The potential combinational immunotherapiesfor treatment of hepatocellular carcinoma

The treatment choices available for hepatocellular carcinoma (HCC) are limited and unsatisfactory. Recent improvements in our understanding of the mechanism involving immune checkpoints, including programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and also progress in the development of medicines make immunotherapy a promising approach to the treatment of numerous cancers, especially HCC. However, around 40% of patients still suffer from a progressive disease when treated with a monotherapy. Several clinical trials applying a combination therapy including immune checkpoint inhibitors have demonstrated the durable antitumor activity of these approaches in HCC patients. These clinical trials were done with the intent of evaluating the safety of these combination therapies, as well as whether they help improve the overall survival of patients. This study reviewed the recent progress in the use of combination therapies including immunotherapy in treating patients with HCC.     

Immune checkpoint inhibitors in gynecologic cancers with lessons learned from non-gynecologic cancers

ABSTRACT

Introduction: The immune system plays a critical role in controlling cancer through a dynamic relationship with cancer cells. Immunotherapy can establish a sustained immune response against recurring cancer cells leading to long-term remissions for cancer patients. The use of immune checkpoint inhibitors, which work by targeting molecules that regulate immune responses, might be a promising avenue of immunotherapeutic research in gynecologic cancers.

Areas covered: This review focuses on the use of immune checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and the programmed death receptors such as PD-1 and PD1-ligand in gynecologic cancers. Combinatorial approaches utilizing immunotherapeutic agents with conventional treatments as well as immune-related response criteria and the adverse effects arising due to checkpoint inhibitor immunotherapy have been also discussed in the review.

Expert opinion: After years of very little success, a better understanding of the pivotal role of the tumor microenvironment in suppressing anticancer immunity and the exploration of treatment regimens using immune checkpoint inhibitors alone or in combination have finally led to the development of effective cancer immunotherapies and to improve survival of patients with certain types of advanced cancers. While the clinical experience with immune checkpoint inhibitors in gynecologic cancer patients remains limited, early signal of clinical activity strongly suggest that immunotherapy will play a significant role in the year to come in at least a subset of gynecologic cancer patients.     

Glypican‐3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment

Liver cancer is the second leading cause of cancer‐related deaths, and hepatocellular carcinoma (HCC) is the most common type. Therefore, molecular targets are urgently required for the early detection of HCC and the development of novel therapeutic approaches. Glypican‐3 (GPC3), an oncofetal proteoglycan anchored to the cell membrane, is normally detected in the fetal liver but not in the healthy adult liver. However, in HCC patients, GPC3 is overexpressed at both the gene and protein levels, and its expression predicts a poor prognosis. Mechanistic studies have revealed that GPC3 functions in HCC progression by binding to molecules such as Wnt signaling proteins and growth factors. Moreover, GPC3 has been used as a target for molecular imaging and therapeutic intervention in HCC. To date, GPC3‐targeted magnetic resonance imaging, positron emission tomography, and near‐infrared imaging have been investigated for early HCC detection, and various immunotherapeutic protocols targeting GPC3 have been developed, including the use of humanized anti‐GPC3 cytotoxic antibodies, treatment with peptide/DNA vaccines, immunotoxin therapies, and genetic therapies. In this review, we summarize the current knowledge regarding the structure, function, and biology of GPC3 with a focus on its clinical potential as a diagnostic molecule and a therapeutic target in HCC immunotherapy.     

Diagnosis and Management of Immune Checkpoint Inhibitor–related Toxicities in Ovarian Cancer: A Series of Case Vignettes

Use of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1 have led to improved survival outcomes for advanced solid-tumor malignancies. This report helps the reader gain a better understanding of adverse events in patients with ovarian cancer on checkpoint inhibitor therapy. We describe 3 hypothetical case vignettes of patients with gynecologic cancer on checkpoint inhibitor immunotherapy and discuss common immune-related adverse events. The typical presentation and onset of immune-related events are different from those associated with conventional chemotherapy. This report highlights the importance of early recognition and management of these events.     

