％已处于广泛期,手术治疗机会小.虽然SCLC起始对含铂方案系统化疗±放疗的一线治疗高度敏感,但多数在一线治疗后短期内即出现复发与转移.尽管近30年来对SCLC治疗不断探索与研究,仍缺乏有效治疗手段,患者长期生存率极低.近年来以免疫检查点...     

免疫检查点抑制剂治疗结直肠癌的研究进展

结直肠癌是常见的消化道恶性肿瘤.免疫检查点抑制剂在肿瘤免疫逃逸中发挥着至关重要的作用,成为抗肿瘤免疫治疗的热点.免疫检查点抑制剂在多种实体瘤的治疗中取得了令人瞩目的效果.在结直肠癌的治疗领域,尤其是针对微卫星不稳定(MSI)和(或)错配修复缺陷(dMMR)的结直肠癌患者,检查点抑制剂亦显示出了良好的疗效及安全性.本文概...     

免疫检查点抑制剂在恶性淋巴瘤中的应用研究进展*

免疫检查点是一类免疫抑制性分子,通过调节免疫反应的强度和广度,从而避免正常组织的损伤和破坏。近年来研究发现肿瘤细胞可通过激活免疫检查点活性,从而逃避免疫系统的监视。免疫检查点抑制剂则通过拮抗免疫检查点蛋白,促进T 细胞活化,进而产生抗肿瘤免疫效应。免疫检查点抑制剂在多种实体瘤的治疗方面已显示出良好的疗效。在淋巴瘤的治疗领域,虽然尚处于起步阶段,检查点抑制剂亦显示出良好的疗效及安全性。本文主要总结免疫检查点蛋白细胞毒性T 淋巴细胞相关抗原- 4（cytotoxic T lymphocyte associated antigen-4,CTLA- 4）、程序性死亡受体- 1（programmed death- 1,PD- 1）及其程序性死亡受体配体- 1（programmed death ligand 1,PD-L1）的生物学活性,并介绍相应抗体药物在淋巴瘤研究中的进展。      

PD-1/PD-L1抑制剂联合治疗在癌症免疫治疗中的研究进展

程序性死亡蛋白-1(programmed cell death-1,PD-1)是一种免疫检查点的负性调控因子,通过与其配体PD-L1/PD-L2结合,抑制T细胞的免疫功能,而PD-1抑制剂则可恢复免疫系统的抗肿瘤作用。较其他治疗手段而言,PD-1抑制剂有显著的临床疗效,然而其仍然存在不足,即目前仍有很大一部分癌症患者对PD-1抑制剂治疗是无效的。研究表明联合治疗可改善PD-1抑制剂单药治疗的有效率。联合治疗包括联合免疫检查点抑制剂、放疗、化疗、癌症疫苗和其他癌症治疗方法。FDA已批准了PD-1抑制剂联合CTLA-4阻断剂治疗,其抗肿瘤效率与肿瘤微环境以及免疫相关因子有关,但关于免疫系统,特别是T细胞对肿瘤阳性响应率的潜在作用机制研究甚少。本文将综述免疫检查点PD-1抑制剂的临床疗效以及其影响因素、作用机制以及PD-1抑制剂联合其他治疗的研究现状。     

免疫检查点抑制剂抗肿瘤治疗中相关性心脏毒性的研究进展

程序性死亡因子-1(PD-1)及程序性死亡受体配体1(PD-L1)抑制剂通过阻断PD-1与PD-L1的相互作用,使负向调控信号受阻,刺激免疫系统,使T淋巴细胞继续杀死肿瘤细胞,从而增强机体的免疫反应,但这也破坏了正常免疫系统的平衡,造成免疫耐受紊乱,发生免疫相关不良反应.本文结合目前最新的研究进展,主要介绍免疫抑制剂—...     

肿瘤免疫检查点抑制剂相关的心脏毒性

随着恶性肿瘤治疗的不断发展, 免疫检查点抑制剂已应用于多种恶性肿瘤的治疗, 使患者的生存时间和生活质量有所改善, 但在应用的过程中不可避免地发生免疫相关不良反应。与化疗药物和靶向药物相同, 免疫抑制剂也会引起心血管事件, 从而影响肿瘤患者的死亡率。随着肿瘤患者生存时间的延长, 会日益成为影响这类疾病预后的关键因素。文章重点论述免疫检查点抑制剂在肿瘤治疗过程中引起的心脏毒性机制、临床表现以及未来发展方向。     

免疫检查点抑制剂的风湿性免疫相关不良反应与治疗

免疫检查点抑制剂(ICIs)在癌症治疗中显示出较好的疗效,但随着ICIs的快速应用,免疫相关不良事件(irAE)也越来越引起人们的关注。几乎全身器官皆可发生irAE,但风湿性irAE似乎具有不同的临床特征。本文就ICIs治疗引起的风湿性irAE的流行病学、临床特征及管理原则进行综述,并探讨其可能的潜在致病机制。     

免疫检查点抑制剂的免疫相关不良事件预测生物标志物研究进展

近年来,以免疫检查点为靶点的肿瘤免疫疗法因疗效显著而备受关注.然而随着免疫检查点抑制剂(ICIs)的推广应用,其相关不良事件(irAEs)的报道也越来越多.irAEs使接受ICIs治疗的肿瘤患者承担着额外的致命风险,限制着ICIs的使用.为帮助患者主动预防irAEs,研究具有irAEs预测价值的生物标志物意义重大.本文...     

