Role Of Immune Checkpoint Inhibitors Research Articles

Role of immune checkpoint inhibitors and novel immunotherapies in uveal melanoma.

Uveal melanoma (UM) is one of the rare malignancies, which can be lethal despite local treatment. Treatment options available now can control UM in early stages, but once it metastasized to distant organs especially liver, prognosis is poor. Immune checkpoint inhibitors (ICIs) are the new revolutionary treatment in management of metastatic cutaneous melanoma. UM and cutaneous melanoma are similar as both of them derived from melanocytes but in terms of mutational load and expression of antigens they are distinct. In most of clinical trials of melanoma, UM patients were excluded and up till now there are only few studies regarding role of ICIs in metastatic UM. Most of these studies showed poor outcome and low survival benefit. Currently, research is going on combinational therapies and novel immunotherapy options. Here in this article we will discuss results of studies regarding ICIs in UM, ongoing trials and new immunotherapeutic options of UM.

Immune Checkpoint Inhibitors in Pediatric Solid Tumors: Status in 2018.

Checkpoint inhibitors have transformed the treatment of cancer in adults. This class of drugs has demonstrated encouraging results in various malignancies such as metastatic melanoma, bladder cancer, renal cancer, and non-small cell lung carcinoma. However, researchers have only begun investigating the effectiveness and tolerability of checkpoint inhibitors in pediatric patients. We conducted a review of PubMed indexed literature and clinicaltrials.gov using combinations of the keywords checkpoint, inhibitor, pediatric, CTLA-4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed cell death-1), and PD-L1 (programmed cell death receptor-1 ligand) to find every recently completed and ongoing trial evaluating checkpoint inhibitors in patients younger than 21 years old. Pertinent articles and clinical trials discussing the role of immune checkpoint inhibitors in the pediatric population were selected for final analysis and manuscript citation. This review presents an overview of the cellular mechanisms involved in checkpoint inhibition and of studies evaluating checkpoint inhibitors in humans. The review also details results and side effects from studies conducted with pediatric patients, current pediatric clinical trials, and future implications. Immune checkpoint inhibitors have the potential to further therapeutic advances in pediatric oncology; however, we need more clinical trials and combination drug strategies targeted toward pediatric cancers.

The role of immune checkpoint inhibitors in non-small cell lung cancer

Lung cancer is the leading cause of cancer-related mortality worldwide. Historically, cytotoxic chemotherapy was the primary treatment. Many advances have been made in the treatment of advanced non-small cell lung cancer (NSCLC) over the past decade, including improved targeted therapies and the development of immunotherapy. Immune checkpoint inhibitors have emerged as the primary immunotherapy in NSCLC and have changed the treatment paradigm for advanced disease. These agents are also starting to be utilized in earlier stages of lung cancer. We review the mechanism of action and utilization of immune checkpoint inhibitors in the treatment of locally advanced and advanced NSCLC.

Role of immune-checkpoint inhibitors in lung cancer.

Immune checkpoint inhibitors, mainly drugs targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) pathways, represent a remarkable advance in lung cancer treatment. Immune checkpoint inhibitors targeting PD-1 and PD-L1 are approved for the treatment of patients with non-small-cell lung cancer, with impressive clinical activity and durable responses in some patients. This review will summarize the mechanism of action of these drugs, the clinical development of these agents and the current role of these agents in the management of patients with lung cancer. In addition, the review will discuss the role of predictive biomarkers for optimal patient selection for immunotherapy and management of autoimmune side effects of these agents.

Recurrent glioma clinical trial, CheckMate-143: the game is not over yet.

Glioblastoma (GBM) is the most common, and aggressive, primary brain tumor in adults. With a median patient survival of less than two years, GBM represents one of the biggest therapeutic challenges of the modern era. Even with the best available treatment, recurrence rates are nearly 100% and therapeutic options at the time of relapse are extremely limited. Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has provided significant clinical benefits in the treatment of various advanced cancers and represented a promising therapy for primary and recurrent GBM. CheckMate 143 (NCT 02017717) was the first large randomized clinical trial of PD pathway inhibition in the setting of GBM, including a comparison of nivolumab and the anti-VEGF antibody, bevacizumab, in the treatment of recurrent disease. However, preliminary results, recently announced in a WFNOS 2017 abstract, demonstrated a failure of nivolumab to prolong overall survival of patients with recurrent GBM, and this arm of the trial was prematurely closed. In this review, we discuss the basic concepts underlying the rational to target PD pathway in GBM, address implications of using immune checkpoint inhibitors in central nervous system malignancies, provide a rationale for possible reasons contributing to the failure of nivolumab to prolong survival in patients with recurrent disease, and analyze the future role of immune checkpoint inhibitors in the treatment of GBM.