Advances in locoregional therapy for hepatocellular carcinoma combined with immunotherapy and targeted therapy

Locoregional therapies (LRTs) of hepatocellular carcinoma (HCC) represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC. Among these, TACE is used throughout the stage Ib to IIIb of HCC treatment. In recent years, immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research. At the same time, targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC, and their clinical application has been quite mature. HCC is the sixth most common malignant tumor in the world. When it comes to its treatment, different therapies have different indications, and their individual efficacies are not satisfactory, which makes the exploration of the use of combination therapy in HCC treatment become a new trend. In this paper, the status of the three therapies and the progress of their combined application are briefly reviewed.     

Immunotherapy in hepatocellular carcinoma: Combination strategies

Liver cancer is one of the most common causes of cancer death globally, and its incidence in the United States is increasing. Patients with advanced hepatocellular carcinoma (HCC) who are not candidates for surgical resection, liver transplant, or locoregional therapies can be treated with systemic therapies. Multiple agents, including sorafenib, lenvatinib, and regorafenib are approved for use as either first- or second-line therapy in this patient population, but all have relatively modest survival benefits. HCC is potentially susceptible to therapy with checkpoint inhibitors, including agents such as nivolumab and pembrolizumab, which are both approved by the Food and Drug Administration for patients previously treated with sorafenib but have not demonstrated superior overall survival in phase III trials. It is clear that more effective approaches are needed to potentiate the effects of checkpoint inhibitors in patients with HCC. This review will outline and appraise the current literature on the use of checkpoint inhibitors in HCC as part of a combination treatment involving an additional mode of therapy. The list of agents that can be paired with checkpoint inhibitors includes an additional checkpoint inhibitor, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors, tyrosine kinase inhibitors, OX-40 agonists, and PT-112 inhibitors. The main non-pharmacologic therapies currently being studied for inclusion in a combination strategy include radiation therapy, trans-arterial chemoembolization, and ablation.     

Diabetic ketoacidosis induced by a single dose of pembrolizumab

Immune checkpoint inhibitors are a new class of anticancer drugs recently approved by the US Food and Drug Administration (FDA) for the treatment of various malignancies. Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death protein-1 (PD-1) receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2). Pembrolizumab was first approved by the FDA in 2014 for the treatment of advanced melanoma and is currently approved for use in non-small cell lung cancer and several other neoplasms. Immune checkpoint inhibitors such as pembrolizumab have been reported to induce immune-mediated side effects, including type 1 diabetes mellitus in very rare cases (0.1% in clinical trials). Here, we report the case of a woman with no known history of diabetes who presented to our emergency department in a state of diabetic ketoacidosis within 3?weeks of receiving only a single dose of pembrolizumab therapy, and without any previous exposure to immunotherapy. This case of abrupt adult-onset type 1 diabetes mellitus is an example of the undesirable side effects that can emerge after only a brief exposure to an immune checkpoint inhibitor. Close monitoring of patients receiving immune checkpoint inhibitors is warranted for the early diagnosis and management of imminent and potentially life-threatening complications.     

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment

Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance. In this Review, we discuss contributing factors that distinguish subsets of patients with glioma who may benefit from ICB. Specifically, we discuss (a) the complex interaction between the tumor immune microenvironment and glioma cells as a potential influence on immunotherapy responses; (b) promising biomarkers for responses to immune checkpoint inhibitors; and (c) the potential contributions of peripheral immune cells to therapeutic responses.     

Research progress and clinical application of predictive biomarker for immune checkpoint inhibitors

Introduction: Immune checkpoint inhibitors (ICIs) have emerged as epochal milestones in the ?eld of anti-cancer immunotherapy. With promising clinical effectiveness, ICIs can significantly prolong the overall survival of patients with advanced cancer of different types. Although their remarkable effectiveness has been demonstrated in clinical application, ICIs display limitations in terms of unique response patterns. Only a subset of patients exhibits objective responses, while others show rapid disease progression. Considering that there is a fair representation of both subsets of patients (responders and non-responders), clinicians ought to effectively stratify patients who will potentially benefit from ICI therapy, and optimize a strategy for patient selection.

Areas covered: In this review, the authors have summarized several key factors involved in the biomarker development of ICI therapy, such as neoantigen production and presentation, the tumor microenvironment, and alternation in specific gene signaling pathways.

