Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy

Abstract

Cancer immunotherapy has been increasingly utilised to treat advanced malignancies. The signalling network of immune checkpoints has attracted considerable attention. Immune checkpoint inhibitors are revolutionising the treatment options and expectations for patients with cancer. The reported clinical success of targeting the T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immune modulation. Indeed, antibodies binding to PD-1 or PD-L1 have shown remarkable efficacy. However, antibody drugs have many disadvantages, such as their production cost, stability, and immunogenicity and, therefore, small-molecule inhibitors of PD-1 and its ligand PD-L1 are being introduced. Small-molecule inhibitors could offer inherent advantages in terms of pharmacokinetics and druggability, thereby providing additional methods for cancer treatment and achieving better therapeutic effects. In this review, we first discuss how PD-1/PD-L1-targeting inhibitors modulate the relationship between immune cells and tumour cells in tumour immunotherapy. Second, we discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with immunotherapy and targeted therapy. Third, this review is the first to summarise the current clinical and preclinical evidence regarding small-molecule inhibitors of the PD-1/PD-L1 immune checkpoint, considering features and responses related to the tumours and to the host immune system.

Trial registration: ClinicalTrials.gov identifier: NCT02812875.     

PD-1/PD-L1 pathway inhibitors in advanced prostate cancer

Introduction: Pharmacological inhibition of immune checkpoint receptors or their ligands represents a transformative breakthrough in the management of multiple cancers. However, immune checkpoint inhibitors have yet to be FDA-approved for the management of metastatic prostate cancer (PCa), the commonest non-cutaneous malignancy in men.

Areas covered: We review our current understanding of the PD-1/PD-L1 pathway in cancer, the use of anti-PD-1/PD-L1 therapeutics in PCa, and potential subgroups of PCa patients who may derive the greatest benefit from these agents (such as men with tumors that have expression of PD-L1 and/or high mutational load). We also review the prior and current clinical trials evaluating the blockade of PD-1/PD-L1 in PCa, highlighting some of the key ongoing studies of greatest relevance to the field.

Expert commentary: Clinical trials investigating PD-1/PD-L1 inhibitors should be encouraged in patients with PCa. While it is unlikely that immune checkpoint monotherapies will produce long-lasting responses in a substantial proportion of patients, there is early evidence of activity in some patient subsets. These subgroups may include those with high PD-L1 expression, those with hypermutated or microsatellite-unstable tumors, and those enriched for germline and/or somatic DNA-repair gene mutations (e.g. intraductal/ductal histology, primary Gleason pattern 5, and perhaps AR-V7-positive tumors).     

A patent review on PD-1/PD-L1 antagonists: small molecules,peptides, and macrocycles (2015-2018)

Introduction: The protein–protein interaction PD1/PD-L1 is an important immune checkpoint and several recently approved monoclonal antibodies show promising anti cancer activities in the clinical practice. However, only a small percentage of cancer patients benefit from PD1/PD-L1 directed mAbs. Moreover, some patients experience immune related side effects upon treatment with these mAbs. Recently, several atomic-resolution structures of human PD1/PD-L1, and small molecules, peptides and mAbs with PD-L1 and PD1 open the field for structure based drug design. Small molecules and peptides targeting PD1/PD-L1 promise to enhance tumor activity while showing less immune related side effects.

Areas covered: We reviewed the small molecules classes and peptides targeting PD1/PD-L1.

Expert opinion: Currently approved PD1/PD-L1 directed therapeutics show room for improvement. Three classes of non mAb small molecule classes have been discovered so far: (cyclic) peptides as direct competitive PD1/PD-L1 antagonists; small molecules disrupting PD1/PD-L1 and inducing a PD-L1 dimerization; and a small molecule class of unknown mode-of-action. An example of the later group CA-170 is currently investigated in a Phase 1 trial in patients with advanced solid tumors and lymphomas. Potential advantages of small molecules over mAbs include high distribution and better tumor penetration, improved PK/PD, less side effects and oral bioavailability.     

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.     

