Immune alterations and emerging immunotherapeutic approaches in lung cancer

INTRODUCTION: Subjects with lung cancer were shown to present a variety of immune abnormalities including cellular immune dysfunction, cytokine alterations, and antigen presentation defects. As discouraging results are commonly seen with the existing therapies in lung cancer, more innovative treatment strategies are needed. AREAS COVERED: The authors review comprehensively the immune abnormalities in individuals with lung cancer, describe the lung cancer immunotherapy candidates that are most advanced in their clinical development, and summarize recent data from clinical trials of these agents. Expert OPINION: Enhancing the immune system represents an appealing avenue for lung cancer therapy. Several immunomodulating agents have activity in this regard including ipilimumab, a monoclonal antibody against the CTLA-4, and talactoferrin, a dendritic cell activator. In addition, a significant activity was shown with belagenpumatucel-L, a whole-cell-based vaccine that blocks the action of TGF-β2. Other promising vaccines are protein-specific vaccines against tumor antigens such as MAGE-A3, EGF, and MUC1. Although some of these immunotherapies may have lackluster performance as single agents in advanced disease, more impressive results are seen in combination with chemotherapy agents. Given their proven activity in lung cancer, these immunotherapies may soon become a powerful addition to the oncologist's toolbox.     

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.     

Immune alterations and emerging immunotherapeutic approaches in lung cancer

Introduction: Subjects with lung cancer were shown to present a variety of immune abnormalities including cellular immune dysfunction, cytokine alterations, and antigen presentation defects. As discouraging results are commonly seen with the existing therapies in lung cancer, more innovative treatment strategies are needed.

Areas covered: The authors review comprehensively the immune abnormalities in individuals with lung cancer, describe the lung cancer immunotherapy candidates that are most advanced in their clinical development, and summarize recent data from clinical trials of these agents.

Expert opinion: Enhancing the immune system represents an appealing avenue for lung cancer therapy. Several immunomodulating agents have activity in this regard including ipilimumab, a monoclonal antibody against the CTLA-4, and talactoferrin, a dendritic cell activator. In addition, a significant activity was shown with belagenpumatucel-L, a whole-cell-based vaccine that blocks the action of TGF-β2. Other promising vaccines are protein-specific vaccines against tumor antigens such as MAGE-A3, EGF, and MUC1. Although some of these immunotherapies may have lackluster performance as single agents in advanced disease, more impressive results are seen in combination with chemotherapy agents. Given their proven activity in lung cancer, these immunotherapies may soon become a powerful addition to the oncologist's toolbox.     

Current knowledge of Ipilimumab and its use in treating non-small cell lung cancer

Introduction: The systemic treatment of non-small cell lung cancer (NSCLC) has changed dramatically with the identification of actionable mutations and the use of targeted agents. Unfortunately, many tumors will acquire resistance and >75% of NSCLC cases lack for an actionable gene aberration. In this setting, immunotherapy rises as effective therapeutic where immune checkpoint inhibitors have entered or are entering the market in many neoplasms, including NSCLC. Ipilimumab is a monoclonal antibody targeting CTLA-4, promoting T-cell activation and its subsequent anti-tumoral immune effect. Ipilimumab might have a very important role in NSCLC as it does in melanoma because of its synergistic effect with PD-1/PDL-1 inhibitors.

Areas covered: We summarize current results of clinical studies of ipilimumab for efficacy and safety in NSCLC and also the current knowledge about potential biomarkers for its efficacy.

Expert Opinion: Combined use of PD-1/PDL-1 and anti-CTL4 inhibitors increases the efficacy against NSCLC and it is a very promising approach not only in NSCLC but also in small cell lung cancer (SCLC) for first or second-line therapy. It’s very important to identify biomarkers that can better select the population of patients that benefit the most with these checkpoint inhibitors.     

Ipilimumab in the treatment of melanoma

INTRODUCTION: Recent advances in the understanding of the complex cellular mechanisms regulating cancer immunity have led to new strategies in the development of cancer immunotherapy. Targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), a key negative regulator of immune activity, with the monoclonal antibody ipilimumab has shown promising clinical benefit in patients with advanced or metastatic melanoma. AREAS COVERED: This review illustrates the pharmacology of ipilimumab and highlights the clinical evidence regarding its efficacy and safety in patients with advanced or metastatic melanoma. The unique clinical response pattern and class-specific immune-related toxicity profile associated with this biologic agent are also characterized. A literature search using PubMed database was undertaken using search words ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4, melanoma and tumor immunity barrier. EXPERT OPINION: Ipilimumab, approved by the FDA for patients with advanced or metastatic melanoma based on the overall survival benefit when compared with a peptide vaccine, is a major breakthrough in the treatment of melanoma. While clinicians are embracing this innovative biologic agent, special attentions in patient selection, class-specific immune-related toxicities and their management as well as treatment response evaluation are needed.     