Expert opinion: Considering the extreme complexity of the immune system, a single biomarker may fail to appropriately stratify patients for ICI therapy. Therefore, future biomarker research should focus on designing an integrated biomarker system that will successfully guide combination therapies to overcome resistance to immunotherapy.     

Research status on immunotherapy trials of gastric cancer

The breakthrough of immune checkpoint inhibitor (ICI) therapy has created extensive opportunities for cancer immunotherapy. Especially, the block of programmed death-1/programmed death ligand 1 (PD-L1) axis using ICIs has become a new therapeutic strategy to treat advanced gastric cancer (GC). However, in the past decade, single-arm and randomized trials for single-drug ICI therapy showed that the therapeutic effect was not satisfactory, including clinical trials for advanced GC. However, after selecting suitable predictive biomarkers and developing a combination of anti-angiogenic targeted drugs and other chemotherapeutic drugs, the objective response rate and progression-free survival of patients with gastric cancer were improved significantly. The United States Food and Drug Administration has approved treatment with pembrolizumab for patients with advanced GC with PD-L1 expression or microsatellite instability-high/mismatch repair deficiency. In this review, the updated data from the latest trial results of combination immunotherapy for GC are presented. Based on the outcome of combination therapy, we discuss its possible molecular mechanism and summarize effective predictive biomarkers. We also discuss possible problems stemming from results of other clinical trials of ICI treatment and propose other directions for ICI therapy.     

Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade

The relationship between cancer and the immune system is complex and provides unique therapeutic opportunities. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory molecule that suppresses T cell effector function following initial activation by costimulatory signals. Fully human monoclonal antibodies targeting CTLA-4 have been shown to increase T cell function and antitumor responses in patients with advanced metastatic melanoma. Responses observed with such immune checkpoint therapy can follow a different pattern from that seen with cytotoxic chemotherapy or targeted therapy and may continue after therapy is discontinued. In addition, the toxicities that are associated with anti–CTLA-4 therapy may differ from those of conventional therapies and consist of inflammatory events in parts of the body that do not contain cancerous cells. Early recognition of these inflammatory events and intervention is important, and the identification of predictive biomarkers continues to be an unfulfilled need in the field of immunotherapy. Combinatorial approaches with targeted therapies, radiation therapy, chemotherapy, or other immune checkpoint agonists/antagonists have the potential to increase the efficacy of CTLA-4 blockade.     

PD-1 checkpoint blockade alone or combined PD-1 and CTLA-4 blockade as immunotherapy for lung cancer?

Introduction: Signaling through T-cell surface, an immune checkpoint protein such as PD-1 or CTLA-4 helps dampen or terminate unwanted immune responses. Blocking a single immune checkpoint or multiple checkpoints simultaneously can generate anti-tumor activity against a variety of cancers including lung cancer.

Area covered: This review highlights the results of recent clinical studies of single or combination checkpoint inhibitor immunotherapy in non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The authors discuss pembrolizumab and pembrolizumab plus ipilimumab, durvalumab and durvalumab plus tremelimumab, nivolumab and nivolumab plus ipilimumab for NSCLC as well as nivolumab and nivolumab plus ipilimumab for SCLC.

Expert opinion: Available data suggest that, in both metastatic NSCLC and SCLC, combined PD-1 and CTLA-4 blockade may produce a higher tumor response rate than PD-1 blockade alone. Nevertheless, combination therapy is associated with an increased toxicity. Several larger-scale studies are currently ongoing. For checkpoint inhibitor immunotherapy in SCLC and NSCLC, combination therapy is associated with a higher incidence of toxicities than single therapy; however, it appears to help increase tumor response rate. The increased response rate, if confirmed in larger scale studies, will likely make combination therapy another useful therapeutic approach for lung cancer.     

Clinical CAR-T Cell and Oncolytic Virotherapy for Cancer Treatment

Immunotherapy has recently garnered success with the induction of clinical responses in tumors, which are traditionally associated with poor outcomes. Chimeric antigen receptor T (CAR-T) cells and oncolytic viruses (OVs) have emerged as promising cancer immunotherapy agents. Herein, we provide an overview of the current clinical status of CAR-T cell and OV therapies. While preclinical studies have demonstrated curative potential, the benefit of CAR-T cells and OVs as single-agent treatments remains limited to a subset of patients. Combinations of different targeted therapies may be required to achieve efficient, durable responses against heterogeneous tumors, as well as the microenvironment. Using a combinatorial approach to take advantage of the unique features of CAR-T cells and OVs with other treatments can produce additive therapeutic effects. This review also discusses ongoing clinical evaluations of these combination strategies for improved outcomes in treatment of resistant malignancies.

