Real Impact of Novel Immunotherapy Drugs in Cancer. The Experience of 10 Last Years

Intense research on immunotherapy has been conducted during recent years. As advances in the field have started changing the landscape of cancer therapy, it is necessary to assess the impact of immunotherapeutic modalities in the treatment of various cancers. Ten years ago, in 2011, ipilimumab was the first of the newest immunotherapeutic drugs against cancer to be approved by the FDA. Then several drugs followed and formed a therapeutic arsenal to fight cancer. Initial studies were performed on metastatic patients, but there are currently several studies in patients with potentially curable cancers. All these developments have created a new environment for oncology which we will present in this article. This review examines the current evidence related to the impact of immunotherapy on various cancers and discusses its potential clinical and research implications, including its effectiveness in comparison to other treatment modalities (chemotherapy, radiotherapy), its toxicity and prospective research opportunities. While constant updates and further research is critical to understand the impact of immunotherapy in cancer therapy, not only does it seem to be important to assess the current state of knowledge highlighting the success but also to determine the challenging aspects of cancer immunotherapy.     

激素预处理对非小细胞肺癌患者免疫检查点抑制剂疗效和安全性影响的网状Meta分析

目的：采用网状Meta分析的方法对非小细胞肺癌患者激素预处理下免疫检查点抑制剂疗效和安全性进行评价。方法：检索PubMed、EMbase、Cocharane、万方、维普、中国知网、中国生物医学文献数据库关于免疫检查点抑制剂联合紫杉醇对比联合白蛋白结合型紫杉醇治疗非小细胞肺癌的大型多中心随机对照试验（RCT）,检索时间为建库至2019年6月。以Stata13.0软件、R-3.6.1软件、WinBUGS软件进行网状Meta分析。结果：最终纳入8项RCT,4项干预措施（免疫检查点抑制剂+铂类+白蛋白结合型紫杉醇,免疫检查点抑制剂+铂类+普通紫杉醇,铂类+白蛋白结合型紫杉醇,铂类+普通紫杉醇）,包含4 005例患者。分析结果显示,在总生存期[HR=0.88,95%CI（0.67,1.17）]及无进展生存期[HR=0.87,95%CI（0.57,1.32）]方面,免疫检查点抑制剂联合铂类+白蛋白结合型紫杉醇与免疫检查点抑制剂联合铂类+紫杉醇相比,差异无统计学意义;在安全性方面,3级及以上不良反应率激素预处理组与未处理组差异无统计学意义。结论：激素预处理对免疫检查点抑制剂的疗效以及安全性无影响,需纳入直接比较研究进一步验证。     

灵芝多糖微乳诱导结直肠癌肿瘤相关巨噬细胞M1极化及其联合PD-1抑制剂协同抗肿瘤研究

目的:验证灵芝多糖微乳诱导结直肠癌肿瘤相关巨噬细胞(TAMs) M1极化能力,以及联合PD-1抑制剂协同抗肿瘤的可行性。方法:采用"一步成乳法"制备灵芝多糖微乳(GLP-M),并对其进行理化性质表征。借助RAW264.7细胞考察GLP-M诱导巨噬细胞极化的能力;通过Transwell小室法考察GLP-M处理巨噬细胞后对肿瘤细胞增殖、凋亡的影响,以及GLP-M处理肿瘤细胞后对巨噬细胞极化的影响;考察GLP-M诱导巨噬细胞产生活性氧(ROS)行为。建立荷MC38鼠源肠癌细胞的皮下移植瘤模型,以生理盐水和灵芝多糖为阴性对照和剂型对照组,设置GLP-M、PD-1抑制剂以及GLP-M+PD-1联合给药组;PD-1抑制剂每3天尾静脉注射1次,给药2次,其余制剂每天灌胃1次,给药6次。考察治疗期间肿瘤生长曲线、体质量变化、生存时间、病理切片等。结果:GLP-M粒径为(58.3±2.1) nm,Zeta电位为(-23.5±1.8) mV,多分散系数(PDI)为0.221±0.003,包封率为(82.5±3.2)%,TEM图显示GLP-M形态圆整、分散均匀。GLP-M干预IL-4诱导的RAW264.7细胞后CD86的表达量升高(33.2±1.9)%,ROS水平升高(39.4±2.5)%,差异均具有统计学意义。在RAW264.7与MC38细胞共培养模型中,GLP-M可以显著提高肿瘤细胞的增殖抑制率和凋亡率,促进巨噬细胞的CD86表达。体内抗肿瘤实验显示:GLP-M、PD-1以及GLP-M+PD-1的肿瘤抑制率分别为(44.3±4.2)%、(51.3±2.7)%和(63.7±4.3)%。GLP-M+PD-1组45 d生存率最高(25%),且该组肿瘤切片结果显示坏死明显,细胞增殖被显著抑制。结论:GLP-M可能通过干预TAMs M1极化的机制提高与PD-1抑制剂等免疫治疗协同抗结直肠癌治疗效能。     

