放射性蛋白药物在PD-1/PD-L1靶向免疫治疗评估中的应用进展

程序性细胞死亡受体1(PD-1)和程序性细胞死亡配体1(PD-L1)靶向治疗作为一种新型免疫疗法,改变了许多癌症的治疗格局,但仅有部分患者可从免疫治疗中获益,其影响因素之一是肿瘤PD-1/PD-L1的表达水平。如何实现对其无创性的活体动态监测,非侵入性核素药物的分子成像可提供潜在的解决方案。放射性核素标记的完整单克隆抗体、抗体片段、多肽等探针进行靶向PD-1/PD-L1显像可实时动态地监测全身PD-1/PD-L1的表达,为免疫治疗过程中实时、无创、动态地筛选潜在受益者,以及预测治疗效果和预后,为PD-1/PD-L1靶向治疗提供了有效手段。通过对放射性蛋白药物在PD-1/PD-L1靶向免疫治疗中的监测和疗效评估的应用进行综述,以期为未来的新型放射性蛋白诊疗药物的临床转化和优化提供依据。     

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers

Background: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aim to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in published or reported recent studies.

Scope: A literature search was made from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: “nivolumab”, “pembrolizumab”, “avelumab”, “GI cancers” “anti-PD1 therapy” and “anti-PD-L1 therapy”. The last search was on 2 November 2016. The most important limitation of our review is that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relies on phase 1 and 2 trials.

Findings: Currently, there are two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PDL1 (atezolizumab) agents approved by FDA. After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer and non-squamous lung cancer, trials which evaluate immune checkpoint blockade in GI cancers are ongoing. Early results of trials have been promising and encouraging for patients with advanced stage gastroesophageal cancer. According to early results of published trials, response to anti-PD1/PD-L1 agents appears to be associated with tumor PD-L1 levels. According to two recently published phase 2 trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI) positive advanced colorectal cancer. However, several phase 2/3 trials are still ongoing.

Conclusion: Both pembrolizumab and nivolumab show promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.     

Investigational drugs for treating anal cancer and future perspectives

Introduction: Anal cancer is a relatively rare malignancy which comprises about 2.5% of all digestive system malignancies in the United States. The majority of cases are squamous cell carcinoma which is closely related to human papilloma virus (HPV) infection. Despite high cure rates with chemoradiation alone, 10 – 20% of patients do develop metastatic disease with little data to guide their treatment.

Areas covered: In this review article, the authors describe the current standard treatment of early and advanced squamous cell carcinoma of the anal canal based on published data. The authors then describe the new approaches to the disease, focusing on new radio sensitizing agents, systemic targeted drugs and immunotherapy.

Expert opinion: The authors believe that current standard treatment options for squamous cell carcinoma of the anal canal are well defined with acceptable results. However the major challenge in the treatment of anal cancer is the lack of randomized or even large single arm Phase II trials due to rarity of the disease, especially in the metastatic disease. But we are slowly making progress. Currently, the most promising areas of research are immunotherapy, targeted therapy and even HPV prevention. We are eagerly anticipating the results of these studies in order to expand the treatment armamentarium.     

PD-L1和OX40靶点肿瘤免疫疗法研究进展

恶性肿瘤作为危害人类健康最严重的疾病之一,其诱因较多、早期无明显症状且易发生转移.随着分子生物学技术的发展和对肿瘤病理机制深入研究,肿瘤免疫疗法逐渐成为人类研究的重点.其中免疫检查点PD-L1是肿瘤免疫治疗经典靶点,它可以与PD-1结合通过激活信号通路抑制T细胞活性,促进肿瘤生长.2016年,第一个PD-L1抑制剂阿特...     

程序性死亡受体1的检测方法及其在乳腺癌中表达的研究进展

近年来,肿瘤的免疫治疗已成为继传统手术、放疗、化疗、内分泌治疗和靶向药物治疗手段之后新的治疗方法,尤其以程序性死亡受体1(PD-1)/程序性死亡配体1(PD-L1)位靶点的免疫检查点抑制治疗使得非小细胞肺癌、黑色素瘤等恶性实体肿瘤患者获得了有效持久的临床获益.PD-L1的检测是免疫检查点抑制剂治疗的关键环节,但在乳腺癌...     

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.     

Atezolizumab for the treatment of non-small cell lung cancer

Introduction: The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1).

Areas covered: This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay.

Expert commentary: PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate.     