Chimeric antigen receptor modified T (CAR-T) cell and oncolytic viruses (OVs) are promising cancer immunotherapy platforms. Herein, Watanabe and colleagues review how these cancer gene therapy agents achieve clinical responses in tumors traditionally associated with poor outcomes and discusses emerging combinatorial strategies with radiotherapy/chemotherapy and other immunotherapies to improve clinical outcomes.     

Immune Checkpoint Inhibitors in Lung Cancer and Melanoma

ObjectiveTo provide a synopsis of immune checkpoint inhibition in solid tumors with a focus on lung cancer and melanoma for the oncology nurse.Data SourcesA literature search was conducted from 2012 to the present using key search terms including: ipilimumab, pembrolizumab, nivolumab, durvalumab, atezolizumab, immune checkpoint inhibitor, NSCLC or SCLC, melanoma, incidence, toxicity, and immune-related adverse events (irAEs).ConclusionImmune checkpoint inhibition has caused a pivotal shift in the treatment of melanoma and lung cancer. Additionally, it has supported the use of immunotherapy as a modality and pillar of cancer treatment. The interdisciplinary team plays an integral role in facilitating patients’ understanding of their treatment modality, symptom management, and guidance through their cancer journey. As more research continues in various tumor types to understand how immune-modulated agents can impact tumor burden, disease control, and quality of life, it is hoped that more patients will have access to these therapies.Implications for Nursing PracticePatient safety is paramount and nurses are aligned to educate, assess, and guide patients during immune checkpoint inhibitor therapy. Developing a rapport and relationship that is based on trust and open communication are vital for helping patients adhere to therapy and safely navigate symptom reporting at the onset of symptoms.     

Combination therapy with oncolytic viruses and immune checkpoint inhibitors

ABSTRACT

Introduction: Immune checkpoint inhibitors (ICI) have dramatically improved the outcome for cancer patients across multiple tumor types. However the response rates to ICI monotherapy remain relatively low, in part due to some tumors cultivating an inherently ‘cold’ immune microenvironment. Oncolytic viruses (OV) have the capability to promote a ‘hotter’ immune microenvironment which can improve the efficacy of ICI.

Areas covered: In this article we conducted a literature search through Pubmed/Medline to identify relevant articles in both the pre-clinical and clinical settings for combining OVs with ICIs and discuss the impact of this approach on treatment as well as changes within the tumor microenvironment. We also explore the future directions of this novel combination strategy.

Expert opinion: The imminent results of the Phase 3 study combining pembrolizumab with or without T-Vec injection are eagerly awaited. OV/ICI combinations remain one of the most promising avenues to explore in the success of cancer immunotherapy.     

Personalized Immuno-Oncology

Cancer immunotherapy, which aims to control the immune system to eradicate cancer cells and prevent their spread, needs to be personalized because anticancer immune responses can be inhibited in several ways that vary from patient to patient. Cancer immunotherapy includes pharmaceuticals such as immune checkpoint inhibitors and monoclonal antibodies (MAbs) as well as cell therapy, immunogene therapy, and vaccines. Combination of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) drugs with other immunotherapy drugs, for example, antibody-drug conjugates, as well as combination of PD-1/PD-L1 drugs with other therapies, for example, chemotherapy and radiation therapy, are being explored. Biomarkers are important for predicting the response to immunotherapy. Molecular diagnostics and sequencing are important technologies for guiding treatment in immuno-oncology. Genomic profiling of tumor mutational burden may enhance the predictive utility of PD-L1 expression and facilitate personalized combination immunotherapy. Optimization of personalized immuno-oncology requires integration of several technologies and selection of those best suited for an individual patient. Advances in immuno-oncology are also attributed to technologies for targeted delivery of anticancer therapeutics such as antigen-capturing nanoparticles for precision targeting and selective delivery. A breakthrough in cell therapy of cancer is a chimeric antigen receptors-T cell, which combines the antigen-binding site of a MAb with the signal activating machinery of a T cell, freeing antigen recognition from major histocompatibility complex restriction. Gene-editing tools such as clustered regularly interspaced short palindromic repeats have a promising application for removing alloreactivity and decreasing immunogenicity of third-party T cells. In conclusion, personalized immuno-oncology is one of the most promising approaches to management of cancer.     