顺铂联合吉西他滨对肺癌PD-1/PD-L1途径的影响

目的 探讨PD-1/PD-L1途径在肺癌中表达情况及顺铂联合吉西他滨的干预效果.方法 将就诊于丽水市中心医院的80例肺癌患者随机分为对照组(A组)、顺铂治疗组(B组)、吉西他滨治疗组(C组)和顺铂联合吉西他滨治疗组(D)组,每组20例,收集各组患者手术切除的肿瘤组织,再以10例良性肺部疾病患者(E组)的手术切除组织作参照,采用Western blot法检测各组组织中PD-1、PD-L1的表达.选择10例同期来医院体检的健康人员(F组)外周血为空白对照,采用流式细胞仪检测B、C、D、F组治疗前后外周血中PD-L1+ CD68+巨噬细胞的表达,ELISA法检测B、C、D、F组治疗前后血清中IL-2、IL-4、IL-10的含量.结果 E组PD-1、PD-L1未见表达,A组PD-1、PD-L1的表达较E组上调(P＜0.01),B、C、D组较A组显著降低(P＜0.05),B、C组比较差异无统计学意义,D组与B、C组相比差异均有统计学意义(P＜0.05);B、C、D、F组均可检测到PD-L1+ CD68+巨噬细胞的表达,但B、C、D组中PD-L1+ CD68+巨噬细胞的比例显著高于F组(P＜0.01).B组和C组均可降低PD-L1+ CD68+巨噬细胞的比例(P＜0.05),而D组PD-L1+ CD68+巨噬细胞比例显著下调(P＜0.01).B、C、D组治疗前外周血血清中IL-2和IL-4含量较F组低(P＜0.01),IL-10含量较F组高(P＜0.01),治疗后B、C、D组外周血血清中IL-2和IL-4的含量较治疗前均有一定程度的上升(P＜0.05),IL-10含量有一定程度的降低(P＜0.05).结论 顺铂联合吉西他滨可下调肺癌组织中PD-1/PD-L1的阳性表达率及表达量,降低PD-L1+ CD68+巨噬细胞阳性表达,恢复PD-L1对IL-2、IL-4,IL-10所产生的影响,较单独用药效果明显.     

Optimizing Patient Outcomes with PD-1/PD-L1 Immune Checkpoint Inhibitors for the First-Line Treatment of Advanced Non–Small Cell Lung Cancer

The rapidly expanding repertoire of immune checkpoint inhibitors (ICIs) now includes two agents, pembrolizumab and atezolizumab, approved for first-line treatment of advanced non–small cell lung cancer (aNSCLC) as monotherapy or as part of chemoimmunotherapy. This review summarizes the clinical evidence supporting these indications, with a focus on strategies to optimize patient outcomes. These strategies include patient and tumor factors, adverse-effect profiles, pharmacokinetic and pharmacodynamic drug interactions, and quality of life and cost-effectiveness considerations. We performed a systematic literature search of the PubMed, Scopus, and Google Scholar databases, as well as a search of the conference proceedings of the American Society of Clinical Oncology, European Society for Medical Oncology, and American Association for Cancer Research (through August 31, 2019). The addition of ICIs to conventional chemotherapy as first-line treatment against aNSCLC is now part of the standard of care options. However, even though ICIs may be cost-effective in patients with aNSCLC, high drug and other associated costs can still be a barrier to treatment for patients. Moreover, the adverse-effect profiles of ICIs differ significantly from conventional chemotherapy, and some immune-related adverse effects may have a lasting impact on quality of life. Therefore, in adhering to a patient-centered model of care, clinicians should be mindful of patient- and treatment-specific factors when considering therapeutic options for patients with aNSCLC. Although the role of the immune system in cancer progression and regression has not been fully elucidated, the full clinical potential of immunotherapeutics in the treatment of cancer likely remains to be unleashed.     

Disproportionality analysis of bullous pemphigoid adverse events with PD-1 inhibitors in the FDA adverse event reporting system

Objectives: Bullous pemphigoid, an autoimmune dermatological disease, may be associated with the use of a relatively new anti-cancer drug class, PD-1 inhibitors, which includes pembrolizumab and nivolumab. This paper analyzes the signals between PD-1 inhibitors and bullous pemphigoid based upon the reported real-world data.