37例进展期胃癌的超声分析

目的探讨超声对进展期胃癌的诊断价值。方法对经病理活检证实的37例胃癌患者术前行超声检查并与手术病理对照。结果 37例进展期胃癌中B超诊断符合36例,准确率为97.3%（36/37）。结论超声检查对胃癌诊断有一定的价值,可以与胃镜检查和X线钡餐检查优势互补。     

Bispecific Antibody-Bound T Cells as a Novel Anticancer Immunotherapy

Chimeric antigen receptor T (CAR-T) cell therapy is one of the promising anticancer treatments. It shows a high overall response rate with complete response to blood cancer. However, there is a limitation to solid tumor treatment. Additionally, this currently approved therapy exhibits side effects such as cytokine release syndrome and neurotoxicity. Alternatively, bispecific antibody is an innovative therapeutic tool that simultaneously engages specific immune cells to disease-related target cells. Since programmed death ligand 1 (PD-L1) is an immune checkpoint molecule highly expressed in some cancer cells, in the current study, we generated αCD3xαPD-L1 bispecific antibody (BiTE) which can engage T cells to PD-L1⁺ cancer cells. We observed that the BiTE-bound OT-1 T cells effectively killed cancer cells in vitro and in vivo. They substantially increased the recruitment of effector memory CD8⁺ T cells having CD8⁺CD44⁺CD62L^low phenotype in tumor. Interestingly, we also observed that BiTE-bound polyclonal T cells showed highly efficacious tumor killing activity in vivo in comparison with the direct intravenous treatment of bispecific antibody, suggesting that PD-L1-directed migration and engagement of activated T cells might increase cancer cell killing. Additionally, BiTE-bound CAR-T cells which targets human Her-2/neu exhibited enhanced killing effect on Her-2-expressing cancer cells in vivo, suggesting that this could be a novel therapeutic regimen. Collectively, our results suggested that engaging activated T cells with cancer cells using αCD3xαPD-L1 BiTE could be an innovative next generation anticancer therapy which exerts simultaneous inhibitory functions on PD-L1 as well as increasing the infiltration of activated T cells having effector memory phenotype in tumor site.     

Atezolizumab in invasive and metastatic urothelial carcinoma

Introduction: Until recently, there has been little advancement in the management of invasive and metastatic urothelial cancer in over 30 years, and outcomes with cisplatin-based chemotherapy remain unchanged. Inhibitors targeting PD-1 signaling on cytotoxic T-cells have revolutionized bladder cancer therapy leading to durable responses. Atezolizumab is an engineered humanized anti-PD-L1 monoclonal antibody that inhibits PD-L1 binding to PD-1 and B7.1, enhancing immune-mediated tumor killing and is currently approved as second-line treatment after failure of platinum-based chemotherapy as well as first-line in cisplatin-ineligible patients.

Areas covered: This article summarizes all reported phase I, II and III clinical trials that assessed the safety and efficacy of atezolizumab in the treatment of locally advanced and metastatic urothelial carcinoma.

Expert commentary: Treatment with atezolizumab showed durable response and a toxicity profile that appears favorable to cytotoxic chemotherapy historically in the treatment of metastatic urothelial cancer among individuals who had progressed after prior platinum-based therapy and among those ineligible for treatment with first-line cisplatin. PD-L1 expression and tumor mutation load associate with response, however further research is needed to identify additional markers to improve prediction of response to atezolizumab.     

Pembrolizumab for melanoma- safety profile and future trends

Background: Pregnant women who continue to smoke expose their developing fetus to a wide range of risks. Assisting these patients to stop smoking can be an important intervention for the health of the baby and the mother. The management of pregnant smokers can be challenging, due to the potential risks of pharmacotherapy. There are a number of options available to the clinician to aid smoking cessation in non pregnant women. These include nicotine replacement therapy (NRT), bupropion, varenicline, and a range of non-drug therapies. Objective: To provide guidance to prescribers on the best way to manage smoking cessation in the pregnant patient, reviewing the risks and efficacy of the different approaches. Methods: An extensive literature search was carried out to find original studies which examined issues surrounding the safety and efficacy of methods of smoking cessation in pregnancy. Results/conclusion: NRT is the agent of choice for smoking cessation in pregnancy as the safety of other therapies in pregnancy have not yet been proved.     

Cancer combinatorial immunotherapy using anti-OX40 agonist and anti-PD-L1 antagonist: a patent evaluation of US2018256711A1

Introduction: OX40 is checkpoint inhibitor in cancer that coordinates the downregulation of the proliferation of antigen-specific lymphocytes. There is a great need to discover and develop new therapies focused on inhibiting the action of OX40 and consequently improving the immune response in the various types of cancer. Authors of patent US2018256711A1 propose a method to eradicate cancer that utilizes anti-OX40 agonist antibody in combination with anti-PD-L1 antagonist antibody.