Treatment of recurrent hepatocellular carcinoma following liver resection,ablation or liver transplantation

Hepatocellular carcinoma(HCC) is the most common primary liver malignancy and causes one third of cancer related deaths world-wide. Approximately one third of patients with HCC are eligible for curative treatments that include hepatic resection, liver transplantation or imaging guided tumor ablation. Recurrence rates after primary therapy depends on tumor biology and pre-treatment tumor burden with early recurrence rates ranging from 30%-80% following surgical resection and ablation. HCC recurs ...     

Inhibiting DNA methylation improves antitumor immunity in ovarian cancer

Cancer cells resist the immune response in a process known as immune editing or immune evasion. Therapies that target the immune system have revolutionized cancer treatment; however, immunotherapies have been ineffective for the majority of ovarian cancer cases. In this issue of the JCI, Chen, Xie, et al. hypothesized that hypomethylating agent (HMA) treatment would induce antitumor immunity to sensitize patients with ovarian cancer to anti-PD-1 immunotherapy. The authors performed a phase II clinical trial to test the combination of guadecitabine, a second-generation HMA, along with pembrolizumab, an immune checkpoint inhibitor of PD-1. The trial included a group of 35 patients with platinum-resistant ovarian cancer. While the clinical benefit from the combined HMA plus immune checkpoint blockade regimen was lower than hoped, the correlate analyses gave important information about which patients with ovarian cancer may be more likely to respond to immune therapy.     

Induced pluripotent stem cells as a novel cancer vaccine

ABSTRACT

Introduction: Although many current cancer therapies are effective, the mortality rate globally is unacceptably high. Cancer remains the second leading cause of death worldwide after heart disease and has caused nearly 10 million deaths in 2018. Additionally, current preventive therapies for cancer are underdeveloped, undermining the quality of life of high-risk individuals. Therefore, new treatment options for targeting cancer are urgently needed. In a recent study, researchers adopted an autologous iPSC-based vaccine to present a broad spectrum of tumor antigens to the immune system and succeeded in orchestrating a strong prophylactic immunity towards multiple types of cancer in mice.

Areas covered: In this review, we provide an overview of how cancer develops, the role of immune surveillance in cancer progression, the current status and challenges of cancer immunotherapy as well as the genetic overlap between pluripotent stem cells and cancer cells. Finally, we discuss the rationale for an autologous iPSC-based vaccine and its applications in murine cancer models.

Expert opinion: The autologous iPSC-based vaccine is a promising preventive and therapeutic strategy for fighting various types of cancers. Continuing efforts and clinical/translational follow-up studies may bring an autologous iPSC-based cancer vaccination approach from bench to bedside.     

Immune checkpoint blockade as a potential therapeutic target in non-small cell lung cancer

ABSTRACT

Introduction: The recent emergence of immune checkpoint blockade therapy and the progression of immunobiology in cancer have spurred an increasing interest in the immunotherapy for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs), designed to directly target immune inhibitory molecules, have demonstrated efficacy in the treatment of patients with advanced NSCLC.

Areas covered: In the present article, the authors summarize the mechanism, efficacy and safety of major ICIs for the treatment of advanced or metastatic NSCLC. Combinations of different ICIs or conventional therapy and/or targeted agents for NSCLC treatment in clinical trials are also updated. In addition, immune-related adverse events and the roles of inhibitory immune checkpoint molecules as potential biomarkers in the immune checkpoint blockade therapy for NSCLC are emphatically elucidated.

Expert opinion: Immunotherapies targeting the immune checkpoint pathways have shown potential to generate durable responses and improve survival for NSCLC patients. Although the toxicity profile of this immunotherapy is manageable, immune-related adverse events and drug resistance may cause therapeutic failure. Therefore, a better understanding of the mechanisms underpinning its function and the potential side effects of ICIs, as well as the identification of predictive biomarkers for patient selection are essential.