The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy.

e15609 Background: Recent data supports a potentially significant role for immune checkpoint inhibitors in the treatment of gastric cancer. However, there are few data on the clinical implications of immunotherapy markers in gastric signet-ring cell carcinoma (SRCC). We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1 (PD-L1), infiltration by CD3+ T cell, microsatellite instability (MSI), and Epstein-Barr Virus (EBV), and the relationship of each factor to survival in SRCC patients. Methods: SRCC samples from 89 patients were stained by immunohistochemistry to evaluate PD-L1, PD-1, CD3+ T cells, and MSI. EBV was detected by DNA in-situ hybridization. Results: All 89 patients had advanced gastric SRCC (89.9% were stage III, 10.1% were stage IV). All patients received 5-FU-based first-line chemotherapy. PD-L1 and PD-1 were expressed in 40.4% and 18.0% of the patients, respectively. There was a significant correlation between PD-L1 and PD-1 expression (r = 0.363, p < 0.001). There was loss of at least 1 of the 4 DNA mismatch repair (DNA-MMR) gene proteins in 32.6% of samples. However, there was no association between the expression of PD-L1, PD-1 or MSI status to overall survival (OS). Only 1 case out of 89 was EBV positive, with concurrent PD-L1 positivity, a high degree of CD3+ T cell infiltration and MSI. Increased CD3+ T cells numbers was associated with increased PD-1 expression (r = 0.256, p = 0.012) and MSI status (r = 0.208, p = 0.05). High CD3+ T cell infiltration was related to better OS (23.7 months, 95% CI: 19.0-38.0 vs 15.8 months, 95% CI: 13.0-22.0, p = 0.033), but was not an independent prognostic factor for survival after multivariate analysis (HR = 0.68, 95% CI: 0.42-1.10, p = 0.116). Conclusions: CD3+ T cell was more infiltrated in PD-1 positive, tumors with MSI and were associated with better OS, indicating an adaptive immune resistance may be occurring. Further research into the cancer characteristics and immunotherapy markers of the gastric SRCC immune microenvironment may highlight targets for immunotherapy.

The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy.

Recent data supports a potentially significant role for immune checkpoint inhibitors in the treatment of gastric cancer. However, there are few data on the clinical implications of immunotherapy markers in gastric signet-ring cell carcinoma (SRCC). We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1(PD-L1), infiltration by CD3+ T cell, microsatellite instability (MSI), and Epstein-Barr Virus (EBV), and the relationship of each factor to survival in 89 advanced SRCC patients. All patients received 5-FU-based first-line chemotherapy. PD-L1 and PD-1 were expressed in 40.4% and 18.0% of the patients, respectively. There was a significant correlation between PD-L1 and PD-1 expression (r=0.363, p<0.001). There was loss of at least 1 of the 4 DNA mismatch repair (DNA-MMR) gene proteins in 32.6% of samples. Only 1 case out of 89 was EBV positive, with concurrent PD-L1 positivity, a high degree of CD3+ T cell infiltration and MSI. Increased CD3+ T cells numbers was associated with increased PD-1 expression (r=0.256, p=0.012) and MSI status (r=0.208, p=0.049). High CD3+ T cell infiltration was related to better OS (23.7 months, 95% CI: 19.0-38.0 vs 15.8 months, 95% CI: 13.0-22.0, p=0.033), but was not an independent prognostic factor for survival after multivariate analysis (HR=0.68, 95% CI: 0.42-1.10, p=0.116). CD3+ T cell was more infiltrated in PD-1 positive, tumors with MSI and were associated with better OS, indicating an adaptive immune resistance may be occurring. Further research into the cancer immunotherapy markers of SRCC immune microenvironment may highlight targets for immunotherapy.

Immune Checkpoint Inhibitors in Gliomas.

Malignant gliomas result in disproportionately high morbidity and mortality compared with other primary tumors, and progression of disease is inevitable. Novel therapies to improve outcomes are needed and immune checkpoint inhibitors hold significant promise. A limited body of preclinical evidence suggests that checkpoint inhibitors may be effective treatment for gliomas. Biomarkers to identify characteristics of gliomas responsive to these therapies will be essential. These may include mismatch repair deficiency and high mutational load that might be germline, somatic, or acquired after therapy. Evidence on the use of immune checkpoint inhibitors in gliomas is evolving. Clinical trials are underway and results are eagerly awaited. Understanding the role of immune checkpoint inhibitors in combination with other treatment modalities for gliomas is crucial to the improvement of outcomes. The design and conduct of future clinical trials need to account for increasingly complex treatment options.

