Checkpoint inhibitors in triple‐negative breast cancer (TNBC): Where to go from here

Advances in cancer immunotherapy and a growing body of research have focused on the role of the antitumor response in breast cancer. Triple‐negative breast cancer (TNBC) is the most immunogenic breast cancer subtype, and there is strong evidence that tumor‐infiltrating lymphocytes in TNBC have prognostic value and are associated with clinical outcome and improved survival. Evading antitumor immunity is a hallmark for the development and progression of cancer. Immunotherapy studies have focused on the role of the programmed cell death‐1 (PD‐1) receptor/programmed death‐ligand 1 (PD‐L1) pathway in maintaining immunosuppression in the tumor microenvironment. Blockade of the PD‐1/PD‐L1 axis has emerged as a promising therapeutic option to enhance antitumor immunity and is actively being investigated in TNBC, with encouraging results. In this article, the authors review the current literature on checkpoint inhibitors in TNBC with a focus on PD‐1/PD‐L1 antibodies and discuss combination strategies and novel approaches for improving antitumor immunity and clinical outcome. Cancer 2018;124:2086‐103 . © 2018 American Cancer Society.     

Biomarkers for immune checkpoint inhibitors: The importance of tumor topography and the challenges to cytopathology

The recent emergence of immune checkpoint inhibitors for cancer therapy has created much excitement among cancer patients, drug and diagnostic developers, and health care professionals. This is due largely to the dramatic and sustained responses among some advanced cancers that were previously refractory to therapy. Unfortunately, these responses are difficult to predict, so the goal of the right drug for the right patient at the right time remains elusive. This is in part due to the complexity of the tumor immune microenvironment and its role in drug efficacy. The application of biomarkers to pathologic specimens to predict responses to therapy remains one of the key roles for pathologists in precision medicine. For the new immune checkpoint inhibitors, the emerging class of biomarkers revolves around the immunohistochemical detection of the drug target (or its ligand), programmed cell death ligand 1, on tumor cells or associated immune cells. The diagnostic terrain is already complex because of the involvement of different technology platforms, antibody clones, scoring systems, and indications for their use. The application of these biomarkers to cytologic specimens is critical because the current drug indications are for advanced‐stage cancers that are often sampled by minimally invasive cytologic means rather than surgical resection. This review summarizes the current state of biomarkers for immune checkpoint inhibitors with an emphasis on the opportunities for and threats to cytologic samples. Cancer Cytopathol 2018;126:11‐9. © 2017 American Cancer Society.     

Irradiation and immunotherapy: From concept to the clinic

In recent years, an increased understanding of T‐cell–regulatory mechanisms has led to the development of a novel class of immune‐checkpoint inhibitors that have robust clinical activity against a broad array of malignancies—even those that historically were not believed to be sensitive to immune therapy. With this, there has been renewed interest in the potential for synergy with more traditional forms of anticancer therapy like radiation therapy (RT). The role of RT in palliation or as definitive treatment for certain malignancies has been well established. Yet, in recent years, the concept has come to light that RT could be an attractive partner for use in combination with other immunotherapies. The effects of RT include not only control of an irradiated tumor but also multiple immunomodulatory effects on both the tumor and the microenvironment, priming tumors for an immune‐mediated response. Herein, the authors summarize relevant preclinical data and rationale supporting the synergy of combined RT and immunotherapy and highlight recent clinical work on promising combination strategies. Cancer 2016;122:1659‐71 . © 2016 American Cancer Society.     

Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study

Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T‐cell activation through overexpression of the inhibitory receptor programmed death 1 (PD‐1) ligands. The PD‐1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single‐arm, open‐label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty‐four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee‐assessed overall response rate was 34.8% (90% confidence interval, 20.8–51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0–71.4). Treatment‐related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment‐related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI‐142533.)     

PD-1/PD-L1 blockade,a novel strategy for targeting metastatic colorectal cancer: A systematic review and meta-analysis of randomized trials

Currently, standard treatment of patients with metastatic colorectal cancer (mCRC) comprises chemotherapy (CT) and/or biological therapy (BT) and/or best supportive care (BSC). The present study performed a meta-analysis on five phase II–III randomized clinical trials, which compared CT/BT/BSC as the control arm with the immune checkpoint inhibitors (ICIs) anti-programmed cell death protein 1 (PD-1) or its ligand (PD-L1) alone or in combination with cytotoxic T lymphocyte antigen 4 or mitogen activated protein kinase kinase inhibitors as the experimental arm, to evaluate whether a standard approach could be overcome using the novel target therapy strategy. Pooled hazard ratio (HR) for progression-free survival was 0.95 in favor of the experimental arm [95% confidence interval (CI), 0.74–1.22; P=0.68]. Heterogeneity was significant: Cochran''s Q, 21.0; P=0.0082; I² index, 76%. Pooled HR for overall survival was 0.88 in favor of the experimental arm (95% CI, 0.75–1.02; P=0.08). Heterogeneity was not significant (Cochran''s Q, 6.0; P=0.31; I² index, 16%). The present meta-analysis demonstrated a trend toward the improvement of survival by PD-1/PD-L1 blockade in mCRC. Further homogeneous studies are necessary to strengthen these results, beyond the known benefits of ICIs in deficient mismatch repair/high microsatellite instability tumors.     