Methods: A pharmacovigilance analysis was performed on the publicly available Adverse Event Reporting System database of Food and Drug Administration. Disproportionality ratios were used to examine a signal between PD-1 inhibitors and bullous pemphigoid. A heat map was generated to depict the signal between PD ?1 inhibitor use and skin toxicity adverse events.

Results: The analysis indicated that there is a significant signal (PRR = 13.82 [95% CI: 9.99–19.11], Chi-squared with Yates’ correction = 420.48) between pembrolizumab use and bullous pemphigoid and that there is a significant signal (PRR = 13.19 [95% CI: 10.57–16.46], Chi-squared with Yates’ correction = 869.71) between nivolumab use and bullous pemphigoid. The signals remained statistically significant after stratifying for sex and age for both pembrolizumab and nivolumab. The signal is supported by 35 case reports in which there was evidence of PD-1 inhibitor use and a pemphigoid adverse event.

Conclusion: When prescribing PD-1 inhibitors, physicians should monitor closely for symptoms of bullous pemphigoid.     

Investigational PD-1 inhibitors in HL and NHL and biomarkers for predictors of response and outcome

Introduction: Inhibitors against the PD-1/PD-L1 pathway are revolutionizing the treatment and management of malignancies.

Areas covered: We summarize our current understanding of the function of PD-1, its role in immune evasion, the clinical data available that support the use of PD-1 antagonist in Hodgkin and non-Hodgkin lymphomas, and potential predictors of response.

Expert opinion: We anticipate that in the next 10 years, agents that modulate the immune system such as PD-1 antagonists will be increasingly used in favor over traditional cytotoxic chemotherapeutic agents. PD-1 antagonists will be combined with future immunotherapies or used as adjuncts to cellular therapy to boost tumor-specific immune responses.     

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。     

PD-1/PD-L1抑制剂致肝功能异常不良反应的回顾性分析

目的 分析程序性死亡蛋白-1/程序性死亡受体-1(programmed death protein 1/programmed death ligand 1,PD-1/PD-L1)抑制剂相关肝脏毒性发生情况,以指导临床合理应用。方法 纳入苏北人民医院2020年7月-2022年3月使用PD-1/PD-L1抑制剂期间出现免疫相关肝脏毒性(immune mediated hepatitis,IMH)的患者共26例,分析患者的年龄、性别、基础疾病、不良反应(adverse drug reactions,ADRs)发生时间、合并用药、临床表现、肝损伤类型、治疗手段和转归情况。结果 26例患者年龄范围为43~80岁,其中男性22例,女性4例; ≥ 3级不良反应中男性3例,女性3例;女性患者 ≥ 3级不良反应比例明显高于男性。发生肝功能异常不良反应的中位时间为27.5 d(2~248 d),其中20例为1~2级不良反应,均为肝脏生化学检查异常;6例为3~4级不良反应,分别为肝细胞损伤型1例、胆汁淤积型2例和混合型3例。停药或对症处理后肝功能恢复时间范围为2~41 d,平均好转时间为(18.45±9.89)d。不良反应恢复后19例患者继续免疫治疗,其中8例患者再次出现肝功能异常。随访22例患者肝功能均预后良好。结论 临床使用PD-1/PD-L1抑制剂需高度警惕IMH,尤其是用药初期和之前发生过IMH的患者。女性患者发生IMH的严重程度可能更高,需及时对症治疗。     

Anti-PD-L1 mediating tumor-targeted codelivery of liposomal irinotecan/JQ1 for chemo-immunotherapy