The Role of Immune Checkpoint Inhibition in the Treatment of Brain Tumors.

The standard of care for malignant gliomas of the brain has changed very little over the last few decades, and does not offer a cure for these rare, but fatal, tumors. The field of immunotherapy has brought potent new drugs into the oncological armamentarium, and is becoming recognized as a potentially important arm in the treatment of glioblastoma for adults. Immune checkpoints are inhibitory receptors found on immune cells that, when stimulated, cause those immune cells to become quiescent. While this is a natural mechanism to prevent excessive inflammatory damage and autoimmunity in otherwise healthy tissues, cancer cells may utilize this process to grow in the absence of targeted immune destruction. Antibodies derived to block the stimulation of these negative checkpoints, allowing immune cells to remain activated and undergo effector function, are a growing area of immunotherapy. These therapies have seen much success in both the preclinical and clinical arenas for various tumors, particularly melanoma and nonsmall-cell lung cancer. Multiple clinical trials are underway to determine if these drugs have efficacy in glioblastoma. Here, we review the current evidence, from early preclinical data to lessons learned from clinical trials outside of glioblastoma, to assess the potential of immune checkpoint inhibition in the treatment of brain tumors and discuss how this therapy may be implemented with the present standard of care.

Current Management of Refractory Germ Cell Tumors and Future Directions.

We review current management strategies for patients with relapsed and refractory germ cell tumors (GCTs), defined as relapsed or persistent disease following at least one line of cisplatin-based chemotherapy. Additionally, we discuss future directions in the management of these patients. Recent studies involving targeted therapies have been disappointing. Nevertheless, studies of the management of refractory germ cell cancer are ongoing, with a focus on optimal utilization of high-dose chemotherapy and autologous stem cell transplant, as well as the role of immune checkpoint inhibitors in refractory germ cell tumors. Studies aiming to identify those patients who may benefit from more intensive treatment up front to prevent the development of refractory disease are also in progress. Testicular germ cell tumors are among the most curable of all solid tumor malignancies, with cure being possible even in the refractory, metastatic setting. Treatment of refractory disease remains a challenging clinical scenario, but potentially practice changing studies are ongoing.

Update on immune checkpoint inhibitors in gynecological cancers.

In recent years, progress in our understanding of immune-modulatory signaling pathways in immune cells and the tumor microenvironment (TME) has led to rejuvenated interest in cancer immunotherapy. In particular, immunotherapy targeting the immune checkpoint receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell-death 1 (PD-1), and programmed cell-death ligand 1 (PD-L1) have demonstrated clinical activity in a wide variety of tumors, including gynecological cancers. This review will focus on the emerging clinical data on the therapeutic role of immune checkpoint inhibitors, and potential strategies to enhance the efficacy of this class of compounds, in the context of gynecological cancers. It is anticipated that future biomarker-directed clinical trials will provide further insights into the mechanisms underlying response and resistance to immunotherapy, and help guide our approach to designing therapeutic combinations that have the potential to enhance the benefit of immunotherapy in patients with gynecologic cancers.

The Role of Checkpoint Inhibition in Non-Small Cell Lung Cancer.

The development of immune checkpoint inhibitors has revolutionized the treatment of cancer. Their use in non-small cell lung cancer (NSCLC) remains in its infancy, but rapid progress has been made in treating metastatic NSCLC. This article outlines the role of immune checkpoint inhibitors in the treatment of malignancy and reviews clinical trials of novel immunotherapies in the setting of metastatic NSCLC. Traditional chemotherapy with a platinum-based doublet has long been the backbone in the treatment of metastatic NSCLC. While the treatment of NSCLC can be targeted to specific mutations such as epidermal growth factor receptor, these subgroups are rare. The development of immunotherapy has expanded the treatment options for patients who have failed initial chemotherapy. Additionally, new studies have shown positive results for the use of immunotherapy in the first-line setting under certain conditions, allowing pembrolizumab to become the first immunotherapy to be approved in the first-line setting. Treatment of NSCLC is constantly changing, and new immune checkpoint inhibitors have shown promising results. Clinical trials are examining their use in the adjuvant setting and in combination with other therapies, and these combination therapies have the potential to show even greater benefits and broader applications than the individual drugs themselves.

The emerging role of immune checkpoint inhibition in malignant lymphoma.