Immune checkpoint inhibitors in advanced non–small cell lung cancer

The emergence of immune checkpoint inhibitors for the treatment of cancer has led to major changes to the therapeutic landscape of lung cancer. Improvements in overall survival relative to standard chemotherapy have been observed in the first‐line and second‐line therapy settings for patients with advanced non–small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. Consequently, every patient with advanced‐stage NSCLC is now a candidate for immune checkpoint inhibitor therapy. However, it is clear that the benefit from therapy is not universal, and identification of biomarkers to select therapy has assumed importance. In addition to programmed cell death receptor ligand 1 expression, both tissue‐based and blood‐based markers are under evaluation to select patients. In an era of increasing costs of care and potential for toxicities related to immune checkpoint inhibition, proper patient selection is critical to the optimal use of this new class of agents. In addition, development of novel combination approaches has also emerged as an important way to improve the efficacy of immune checkpoint inhibition. Studies in earlier stages of NSCLC are already underway with the hope of improving the cure rate. In this article, the authors review the current landscape of immune checkpoint inhibitors in the treatment of advanced NSCLC. Cancer 2018;124:248‐61 . © 2017 American Cancer Society.     

To treat or not to treat: Patient exclusion in immune oncology clinical trials due to preexisting autoimmune disease

Newly developed immune checkpoint inhibitors (ICIs) demonstrate impressive clinical activity. However, they can also cause life-threatening side effects. The efficacy and toxicity associated with ICIs both derive from unregulated, enhanced immune activation. Health care providers have been hesitant to prescribe these medications to patients who have preexisting autoimmune disease (AD) because of concerns that this may exacerbate their underlying immune condition. These patients have also been excluded from ongoing ICI clinical trials. However, new data suggest that the potential benefits of ICI treatment may outweigh the potential risks for this patient group as long as physicians also provide sufficient monitoring for AD exacerbations or other side effects. Therefore, it may be appropriate to include patients with advanced malignancies and preexisting AD in ICI clinical trials when no other effective cancer treatment options exist. Overall, physicians should avoid excluding patients from ICI therapy unnecessarily when the potential benefits outweigh the potential risks.     

Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors

Blockade of programmed cell death ligand‐1 with durvalumab has shown efficacy and safety in large, international studies of patients with advanced solid tumors. A phase 1, non‐randomized, open‐label multicenter study was initiated to evaluate durvalumab in a Japanese population. The first part of this study used a standard 3 + 3 dose‐escalation design to determine the optimal dosing schedule of durvalumab. Primary objective was evaluation of safety and tolerability of durvalumab monotherapy. Secondary objectives were to evaluate maximum tolerated dose (MTD), immunogenicity, pharmacokinetics, and efficacy. Twenty‐two patients (median age, 61.5 years; range, 41‐76; 64% male) received durvalumab at doses of 1, 3, or 10 mg/kg every 2 weeks (q2w), 15 mg/kg q3w, or 20 mg/kg q4w. Twenty patients discontinued before completing 12 months of treatment as a result of progressive disease and two due to adverse events (AE). The most common treatment‐related AE (trAE) were rash (18%) and pruritus (14%); two patients had grade ≥3 trAE including one patient each with hyponatremia and hypothyroidism. No patient experienced a dose‐limiting toxicity (DLT) during the DLT evaluation period and the MTD was not identified. There were no AE leading to a fatal outcome during study treatment. Durvalumab showed dose‐proportional pharmacokinetics across the 1‐20 mg/kg dose range; incidence of positive titers for antidrug antibodies was 9%. One patient with lung cancer had a partial response and disease control rate at 12 weeks was 36%. In conclusion, durvalumab at the doses and regimens evaluated was safe and well tolerated in Japanese patients with advanced solid tumors.     

Clinical significance of programmed cell death‐ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI‐H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death‐ligand 1 (PD‐L1) and related proteins in MSI‐H and microsatellite‐stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI‐H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI‐H and MSS CRCs, respectively, were immunohistochemically evaluated for PD‐L1, PD‐1, CD8 and CD68. PD‐L1 expression was evaluated separately for tumor cells (PD‐L1 [T]) and tumor‐infiltrating myeloid cells in the stroma (PD‐L1 [I]). PD‐L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI‐H CRCs, while PD‐L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD‐L1 (T) and PD‐L1 (I) expression levels in MSI‐H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early‐stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD‐L1 (I), CD8‐positive cells and CD68‐positive macrophages were present at the invasive front than in the central tumor in MSI‐H CRCs (p < 0.005). PD‐L1 was expressed on both tumor cells and CD68/CD163‐positive (M2) macrophages at the invasive front of MSI‐H CRCs. In conclusion, PD‐L1‐positive tumor cells and M2‐type tumor‐associated macrophages may contribute to tumor invasion and immune escape at the invasive front.     