Myalgia and Arthralgia Immune-related Adverse Events (irAEs) in Patients With Genitourinary Malignancies Treated With Immune Checkpoint Inhibitors

BackgroundMyalgia and arthralgia immune-related adverse events (irAEs) in patients treated with checkpoint inhibitors (CPIs) present a clinical challenge. We describe the clinical characteristics and treatment of myalgia and arthralgia irAEs in CPI-treated patients with genitourinary (GU) malignancies.Patients and MethodsPatients with GU malignancies who were treated with CPIs and developed myalgia and arthralgia irAEs that resulted in interruption or discontinuation of CPI therapy were reviewed. Patient-, disease-, and irAE-related data were collected and analyzed.ResultsTwenty-one patients were identified. Eighteen (86%) had renal cell carcinoma; 3 (14%) had urothelial carcinoma. The majority (71%) were male; the median age at diagnosis was 56 years (range, 36-78 years). CPI therapy included anti-programmed death-ligand 1 (29%), anti-programmed cell death protein 1 (48%), and combined programmed cell death protein 1/cytotoxic T-lymphocyte-associated protein 4 antibodies (24%). The median time from CPI initiation to myalgia and arthralgia irAE was 5.1 months (range, 0.23-50.5 months). All patients were treated with prednisone with a median initial dose of 40 mg/d (range, 10-90 mg/d) for a median duration of 64 weeks (range, 3-242 weeks). Treatment with methotrexate (14%), infliximab (14%), tocilizumab (10%), gabapentin (10%), and etanercept (5%) was also required in some patients. Six (29%) patients restarted CPI therapy following symptom improvement, 3 (15%) switched to a subsequent therapy, and 12 (55%) patients had an ongoing sustained response to therapy (median, 14.5 months; range, 3-55 months) despite no subsequent anti-cancer therapy.ConclusionMyalgia and arthralgia irAEs in CPI-treated patients with GU malignancies vary in timing of presentation, severity, and treatment. Multidisciplinary teams that include a rheumatologist are critical for optimal management. Durable response to CPIs can be maintained even after therapy discontinuation.     

Cutaneous Adverse Events Associated with Immune Checkpoint Inhibitors: A Review Article

Immune checkpoint inhibitors (ICIs) have emerged as novel options that are effective in treating various cancers. They are monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). However, activation of the immune systems through ICIs may concomitantly trigger a constellation of immunologic symptoms and signs, termed immune-related adverse events (irAEs), with the skin being the most commonly involved organ. The dermatologic toxicities are observed in nearly half of the patients treated with ICIs, mainly in the form of maculopapular rash and pruritus. In the majority of cases, these cutaneous irAEs are self-limiting and manageable, and continuation of the ICIs is possible. This review provides an overview of variable ICI-mediated dermatologic reactions and describes the clinical and histopathologic presentation. Early and accurate diagnosis, recognition of severe toxicities, and appropriate management are key goals to achieve the most favorable outcomes and quality of life in cancer patients.     

Incidence,Clinical Characteristics,and Predictors of Cardiovascular Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors

BackgroundCardiovascular immune-related adverse events (CV–irAEs) associated with immune checkpoint inhibitors (ICIs) may have been underreported given that most previous reports were retrospective. We aimed to evaluate the incidence, clinical characteristics, and predictors of CV–irAEs and determine the feasibility of serial cardiac monitoring using a combination of B-type natriuretic peptide, cardiac troponin T, and electrocardiogram for the prediction of future symptomatic (grade ≥2) CV–irAEs.Materials and MethodsThis was a prospective observational study that included 129 consecutive patients with non–small-cell lung cancer who received ICI monotherapy at a single center. Serial cardiac monitoring was performed during ICI monotherapy.ResultsA total of 35 (27%) patients developed any grade ≥1 CV–irAEs with a median time of onset of 72 (interquartile range 44-216) days after ICI treatment initiation. Multivariate Fine–Gray regression analysis showed that prior acute coronary syndrome (adjusted hazard ratio [HR] 3.15 (95% [CI], 2.03-4.91), prior heart failure hospitalization (adjusted HR 1.65 [95% CI, 1.17-2.33]), and achievement of disease control (adjusted HR 1.91, [95% CI, 1.16-3.14]) were significantly associated with grade ≥1 CV–irAEs. Serial cardiac monitoring revealed that patients with preceding grade 1 CV–irAEs were associated with a significantly higher risk of onset of grade ≥2 CV–irAEs compared with those without preceding grade 1 CV–irAEs (HR: 6.17 [95% CI, 2.97-12.83]).ConclusionCV–irAEs were more common than previously recognized and have several predictors. Moreover, serial cardiac monitoring may be feasible for the prediction of future grade ≥2 CV–irAEs.     

Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Background

Immune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs.

Methods

We performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate.

Results

Most patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not.

Conclusion

We found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings.

Implications for Practice

This study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.