To evade elimination by the host immune system, tumor cells commonly exploit physiological immune checkpoint pathways, restraining efficient anti-tumor immune cell function. Growing understanding of the complex dialog between tumor cells and their microenvironment contributed to the development of immune checkpoint inhibitors. This innovative strategy has demonstrated paradigm-shifting clinical activity in various malignancies. Antibodies targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein-4 are also being investigated in lymphoid malignancies with varying levels of activity and a favorable toxicity profile. To date, evaluated only in the setting of relapsed or refractory disease, anti-programmed death 1 antibodies such as nivolumab and pembrolizumab show encouraging response rates particularly in classical Hodgkin lymphoma but also in follicular lymphoma and diffuse-large B-cell lymphoma. As the first immune checkpoint inhibitor in lymphoma, nivolumab was approved for the treatment of relapsed or refractory classical Hodgkin lymphoma by the Food and Drug Administration in May 2016. In this review, we assess the role of the pathways involved and potential rationale of checkpoint inhibition in various lymphoid malignancies. In addition to data from current clinical trials, immune-related side effects, potential limitations and future perspectives including promising combinatory approaches with immune checkpoint inhibition are discussed.

The role of immune checkpoint inhibition in the treatment of ovarian cancer

The introduction of immune checkpoint inhibitors has revolutionized treatment of multiple cancers and has bolstered interest in this treatment approach. So far, emerging clinical data show limited clinical efficacy of these agents in ovarian cancer with objective response rates of 10–15% with some durable responses. In this review, we present emerging clinical data of completed trials of immune checkpoint inhibitors and review ongoing studies. In addition we examine the current knowledge of the tumor microenvironment of ovarian cancers with a focus on the significance of PD-L1 expression and tumor-infiltrating lymphocytes on predicting response to immune checkpoint blockade. We evaluate approaches to improve treatment outcomes through the use of predictive biomarkers and patient selection. Finally, we review management considerations including immune related adverse events and response criteria.

Checkpoint Inhibitors in Metastatic EGFR-Mutated Non–Small Cell Lung Cancer—A Meta-Analysis

IntroductionWe performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC. MethodsRandomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation–defined subgroups. We used the fixed-effects inverse variance–weighted method to pool estimates of treatment efficacy. Statistical tests were two sided. ResultsIn the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61–0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58–0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70–1.55, p < 0.81; treatment-mutation interaction p = 0.03). ConclusionIn EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients.

Immunooncology in Urologic Cancers: Current Status

Immune checkpoint inhibitors are establishing itselves as a new systemic treatment option (in addition to chemotherapy and targeted therapy) for metastatic tumours. (Re)activating the immune system, these antibodies may lead to impressive remissions lasting for a long time in some patients. Regarding urological tumours, the anti-PD-1 antibody Nivolumab (Opdivo(®)) has been approved this year for advanced, previously treated renal cell carcinoma. In the United States, Atezolizumab (Tecentriq(®)) has been approved for metastatic urothelial carcinoma after platinum-based chemotherapy. In patients pre-treated with antiangiogenic drugs, Nivolumab has achieved a higher rate of remission (25 vs. 5%) and a 5.4-month increase in overall survival compared with Everolimus. An indirect comparison with chemotherapy demonstrates an increased remission rate (15%) and an increased 1-year survival rate (37%) for urothelial carcinoma after platinum-based chemotherapy with Atezolizumab. The frequency of side-effects resulting from these treatments is comparatively low. However, some patients experience what is called immune-mediated side-effects, which must be recognised and treated in a timely manner. Immune checkpoint inhibitors are being tested in numerous ongoing phase III clinical trials and have the potential to replace current first-line treatment options for metastatic tumours such as urothelial and renal cell carcinoma. These trials are also investigating anti-PD-1/anti-PD-L1 antibodies in combination with CTLA4 immune checkpoint inhibitors or antiangiogenic treatments. Approval trials are also investigating the role of immune checkpoint inhibitors in the adjuvant setting.

Targeting Immune Checkpoints in Hematologic Malignancies.