Negative influence of programmed death‐1‐ligands on the survival of esophageal cancer patients treated with chemotherapy

The programmed death‐1/programmed death‐1 ligands (PD‐1/PD‐L) pathway plays an important role in immunological tumor evasion. However, the clinical significance of the PD‐L (L1 and L2) expression in esophageal cancer treated with chemotherapy has not been fully investigated. We examined the expression of PD‐L of the primary tumors obtained from 180 esophageal cancer patients who underwent radical resection with or without neoadjuvant chemotherapy (NAC) using immunohistochemical staining. The relationship between the expression patterns and clinico‐pathological characteristics was examined. In the present study, 53 patients (29.4%) and 88 patients (48.3%) were classified into positive for PD‐L1 and PD‐L2 expression, respectively. In all the patients examined, overall survival rates of the patients with tumors positive for PD‐L1 or PD‐L2 were significantly worse than those with tumors negative for PD‐L1 or PD‐L2 (P = 0.0010 and P = 0.0237, respectively). However, subgroup analysis showed that these tendencies are only found in the patients treated with NAC, and not in those without NAC. The patients with positive PD‐L1 expression had a significantly higher rate of NAC history (P = 0.0139), but those with positive PD‐L2 expression did not have a significantly high rate of NAC history (P = 0.6127). There is no significant relationship between PD‐L1 expression and response to chemotherapy (P = 0.3118), but patients with positive PD‐L2 expression had significantly inferior responses to chemotherapy (P = 0.0034). The PD‐1/PD‐L pathway might be an immunological mechanism associated with the long‐term effectiveness of chemotherapy in esophageal cancer patients. Further investigation into the roles of PD‐1 pathway in chemotherapy could lead to the development of better treatment options for this disease.     

食管鳞状细胞癌患者外周血PD-1和PD-L1的表达及其临床意义

目的:检测食管鳞癌患者外周血中程序性死亡分子1 (programmed cell death 1,PD-1)、程序性死亡分子1配体(pro-grammed cell death ligand 1,PD-L1)及IFN-γ表达情况,并分析其临床意义.方法选取2016年6月至2017年4月河北医科大学第四医院胸外科90例食管鳞状细胞癌患者(其中50例患者行手术治疗)和40例健康对照者为研究对象,收集研究其外周血液标本,采用酶联免疫吸附方法检测血清中可溶性PD-1 (sPD-1)、可溶性PD-L1 (sPD-L1)及IFN-γ的表达水平.采用SPSS 24.0软件对数据进行检验和相关性分析.结果:食管鳞癌组血清中sPD-l、sPD-L1及IFN-γ水平均明显高于正常对照组(P＜0.05);食管鳞癌组手术前血清sPD-L1、IFN-γ水平均明显高于术后(P＜0.05),而sPD-1水平两组比较无明显差异(P＞0.05).sPD-1、sPD-L1的表达水平与临床病理特征无明显相关(P＞0.05),IFN-γ的表达水平与淋巴结转移情况相关(P＜0.05),与T分期、TNM分期、肿瘤体积大小、肿瘤部位、组织分化程度、性别、年龄无明显相关(P＞0.05).血清中sPD-L1表达水平与IFN-γ无明显相关(P＞0.05).结论:食管鳞癌患者血清中sPD-L1较正常人表达升高,且术后表达较术前减少,说明血清中sPD-L1表达水平与病情发展变化有一定相关性.     

PD-1/PD-L1抑制剂治疗晚期肝细胞癌的机制及研究进展

原发性肝癌起病隐匿,恶性程度高,易发生进展及转移,往往发现疾病时已是肝癌中晚期。较长一段时间内,对于肝癌的主要治疗手段包括手术、放化疗、介入治疗及靶向治疗。但传统治疗方法疗效有限,近年来,随着对原发性肝癌的免疫系统研究逐步深入,免疫治疗已然成为一种新兴的治疗手段,其中以程序性死亡蛋白-1（PD-1）/程序性死亡蛋白配体-1（PD-L1）为靶点的免疫疗法在非小细胞肺癌及肾细胞癌的临床应用中取得了明显疗效。因此,许多研究者开始进一步探索PD-1/PD-L1抑制剂在肝癌中的治疗效果。本文将对PD-1/PD-L1抑制剂治疗肝癌的机制及现阶段国内外多项免疫治疗取得的成效作一综述。