Immune checkpoint blockade therapy has become a first-line treatment in various cancers. But there are only a small percent of colorectal patients responding to PD-1/PD-L1 blockage immunotherapy. How to increase their treatment efficacy is an urgent and clinically unmet need. It is acknowledged that immunogenic cell death (ICD) induced by some specific chemotherapy can enhance antitumor immunity. Chemo-based combination therapy can yield improved outcomes by activating the immune system to eliminate the tumor, compared with monotherapy. Here, we develop a PD-L1-targeting immune liposome (P-Lipo) for co-delivering irinotecan (IRI) and JQ1, and this system can successfully elicit antitumor immunity in colorectal cancer through inducing ICD by IRI and interfering in the immunosuppressive PD-1/PD-L1 pathway by JQ1. P-Lipo increases intratumoral drug accumulation and promotes DC maturation, and thereby facilitates adaptive immune responses against tumor growth. The remodeling tumor immune microenvironment was reflected by the increased amount of CD8⁺ T cells and the release of IFN-γ, and the reduced CD4⁺Foxp3⁺ regulatory T cells (Tregs). Collectively, the P-Lipo codelivery system provides a chemo-immunotherapy strategy that can effectively remodel the tumor immune microenvironment and activate the host immune system and arrest tumor growth.     

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.     

Safety of pembrolizumab for the treatment of melanoma

Introduction: The immune checkpoint inhibitor pembrolizumab is the first anti-programmed-death-1 (PD-1) drug licensed by the FDA. It has been approved for the treatment of advanced melanoma, thanks to its positive results in terms of efficacy and its favorable toxicity profile. However, it is not exempt from side effects. In general, these are usually mild and easily manageable but there are pembrolizumab-induced immune-related adverse events (irAEs) that can be severe. Therefore, the understanding, diagnosis and management of those side effects are essential for the optimal care of patients treated with pembrolizumab.

Areas covered: In this article, the safety and efficacy of pembrolizumab in melanoma are extensively reviewed as well as its mechanism of action and the role of the PD-1 pathway in cancer. Also, its profile of side effects is compared with other immune checkpoint inhibitors such as ipilimumab and nivolumab.

Expert opinion: Pembrolizumab is generally a well-tolerated drug but irAEs are not infrequent. However, these are usually mild and easily manageable in most cases. Early diagnosis and correct management of side effects induced by immune checkpoint inhibitors such as pembrolizumab should be areas of further work in forthcoming years.     

Characterization of B cell-mediated PD-1/PD-L1 interaction in pancreatic cancer patients

Pancreatic ductal adenocarcinoma (PDAC) is a common type of pancreatic cancer with one of the worst survival rate of all malignancies. Recent studies have identified that immunosuppressive B cells could employ the PD-1/PD-L1 pathway to suppress antitumour T cell responses; hence, we examined the expression and function of PD-L1 in B cells. We found that the PD-L1 expression was significantly enriched in tumour-infiltrating (TI) B cells than in peripheral blood (PB) B cells from the same patients. Additionally, the PB B cells from stage III and stage IV PDAC patients presented significantly higher PD-L1 than the PB B cells from healthy controls. High PD-L1 expression in PB B cells could be achieved by stimulation via CpG and less effectively via anti-BCR plus CD40L, but not by coculture with pancreatic cancer cell lines in vitro. Also, STAT1 and STAT3 inhibition significantly suppressed PD-L1 upregulation in stimulated B cells. CpG-stimulated PB B cells could inhibit the IFN-γ expression and proliferation of CD8 T cells in a PD-L1-dependent manner. Also, TI CD8 T cells incubated with whole TI B cells presented significantly lower IFN-γ expression and lower proliferation, than TI CD8 T cells incubated with PD-L1⁺ cell-depleted TI B cells, suggesting that PD-L1⁺ B cells could also suppress CD8 T cells in the tumour. Overall, this study identified that B cells could suppress CD8 T cells via PD-L1 expression, indicating a novel pathway of immuno-regulation in pancreatic cancer.     

PD-1/PD-L1信号通路在黑色素瘤中的研究进展

细胞程序性死亡因子1(programmed death-1,PD-1)及其配体1(programmed death-ligand 1,PD-L1)是一对共刺激分子,激活细胞程序性死亡因子1及其配体1信号通路可抑制肿瘤特异性T细胞活性,有助于肿瘤细胞逃避免疫监视.而阻断该通路可以激活机体抗肿瘤免疫应答,抑制肿瘤细胞的生长...