Atypical clinical response patterns to ipilimumab

Patients with advanced melanoma have few treatment options, and survival is poor. However, improved understanding of how the immune system interacts with cancer has led to the development of novel therapies. Ipilimumab is a monoclonal antibody that inhibits cytotoxic T-lymphocyte antigen-4 (CTLA-4), a key negative regulator of host T-cell responses. This article presents cases of patients receiving ipilimumab in clinical trials along with a discussion of their significance and relevance to nursing practice. The patients showed different response patterns to ipilimumab and also had various typical immune-related adverse events (irAEs), which were managed successfully. The atypical response patterns produced by ipilimumab likely reflect its mechanism of action, which requires time for the immune system to mount an effective antitumor response. Meanwhile, lesions may appear to enlarge as a consequence of enhanced T-cell infiltration, although this may not necessarily be true disease progression. Patients receiving ipilimumab may respond very differently compared to how they might react to chemotherapy. Responses can take weeks or months to develop; therefore, clinicians should not terminate treatment prematurely, providing the patient's condition allows for continuation. Early recognition of irAEs combined with prompt management will ensure that events are more likely to resolve without serious consequences.     

The monoclonal antibody to cytotoxic T lymphocyte antigen 4, ipilimumab (MDX-010), a novel treatment strategy in cancer management

Background: Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an inhibitory regulator of the T cell immune response against tumor cells. Ipilimumab (MDX-010) is a monoclonal antibody directed against CTLA-4. Objective: To describe the basic mechanism of ipilimumab and discuss data available to date with regards to its safety and efficacy profile. Methods: Data from clinical trials including abstracts were reviewed using the PubMed Database as well as the American Society of Clinical Oncology Abstract Database. Conclusions: CTLA-4 inhibition with a monoclonal antibody is usually well tolerated and has efficacy as a therapeutic agent in a variety of cancers. The most clinically important toxicities have been related to autoimmune events, and guidelines for treatment of these effects are now available. Preliminary results indicate that therapy with ipilimumab leads to durable responses. Pharmacokinetics and pharmacodynamics are different from those of traditional chemotherapy agents. Phase III studies are currently underway for melanoma.     

Update on anti-CTLA-4 antibodies in clinical trials

Breaking immune tolerance against tumor self-antigens is presently an area of intense research in the design of cancer therapies. One possible method to enhance immune system activation against tumor antigens is by blocking the inhibitory co-stimulatory signals mediated by cytotoxic T lymphocyte antigen 4, (CTLA-4) expressed on activated T cells. The fully human monoclonal antibodies that are directed against human CTLA-4, ipilimumab (Medarex/Bristol-Myers Squibb) and CP-675,206 (Pfizer/Abgenix, now Amgen), have demonstrated activity against metastatic melanoma, hormone refractory prostate cancer and other malignancies. They have also uncovered unusual immune-related adverse events manifesting as self-limiting inflammatory reactions of the bowel, skin and pituitary. This article reviews preclinical development and data generated from Phase I, II and III studies with regard to the end points reported and immune-related adverse events.     

Update on anti-CTLA-4 antibodies in clinical trials

Breaking immune tolerance against tumor self-antigens is presently an area of intense research in the design of cancer therapies. One possible method to enhance immune system activation against tumor antigens is by blocking the inhibitory co-stimulatory signals mediated by cytotoxic T lymphocyte antigen 4, (CTLA-4) expressed on activated T cells. The fully human monoclonal antibodies that are directed against human CTLA-4, ipilimumab (Medarex/Bristol-Myers Squibb) and CP-675,206 (Pfizer/Abgenix, now Amgen), have demonstrated activity against metastatic melanoma, hormone refractory prostate cancer and other malignancies. They have also uncovered unusual immune-related adverse events manifesting as self-limiting inflammatory reactions of the bowel, skin and pituitary. This article reviews preclinical development and data generated from Phase I, II and III studies with regard to the end points reported and immune-related adverse events.     