Areas covered: Patent US2018256711A1 describes a method of cancer combinatorial treatment consisting of the utilization of a pharmaceutical cocktail containing anti-OX40 and an anti-PD-L1 antibody.

Expert opinion: The results of the clinical trials only support trials regarding the tolerability of combinatorial therapy, even when the objectives of determining the safety and pharmacokinetics of the treatment are proposed.     

The PD-1/PD-L1 pathway: biological background and clinical relevance of an emerging treatment target in immunotherapy

Introduction: The co-inhibitory receptor programmed death 1 (PD-1) and its ligands are key regulators in a wide spectrum of immune responses and play a critical role in autoimmunity and self-tolerance as well as in cancer immunology. Emerging evidence suggests that cancer cells might use the PD-1/PD-ligand (PD-L) pathway to escape anti-tumor immunity. Based on this evidence, early phase human clinical trials targeting the PD-1/PD-L pathway are currently underway for multiple human cancers.

Areas covered: The role of the PD-1/PD-L pathway in autoimmune disease, viral infections as well as in malignant neoplasms is discussed and an overview of the existing therapeutics as well as the results of clinical trials targeting this pathway in cancer is given.

Expert opinion: The PD-1/PD-L pathway represents an important mechanism of immune evasion for malignant neoplasms. Early clinical trials indicate effectiveness of PD-1/PD-L pathway blockade in several solid cancers. However, greater insight into the exact mechanisms by which tumors are able to evade anti-tumor immunity is needed to increase clinical effectiveness, for example by combination blockade of diverse co-inhibitory receptors.     

YPD-30, a prodrug of YPD-29B,is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.     

Current status and development of anti-PD-1/PD-L1 immunotherapy for lung cancer

Lung cancer is the leading cause of cancer deaths worldwide, mainly because it is usually in the advanced stage at the time of diagnosis. Although great progress has been made in the diagnosis and treatment of lung cancer in the past 25 years, the prognosis of lung cancer patients remains unsatisfactory. Agents targeting immune checkpoints have shown potential to improve therapeutic outcomes in patients with lung cancer. Inhibitors of PD-1/PD-L1 have been approved for the treatment of different types of lung cancer by FDA. Nevertheless, with the increasing number of clinical trails, the adverse events have emerged. Therefore, attention has been paid to finding out the factors influencing the therapeutic effect of anti-PD-1/PD-L1 therapy and reducing the occurrence of adverse events. Combination therapy may be an effective strategy to reduce the adverse events and improve the therapeutic effect. In this review, we summarized the current status and progress of anti-PD1/PD-L1 agents in lung cancer treatment.     

Targeted agents for HER2-positive breast cancer in older adults: current and future perspectives

ABSTRACT

Introduction: One-third of breast cancer (BC) cases worldwide occur in women aged 65 years and older, with 10 to 15% overexpressing the human epidermal growth factor receptor 2 (HER2). Although several HER2-targeted therapies have been developed, the lack of data regarding their use in older patients hampers evidence-based decision-making for this population.

Areas Covered: We review current evidence on the efficacy and safety of HER2-targeted therapies in older adults with BC, focusing on approved therapies such as trastuzumab, lapatinib, pertuzumab, ado-trastuzumab-emtansine, and neratinib. Additionally, we discuss drugs under development to target the HER2-receptor, and to overcome resistance to existing therapies. Finally, we highlight the cardiotoxicity of HER2-targeted drugs among older adults.

Expert Opinion: Older adults are underrepresented in trials of HER2-targeted therapies in BC. We propose strategies to increase recruitment of older adults in clinical trials in order to increase the evidence base to treat this growing population.     

Vinflunine: clinical perspectives of an emerging anticancer agent

Background: Vinflunine is a novel second generation of Vinca alkaloid. The binding of vinflunine to tubulin and subsequent cellular arrest in mitosis is the core mechanism of this antineoplastic agent. In addition, its potential vascular-disrupting and antiangiogenic activities uphold further clinical development of this compound. Objective: To review and summarise the pharmacological and latest clinical data, and discuss the impact of vinflunine on current treatment regimens. Methods: A review of published literature and conference abstracts for results of previous preclinical and latest clinical studies in all cancer types was performed. Results/conclusions: Noteworthy results from Phase II studies for treatment of non-small cell lung cancer (NSCLC), breast cancer and bladder cancer supported Phase III studies. One of the Phase III studies for treatment of advanced NSCLC showed important results. Encouraging results of combination use of vinflunine and other biologic agents also opened areas to investigate its synergistic or auxiliary role to existing therapies.