CTLA4 antagonists in phase I and phase II clinical trials,current status and future perspectives for cancer therapy

Introduction: In cancer, the immune response to tumor antigens is often suppressed by inhibitors and ligands. Checkpoint blockade, considered one of the most promising frontiers for anti-cancer therapy, aims to stimulate the immune anti-cancer response. Agents such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) inhibitors offer prolonged survival with manageable side effects.

Areas covered: We summarize the recent clinical successes of CTLA-4 inhibitors and place a strong emphasis on those in early phase clinical trials, often in combination with other immune check-point inhibitors, i.e., programmed cell death protein 1 (PD-1) and BRAF/mitogen-activated protein kinase inhibitors.

Expert opinion: Recent phase I and phase II clinical trials confirm the efficacy of anti-CTLA-4 therapy for treatment of cancers such as renal cell carcinoma. These studies also indicated increased efficacy with combined immune checkpoint blockade with PD-1 or Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) inhibitors. Researchers must search for new immune targets that may enable more effective and safe immune checkpoint blockade and cancer therapy. This goal may be achieved by next-generation combination therapies to overcome immune checkpoint therapy resistance.     

Regorafenib in the treatment of colorectal cancer

Introduction: Colorectal cancer (CRC) is among the most frequently diagnosed malignancies, and is commonly associated with metastatic disease at presentation. While chemotherapy represents a mainstay of management, options at the time of disease progression are limited. Regorafenib is a novel multikinase inhibitor which has been evaluated for patients with chemo-refractory metastatic CRC (mCRC) and is currently approved for use in a last-line-of-treatment setting.

Areas covered: Articles searchable on MEDLINE/PubMed were reviewed to provide context for use of regorafenib in the management of mCRC. Specific drug properties are discussed, including chemistry, pharmacodynamics, pharmacokinetics, and metabolism. Additionally, clinical efficacy is reported with consideration of Phases I–III data.

Expert opinion: Phase III evaluation has confirmed the efficacy of regorafenib for patients with chemo-refractory mCRC. Importantly, the rapid accrual of the CORRECT trial revealed the degree of unmet need for this patient population, and proved that it was feasible to compare novel agents to placebo when multiple lines of standard therapy have failed. In the coming years, the role of regorafenib in the management of mCRC should be further clarified, especially through identification of the patient population with greatest anticipated benefit and exploration of its use as an adjuvant or maintenance agent.     

免疫检查点抑制剂与抗血管生成药物合用治疗肿瘤的研究进展

免疫检查点抑制剂(immune checkpoint inhibitor,ICI)通过阻断免疫负调节信号激活机体的抗肿瘤免疫应答,临床试验表明,ICI仅对部分晚期癌症患者有效。而通过阻断肿瘤血管生成常用的抗血管生成药物尽管可以抑制肿瘤的生长,对患者的生存期却未体现出改善,且存在耐药等应用局限。肿瘤免疫反应与血管生成密切相关,同时,肿瘤血管生成高度依赖于免疫抑制微环境。近来一些研究表明,ICI联合血管生成抑制剂不但可以减轻其治疗耐药性,且疗效优于任何单一疗法。联合疗法加强血管正常化和免疫重编程之间的正反馈循环,调节肿瘤免疫微环境以诱导机体持久的抗肿瘤免疫反应。该文对ICI联合抗血管生成疗法的最新进展展开论述,以期为后续研究提供新的思路与借鉴。     