Immune alterations in malignant melanoma and current immunotherapy concepts

Introduction: Malignant melanoma is a highly aggressive, immunogenic tumor that has the ability to modulate the immune system to its own advantage. Patients with melanoma present numerous cellular immune defects and cytokine abnormalities, all leading to suppression of the host anti-tumor immune response. Innovative treatment strategies can be achieved through employing our knowledge of the melanoma-induced immune alterations.

Areas covered: The authors review comprehensively the immune abnormalities in individuals with melanoma, and provide a summary of currently available melanoma immunotherapy agents that are currently on the market or undergoing clinical trials.

Expert opinion: Ipilimumab, a monoclonal antibody directed against the CTLA-4, is one of the current forefront treatment strategies in malignant melanoma. Novel immunomodulating agents have shown clear activity in patients with malignant melanoma. These include anti-PD-1 and anti-PD-1 ligand antibodies that may soon become important items in the anti-melanoma armamentarium. Combinations of different immunotherapy agents, between themselves or with other agents, are currently being studied in an attempt to further enhance the antineoplastic effect in patients with malignant melanoma.     

Diagnostic and therapeutic biomarkers for lung cancer patients

Identification of sensitive biomarkers predictive of diagnosis, prognosis and drug sensitivity could have a clinically significant impact on non-small cell lung cancer (NSCLC) treatment strategies. Recently, molecular-targeted therapies have been developed for NSCLC treatment. NSCLC patients with epidermal growth factor receptor (EGFR) gene mutations have shown a dramatic response to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib. In addition, target therapies against echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein present in approximately 5% of the Japanese patients with adenocarcinomas are currently under development. In this paper, we reviewed diagnostic and therapeutic biomarkers for lung cancer patients.     

Immunotherapy of non-small cell lung cancer: report from an international experts panel meeting of the Italian association of thoracic oncology

ABSTRACT

Introduction: The potential long term survival gain, related to immune adaptability and memory, the potential activity across multiple tumour types through targeting the immune system, and the opportunity for combinations offered by the unique mechanism of actions and safety profile of these new agents, all support the role of immunotherapy in the cancer treatment pathway or paradigm.

Areas covered: The authors discuss the recent advances in the understanding of immunology and antitumor immune responses that have led to the development of new immunotherapies, including monoclonal antibodies that inhibit immune checkpoint pathways, such as Programmed Death-1 (PD-1) and Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4). Currently, two PD-1 inhibitors are available in clinical practice for treatment of advanced non-small cell lung cancer (NSCLC): nivolumab and pembrolizumab.

Expert opinion: Ongoing research will dictate future strategies, including the potential incorporation of immunotherapy in stage dependent treatment settings (early stage locally advanced disease and first line therapy for metastatic disease). Immunotherapy combinations are promising avenues, and careful selection of patients, doses of each agent and information supporting strategies (i.e. concomitant or sequential) is still needed.     

Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy

Cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade with a monoclonal antibody yields durable responses in a subset of cancer patients and has been approved by the FDA as a standard therapy for late-stage melanoma. We recently identified inducible co-stimulator (ICOS) as a crucial player in the antitumor effects of CTLA-4 blockade. We now show that concomitant CTLA-4 blockade and ICOS engagement by tumor cell vaccines engineered to express ICOS ligand enhanced antitumor immune responses in both quantity and quality and significantly improved rejection of established melanoma and prostate cancer in mice. This study provides strong support for the development of combinatorial therapies incorporating anti–CTLA-4 and ICOS engagement.Harnessing T cell responses to eradicate tumors has been difficult in part because of the complexity of regulation of T cell responses. Early T cell activation requires an antigen-specific signal mediated by the TCR plus additional co-stimulatory signals generated by engagement of molecules such as CD28 with their ligands (Harding et al., 1992). CD28 co-stimulation is subject to down-regulation by inhibitory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4; Walunas et al., 1994; Krummel and Allison, 1995). Beginning in 1996, we showed that inhibitory signals mediated by CTLA-4 were responsible for limiting antitumor responses in a series of mouse models because administration of antibodies blocking the interaction of CTLA-4 with its ligands could result in tumor rejection and long-lived immunity (Leach et al., 1996).These preclinical studies led to the generation of antibodies to human CTLA-4, ipilimumab and tremelimumab (Sharma et al., 2011). To date, over 20,000 patients have been treated with these antibodies, the majority receiving ipilimumab. Objective responses have been observed in patients with melanoma, ovarian, prostate, renal cell, and lung cancers. A randomized phase III clinical trial with ipilimumab was reported in 2010, showing a significant increase in survival for patients with advanced melanoma who received ipilimumab therapy (Hodi et al., 2010). Treatment with ipilimumab improved median overall survival by 3.7 mo and ∼23% of treated patients were alive with durable clinic benefit for the 4.5 yr of follow up. Ipilimumab was the first therapy of any kind to show a survival benefit in phase III trials (Hodi et al., 2010; Robert et al., 2011) for patients with advanced melanoma and was approved in March 2011 by the Food and Drug Administration (FDA) as both first and second line therapy for the treatment of patients with advanced melanoma. A recent retrospective study of 177 metastatic melanoma patients from the earliest clinical trials of ipilimumab showed an 88-mo median duration of objective responses (Prieto et al., 2012). And a recent trial of ipilimumab in combination with an antibody to PD-1 (nivolumab) in metastatic melanoma showed an objective response rate of ∼50% (Wolchok et al., 2013).Together these data demonstrate that blockade of inhibitory signals mediated by CTLA-4 can be quite effective against large bulky tumors and metastatic disease. However, there is clearly a need to extend the therapeutic benefit of this treatment to more patients. We have uncovered a novel immune-based strategy that can significantly enhance the efficacy of CTLA-4 blockade.In a presurgical clinical trial in which patients with localized bladder cancer were treated with ipilimumab, the frequency of T cells expressing inducible co-stimulator (ICOS) was significantly increased both in tumor tissues and peripheral blood of patients (Liakou et al., 2008). ICOS is a T cell–specific molecule that belongs to the CD28/CTLA-4 family (Hutloff et al., 1999; Sharpe and Freeman, 2002). ICOS expression is up-regulated upon T cell activation, which is enhanced in the setting of CTLA-4 blockade, thereby leading to a higher frequency of ICOS⁺ T cells detected in cancer patients receiving anti–CTLA-4 therapy, with the ICOS⁺ population containing the bulk of tumor-specific, IFN-γ–producing CD4 T cells (Liakou et al., 2008; Carthon et al., 2010; Vonderheide et al., 2010). In a retrospective study of advanced melanoma patients, we also found a significant correlation between sustained elevation of ICOS⁺ CD4 T cells in the peripheral blood after ipilimumab treatment and increased survival (Carthon et al., 2010). These clinical studies suggested that ICOS might play an important role in the therapeutic effect of anti–CTLA-4. Our finding that mice deficient in ICOS or ICOS ligand (ICOSL) had impaired antitumor responses after treatment with anti–CTLA-4, as compared with wild-type mice, further supported the notion that the ICOS/ICOSL pathway is critical for the therapeutic effect of anti–CTLA-4 (Fu et al., 2011). These data prompted us to investigate the potential benefit of providing additional signal to the ICOS pathway in the setting of CTLA-4 blockade as a strategy to further improve antitumor responses.     

Managing immune-related adverse events to ipilimumab: a nurse's guide

Ipilimumab is a U.S. Food and Drug Administration-approved novel T-cell potentiator that improves survival in metastatic melanoma. Ipilimumab blocks cytotoxic T-lymphocyte antigen-4, a negative regulator of the immune response, thus promoting T-cell activation and prolonging a patient's antitumor response. However, that action may produce a mechanism-related spectrum of immune-related adverse events (irAEs), which can become severe and life-threatening if left unrecognized and untreated. This article describes the clinical properties of ipilimumab, specifically in regard to its unique profile of irAEs. Guidelines to manage irAEs are reviewed with a particular emphasis on the contribution of nurses to patient care and education. The nurse's role in facilitating communication among the oncology team, primary practice team, patients, and caregivers is fundamental to early recognition and effective management of irAEs so that patients can continue on therapy. As a regular, ongoing presence in patient care, the oncology nurse is well placed to deliver information, assess patients' understanding of that information, and support them through their cancer experience. Checklists of irAE symptoms may be useful for patients and nurses alike. In addition, education on ipilimumab's mechanism of action and how it contributes to irAEs should form an integral part of the patient treatment plan.     

Intralesional and systemic immunotherapy for metastatic melanoma

ABSTRACT

Introduction: Immunotherapy has revolutionized the treatment of metastatic melanoma and dramatically improved patient outcomes. Ipilimumab, an inhibitor of cytotoxic T-lymphocyte antigen-4 (CTLA-4), was the first immunotherapeutic agent to demonstrate improved survival in advanced melanoma. More recently, other immune checkpoint inhibitors, including the programmed death-1 (PD-1) inhibitors pembrolizumab and nivolumab, have demonstrated efficacy in locally advanced unresectable and metastatic melanoma. In addition to systemically delivered immunotherapies, intralesional therapies such as talimogene laherparepvec (TVEC) play an important role in the treatment of locoregionally advanced and metastatic melanoma.