The use of antibodies that target immune checkpoint molecules on the surface of T-lymphocytes and/or tumor cells has revolutionized our approach to cancer therapy. Cytotoxic-T-lymphocyte antigen (CTLA-4) and programmed cell death protein 1 (PD-1) are the two most commonly targeted immune checkpoint molecules. Although the role of antibodies that target CTLA-4 and PD-1 has been established in solid tumor malignancies and Food and Drug Administration approved for melanoma and non-small cell lung cancer, there remains a desperate need to incorporate immune checkpoint inhibition in hematologic malignancies. Unlike solid tumors, a number of considerations must be addressed to appropriately employ immune checkpoint inhibition in hematologic malignancies. For example, hematologic malignancies frequently obliterate the bone marrow and lymph nodes, which are critical immune organs that must be restored for appropriate response to immune checkpoint inhibition. On the other hand, hematologic malignancies are the quintessential immune responsive tumor type, as proven by the success of allogeneic stem cell transplantation (allo-SCT) in hematologic malignancies. Also, sharing an immune cell lineage, malignant hematologic cells often express immune checkpoint molecules that are absent in solid tumor cells, thereby offering direct targets for immune checkpoint inhibition. A number of clinical trials have demonstrated the potential for immune checkpoint inhibition in hematologic malignancies before and after allo-SCT. The ongoing clinical studies and complimentary immune correlatives are providing a growing body of knowledge regarding the role of immune checkpoint inhibition in hematologic malignancies, which will likely become part of the standard of care for hematologic malignancies.

Immune factors and viral interactions inbraincancer etiology and outcomes, The 2016 Brain Tumor Epidemiology Consortium Meeting report.

The Brain Tumor Epidemiology Consortium (BTEC) is an international consortium that aims to advance development of multicenter and interdisciplinary collaborations that focus on research related to the etiology, outcomes, and prevention of brain tumors. The 17th annual BTEC meeting was held in Barcelona, Spain on June 21 – 23, 2016. The meeting focused on immune and viral factors that influence brain tumor development. Fundamentals of innate and adaptive immunity were reviewed, the role of immune checkpoint inhibitors in primary and secondary brain tumors was addressed, vaccination strategies for glioma treatment were presented, and the potential contribution of immune dysfunction and viruses tropic for glial cells in gliomagenesis was discussed. Further contributions addressed the risk of non-ionizing radiation, molecular and birth characteristics on brain tumor induction/outcomes, and patterns of care and effects of different treatments on brain tumor survival in the real world setting. The next BTEC meeting will be held in June 2017 in Banff, Canada, and will focus on brain tumor epidemiology in the era of precision medicine.

Immune Checkpoint Inhibitors in Older Adults.

Cancer is primarily a disease of older adults. The treatment of advanced stage tumors usually involves the use of systemic agents that may be associated with significant risk of toxicity, especially in older patients. Immune checkpoint inhibitors are newcomers to the oncology world with improved efficacy and better safety profiles when compared to traditional cytotoxic drugs. This makes them an attractive treatment option. While there are no elderly specific trials, this review attempts to look at the current available data from a geriatric oncology perspective. We reviewed data from phase III studies that led to newly approved indications of checkpoint inhibitors in non-small cell lung cancer, melanoma, and renal cell cancer. Data were reviewed with respect to response, survival, and toxicity according to three groups: <65years, 65-75years, and >75years. Current literature does not allow one to draw definitive conclusions regarding the role of immune checkpoint inhibitors in older adults. However, they may offer a potentially less toxic but equally efficacious treatment option for the senior adult oncology patient.

Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis.

BackgroundA better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies.MethodsImmunohistochemical expression of stromal tumor-infiltrating lymphocytes (TILs: CD4, CD8, CTLA4), macrophage/microglial cells (CD68), programmed cell death protein 1 receptor (PD-1), programmed cell death protein 1 receptor ligand (PD-L)1, PD-L2 and glial fibrillary acid protein was assessed in 84 BCBM and their microenvironment.ResultsMedian survival after BCBM excision was 18.3 months (range 0–99). Median number of CD4+, CD8+ TILs and CD68+ was 49, 69 and 76 per 1 mm2, respectively. PD-L1 and PD-L2 expression in BCBM was present in 53 % and 36 % of cases, and was not related to BCBM phenotype. PD-1 expression on TILs correlated positively with CD4+ and CD8+ TILs (r = 0.26 and 0.33), and so did CD68+ (r = 0.23 and 0.27, respectively). In the multivariate analysis, survival after BCBM excision positively correlated with PD-1 expression on TILs (hazard ratio (HR) = 0.3, P = 0.003), CD68+ infiltration (HR = 0.2, P < 0.001), brain radiotherapy (HR = 0.1, P < 0.001), endocrine therapy (HR = 0.1, P < 0.001), and negatively with hormone-receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive phenotype of primary tumor (HR = 2.6, P = 0.01), HER2 expression in BCBM (HR = 4.9, P = 0.01).ConclusionsPD-L1 and PD-L2 expression is a common occurrence in BCBM, irrespective of primary tumor and BCBM phenotype. Favorable prognostic impact of PD-1 expression on TILs suggests a beneficial effect of preexisting immunity and implies a potential therapeutic role of immune checkpoint inhibitors in BCBM.