PD-1/PD-L1抑制剂联合其他免疫检查点抑制剂治疗三阴性乳腺癌的研究进展#br#

三阴性乳腺癌（TNBC）具有全身转移率高、对常规治疗不敏感以及容易产生耐药性等特点,导致患者的预后较差。随着对机体免疫系统抗肿瘤机制及TNBC免疫特点的不断探究,以程序性细胞死亡蛋白1（PD-1）和程序性死亡蛋白配体1（PD-L1）为代表的免疫检查点抑制剂为TNBC提供了新的治疗方案,但PD-1/PD-L1抑制剂单药治疗的效果不甚理想。本文就PD-1/PD-L1抑制剂联合其他具有不同机制的免疫检查点抑制剂在TNBC患者中的应用进行综述。     

免疫检查点抑制剂对耐药结直肠癌的研究现状

错配修复缺陷(dMMR)/微卫星高频不稳定(MSI-H)结直肠癌因其致癌机制引起程序性细胞死亡蛋白1(PD-1)/程序性细胞死亡配体1(PD-L1)上调,对5-氟尿嘧啶(5-FU)等为基础的化疗方案产生肿瘤免疫性抵抗,出现耐药性.本文从以下几方面进行综述:dMMR/MSI-H结直肠癌耐药的特点和PD-1/PD-L1抑制...     

Safety evaluation of pembrolizumab for treating recurrent head and neck squamous cell carcinoma

ABSTRACT

Introduction

Programmed death 1 (PD-1) blockade has changed the therapeutic landscape of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) with convincing overall response rates and overall survival benefits when compared to chemotherapy alone. The toxicity profile of pembrolizumab appears to be similar to that of other PD-1 or PD-L1 inhibitors, with frequent diarrhea, hypothyroidism or cutaneous rash cases, and rare cases of grade 3 to 5 pneumonitis.     

非小细胞肺癌免疫治疗之假性进展和超进展

随着医疗技术日益发展,肿瘤治疗取得了显著的进步。其中,免疫治疗为肺癌患者开辟了一条全新的道路,其代表药物——PD-1/PD-L1抑制剂的应用显著延长了部分非小细胞肺癌(NSCLC)患者的整体生存率,但在使用过程中也可能出现假性进展或超进展(HPD)现象,其发生机制尚未明确。本文将对假性进展和HPD的定义、发生机制以及可供参考的生物标志物及鉴别方法进行系统地综述。     

Emerging first line treatment options for bladder cancer: a review of phase II and III therapies in the pipeline

Introduction: The treatment of urothelial carcinoma (UC) had remained unchanged for several years until the recent FDA approval of immune checkpoint inhibitors (CPIs) in the salvage setting. Novel dual CPI-CPI and CPI-chemotherapy combinations are now being investigated aggressively as first line therapy for metastatic disease.

Areas covered: We discuss the recent insights into the tumor biology of UC, which may impact the prognosis as well as assist in developing precision medicine. This is followed by an overview of existing treatment including conventional chemotherapy as well as the trials that led to the recent approval of PD-1 and PD-L1 inhibitors. Ongoing phase II and phase III trials developing PD-1/PD-L1 inhibitors, CTLA-4 inhibitors and VEGF inhibitors as first-line therapy are discussed.

Expert opinion: The treatment paradigm for the first-line therapy of UC is expected to shift from conventional platinum-based combination chemotherapy towards novel therapy incorporating CPI immunotherapy. Finding the right combination of drugs in the appropriate disease setting and identifying the right patient population based on biomarkers are important questions to be answered. Another major challenge will be the financial burden associated with these new drugs.     

Phase II evaluation of topotecan in patients with advanced colorectal cancer. A Southwest Oncology Group trial (SWOG 9241)

The topoisomerase-1 inhibitor, topotecan, was tested in 48 eligible patients with advanced colorectal cancer. The patients had no prior chemotherapy and a Southwest Oncology Group performance status of 0–2. Topotecan was administered intravenously at 1.5 mg/m²/day for five days and repeated every 21 days. The major toxicity was hematologic with 19 out of 48 (40%) patients having grade IV granulocytopenia and 4 out of 48 (8%) patients demonstrating grade IV thrombocytopenia. Two patients (4%) demonstrated partial response. Thirty patients have died and the Kaplan-Meier estimate of median survival is 9 months (95% confidence interval; 7–16 months). Topotecan in this dose and schedule does not appear active in patients with advanced colorectal cancer.     