Areas covered: This review provides an overview of the mechanisms behind immune checkpoint inhibitors. Clinical evidence of their efficacy is presented and discussion of new patterns of response and associated immune related adverse events associated with immunotherapy are provided.

Expert opinion: Treatment options for locally advanced and metastatic melanoma are expanding with new developments in immunotherapy and immune checkpoint inhibitors. The utility of these novel therapies in the adjuvant setting is currently being explored. The ideal treatment of metastatic melanoma continues to be multimodal, combining systemic treatments, intralesional and regional therapies, surgery and radiotherapy to achieve optimal outcomes.     

Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is a highly immunogenic neoplasm, and cytokine-based immunotherapies have been used for decades with limited success. In recent years, antibody-based immunotherapies targeting immune checkpoint receptors PD-1 and CTLA-4 have demonstrated clinical efficacy in metastatic RCC (mRCC) patients, leading to FDA approval of the combination of nivolumab and ipilimumab in treatment-naïve patients with intermediate- or poor-risk disease in April 2018.

Areas covered: The pharmacodynamics and pharmacokinetics of nivolumab and ipilimumab are reviewed. Clinical safety and efficacy results from pivotal phase I and III trials of the combination of nivolumab plus ipilimumab in mRCC are summarized, and the combination is reviewed in the context of other available systemic therapies for RCC. Ongoing clinical studies involving the combination of nivolumab plus ipilimumab in RCC are discussed.

Expert opinion: The combination of nivolumab and ipilimumab has demonstrated superior efficacy for treatment-naïve patients with intermediate- and poor-risk mRCC with clear cell histology and is likely to replace anti-angiogenic therapies as the treatment-of-choice in this patient population in the United States. Development of additional combination strategies, novel trial designs, and predictive biomarkers of response will be important to further optimize therapeutic selection and clinical outcomes.     

晚期非小细胞肺癌免疫治疗进展

肺癌是我国最常见的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)约占85%,且大部分NSCLC患者在确诊时疾病已进展至晚期,病死率较高。近年来,临床对于晚期NSCLC的治疗已从传统的手术治疗、化学治疗、放射治疗、靶向治疗走向了免疫治疗。免疫检查点抑制剂(ICIs)治疗晚期NSCLC体现出了良好的抗肿瘤活性,尤其体现在细胞毒性T淋巴细胞相关抗原-4(CTLA-4)、程序性死亡受体-1(PD-1)、程序性死亡配体-1(PD-L1)抑制剂。基于此,本文将重点综述CTLA-4、PD-1、PD-L1抑制剂在晚期NSCLC中的治疗进展,以期提高患者的临床获益率,为临床选择合理治疗方案提供参考。     

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.     

Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma

Ipilimumab, a fully human monoclonal antibody, which blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in 2 phase III trials of patients with advanced melanoma. To gain an understanding of its mechanism of action, the effects of ipilimumab on T-cell populations and on humoral immune responses were studied in patients with advanced melanoma from 2 phase II trials. Antibody levels against 5 tumor antigens were assessed at baseline and up to 12 weeks after ipilimumab treatment. Serologic reactivity to the cancer-testis antigen NY-ESO-1 increased by at least 5-fold at week 12 of treatment in 10% to 13% of patients. Increased antibody levels were also observed to the tumor antigens Melan-A, MAGE-A4, SSX2, and p53. Immunocompetence was evaluated with tetanus boosters administered before ipilimumab and pneumococcal and influenza vaccines given 5 days after ipilimumab treatment. At week 7, most patients who received ipilimumab and vaccine showed greater humoral responses relative to baseline titers. For peripheral T-cell populations, statistically significant increases in the percent of activated (HLA-DR) CD4 and CD8 T cells with concomitant decreases in naive CD4 and CD8 T cells were observed after ipilimumab treatment. These changes were evident by week 4 of treatment. Increases were also observed in central memory, effector memory, and activated ICOS CD4 T cells, but not in ICOS CD8 T cells or in FoxP3 CD4 regulatory T cells. These results suggest that ipilimumab can enhance immune responses mediated by different T-cell populations, and humoral immunity, in melanoma patients.     

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.