The potential role of immunotherapy to treat colorectal cancer

Introduction: Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer-related death worldwide. Surgery, chemotherapy, radiation therapy and anti-angiogenic therapies form the backbone of treatment for CRC in various stages. Immunotherapy is frequently used either alone or in combination with chemotherapy for the treatment of various cancers such as melanoma, prostate cancer and renal cell cancer. Current CRC research is moving forward to discover ways to incorporate immunotherapies into the treatment of CRC.

Areas covered: The aim of this review is to summarize the potential role of immunotherapy in CRC. Herein, the authors provide a brief overview of immune modulatory cells, immune surveillance and escape in CRC. They also review vaccine trials in addition to cytokines and monoclonal antibodies. This coverage includes ongoing trials and checkpoint inhibitors such as cytotoxic T lymphocyte antigen-1, programmed cell death-1, and PDL1.

Expert opinion: Checkpoint inhibitors in combination with either chemotherapy or chemo-antiangiogenic-therapy may represent a future therapeutic approach for CRC incorporating immune system targeting. Given the success of immune-based therapy in other tumor types, the authors anticipate that a similar breakthrough in CRC will be forthcoming.     

Advancing pharmacological treatment options for advanced gastric cancer

Introduction: Gastric cancer is the third most common cause of cancer-related deaths worldwide. Improvement of conventional chemotherapy has been modest in the past decades.

Areas covered: We review recent important studies of metastatic or recurrent gastric cancer. For human epidermal growth factor receptors 2 (HER2) negative cancer, standard treatments are combinations of fluoropyrimidine and platinum with or without epirubicin or docetaxel in first-line therapy. Controversy exists regarding the use of triplet chemotherapies due to their toxicity. For HER2 positive cancer, standard treatments are combinations of fluoropyrimidine and cisplatin with trastuzumab. As second- or third-line treatment, taxanes or irinotecan prolonged survival compared with best supportive care alone, but the extension of overall survival was only 1 – 2 months. A recent study demonstrated that ramucirumab plus paclitaxel improved survival as a second-line therapy.

Expert opinion: Most trials have failed to demonstrate a benefit of targeted agents. It is important to identify predictive biomarkers to enrich an appropriate patient population for targeted agents such as HER2 status for trastuzumab.     

Th9 cells are subjected to PD-1/PD-L1-mediated inhibition and are capable of promoting CD8 T cell expansion through IL-9R in colorectal cancer

Th9 cells are named after their expression of IL-9. Studies in recent years demonstrated that Th9 cells could contribute to antitumor immunity by enhancing the recruitment and activation of mast cells, natural killer cells, CD8 T cells, and dendritic cells in the tumor microenvironment. To determine whether Th9 cells participate in colorectal cancer (CRC), we collected resected tumor samples from 20 CRC patients. In the tumor-infiltrating lymphocytes (TILs), IL-9⁺IL-4⁻ CD4⁺ T cells could be observed and were present at higher frequencies than the IL-9⁺IL-4⁺ and the IL-9⁻IL-4⁺ cells, suggesting that the majority of IL-9-producing TILs were bona fide Th9 cells. IL-9-secreting TILs presented particularly high PD-1 expression directly ex vivo. The expression of IL-9 was significantly reduced with PD-L1-mediated inhibition, which in turn was suppressed by anti-PD-1 blocking. Interestingly, the circulating CD4⁺ T cell compartment in CRC patients also presented Th9 enrichment, characterized by higher IL-9⁺IL-4⁻ and IL-9⁺IL-4⁺ cell frequencies in the CXCR3⁻CCR6⁻ compartment as compared to that in non-cancer controls. Using exogenous TGF-β and IL-4, we were capable of enriching Th9 cells without concurrent enrichment of Th2 cells. Th9-enriched CD4⁺ T cells, but not Th9-non-enriched cells, significantly increased the expansion of activated CD8⁺ T cells, in a manner that was dependent on the expression of IL-9R. In addition, the frequencies of Th9 cells in the tumor were positively correlated with the frequencies of CD8⁺ TILs. Together, we demonstrated that Th9 cells infiltrated CRC tumor, could be regulated via the PD-1/PD-L1 pathway, and could contribute the CD8⁺ T cell expansion.