scholarly journals New strategies in immunotherapy for lung cancer: beyond PD-1/PD-L1

2018 ◽  
Vol 12 ◽  
pp. 175346661879413 ◽  
Author(s):  
Nicolas Villanueva ◽  
Lyudmila Bazhenova
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Treatment Approach ◽  
Checkpoint Inhibitors ◽  
T Cell Response ◽  
Immune Checkpoints ◽  
Effector T Cell ◽  
Programmed Death ◽  
Programmed Death Protein 1 ◽  
New Strategies

Immunotherapy has significantly altered the treatment landscape for many cancers, including non-small cell lung cancer (NSCLC). Currently approved immuno-oncology agents for lung cancer are aimed at the reversal of immune checkpoints, programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1). Although responses to checkpoint inhibitors are encouraging, and in some cases durable, these successes are not universal among all treated patients. In order to optimize our treatment approach utilizing immunotherapy, we must better understand the interaction between cancer and the immune system and evasion mechanisms. In this review, we will provide an overview of the immune system and cancer, and review novel therapies that promote tumor antigen release for immune system detection, activate the effector T-cell response, and reverse inhibitory antitumor signals.

scholarly journals Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

2021 ◽  
Vol 11 ◽  
Author(s):  
Kenneth K. W. To ◽  
Winnie Fong ◽  
William C. S. Cho
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Poor Response ◽  
The Poor ◽  
Programmed Death ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Mutated ◽  
New Strategies

Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

Non–Small Cell Lung Cancer, PD-L1, and the Pathologist

2016 ◽  
Vol 140 (3) ◽  
pp. 249-254 ◽  
Author(s):  
Keith M. Kerr ◽  
Marianne C. Nicolson
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Immune Checkpoints ◽  
Great Promise ◽  
Small Cell Lung ◽  
Programmed Death ◽  
Wide Range

Context Although most primary cancers of the lung carry a heavy mutational load and will potentially present many “nonself” antigens to the immune system, there are a wide range of possible mechanisms for tumors to avoid so-called immune surveillance. One such mechanism is the adoption of immune checkpoints to inhibit the host immune response. Immune checkpoint inhibitors show great promise in the treatment of advanced non–small cell lung cancer. Objective —To discuss the possibility of biomarker selection of patients for these therapies. This is becoming a much debated issue, and the immunohistochemical detection of Programmed Death Ligand 1 (PD-L1), the ligand for the inhibitory Programmed Death receptor 1 (PD-1) checkpoint, is one possible biomarker. Data so far available show some conflicting results, but PD-L1 immunohistochemistry looks likely to be introduced into clinical use for selecting patients for treatment with anti–PD-1 or anti–PD-L1 therapies. Given that there are 4 such drugs rapidly approaching regulatory approval, each with its own independent PD-L1 immunohistochemistry biomarker test, both oncologists and pathologists face some significant challenges. Data Sources Peer-reviewed literature and meeting proceedings, especially during the last 12 months, were used. Conclusions —The biology of PD-1/PD-L1 is complex, the clinical data for these drugs show considerable variation, the selection performance of the PD-L1 biomarker test is not perfect, and the existence of 4 drug/test combinations adds significantly to the problems faced. This article addresses some of the background to this therapeutic problem and discusses some of the issues ahead.

scholarly journals Current trends in the immunotherapy of metastatic and recurrent squamous cell carcinoma of the head and neck

2020 ◽  
Vol 10 (3) ◽  
pp. 41-47
Author(s):  
Yu. V. Kostalanova ◽  
K. A. Ganina ◽  
A. A. Makhonin ◽  
A. G. Gabrielyan
Keyword(s):  
Squamous Cell Carcinoma ◽  
Immune System ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Programmed Death ◽  
Recurrent Squamous Cell Carcinoma

The immune system plays a key role in the development and progression of head and neck squamous cell carcinoma. Understanding the dysregulation and blockage of the immune system of malignant tumors in this location can improve treatment outcomes. A special group is made up of patients who have a widespread process and relapse after chemotherapy with platinum drugs, because they have a very poor prognosis and limitations in the possibilities of further treatment. To date, the most important data relate to drugs acting on the PD-1 (programmed cell death protein 1)/PD-L1 (programmed death ligand 1) immune checkpoints, which are used by the tumor to block the immune system, which have allowed to increase the effectiveness of treatment. The article presents a clinical case demonstrating the effectiveness of the use of checkpoint inhibitors after the use of platinum preparations.

Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

2020 ◽  
Vol 20 (9) ◽  
pp. 720-727
Author(s):  
Jianguo Qiu ◽  
Wei Tang ◽  
Chengyou Du
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Immune Checkpoint ◽  
Graft Rejection ◽  
Checkpoint Inhibitors ◽  
Liver Graft ◽  
Immune Checkpoints ◽  
Term Survival ◽  
Liver Preservation ◽  
Programmed Death

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied. Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT. Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed. Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival. Conclusions: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

scholarly journals Vigorous Premalignancy-specific Effector T Cell Response in the Bone Marrow of Patients with Monoclonal Gammopathy

2003 ◽  
Vol 198 (11) ◽  
pp. 1753-1757 ◽  
Author(s):  
Madhav V. Dhodapkar ◽  
Joseph Krasovsky ◽  
Keren Osman ◽  
Matthew D. Geller
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cell Response ◽  
Direct Evidence ◽  
Human Cancer ◽  
T Cell Response ◽  
Immune Recognition ◽  
Effector T Cell ◽  
Specific Effector

Most approaches targeting the immune system against tumors have focused on patients with established tumors. However, whether the immune system can recognize preneoplastic stages of human cancer is not known. Here we show that patients with preneoplastic gammopathy mount a vigorous T cell response to autologous premalignant cells. This preneoplasia-specific CD4+ and CD8+ T cell response is detected in freshly isolated T cells from the BM. T cells from myeloma marrow lack this tumor-specific rapid effector function. These data provide direct evidence for tumor specific immune recognition in human preneoplasia and suggest a possible role for the immune system in influencing the early growth of transformed cells, long before the development of clinical cancer.

scholarly journals Deubiquitination and Stabilization of PD-L1 by USP21

2021 ◽  
Author(s):  
Shuying Yang ◽  
Youqian Wu ◽  
Huanhuan Yan ◽  
Bing Shan ◽  
Dongheng Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Squamous Cell Carcinoma ◽  
Mass Spectrometry Analysis ◽  
Polyubiquitin Chains ◽  
Spectrometry Analysis ◽  
Protein Levels ◽  
Programmed Death ◽  
Programmed Death Protein 1 ◽  
Novel Strategy

Abstract Background: The immunotherapy for different types of cancers that targeting programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) has highlighted the importance of suppressing specific T cell responses. Recently, several studies have shown that the expression level of PD-L1 in tumor cells is positively correlated with tumor metastasis as well as recurrence rate. The potent effects of post-translational modifications (PTMs) for PD-L1, such as ubiquitination, glycosylation, phosphorylation and palmitoylation, have been reported to be related to immunosuppression. However, the regulation of PD-L1 degradation in cancers is still not well understood. In this paper, we mainly investigate the deubiquitination regulation of PD-L1. Methods: The protein levels of PD-L1 and USP21 were detected by Immunoblotting and immunohistochemistry. The interaction between PD-L1 and USP21 was determined by co-immunoprecipitation. The deubiquitination of PD-L1 was determined by in vitro deubiquitination assay. The deubiquitination sites of PD-L1 were identified by mass spectrometry analysis. The expression of mRNA in target tissues was presented by bioinformatics analysis.Results: Overexpression of USP21 significantly increased PD-L1 abundance and knockdown of USP21 induced degradation of PD-L1. In vitro deubiquitination assay showed that USP21-WT reduced polyubiquitin chains from PD-L1 while USP21-C221A did not. Furthermore, five lysines in intracellular segment of PD-L1 are potential deubiquitin sites and cancer-derived mutations of PD-L1 in Asp276 have the ability to enhance the deubiquitination of PD-L1 mediated by USP21. Finally, we found that USP21 is the frequently amplified deubiquitinase in lung cancer, especially in lung squamous cell carcinoma, and its amplification co-occurs with the upregulation of PD-L1 levels. Moreover, IHC analysis showed stronger staining of PD-L1 and USP21 in lung cancer samples than adjacent tissues. Conclusion: We identified USP21 as a novel deubiquitinase of PD-L1. Hopefully, targeting PD-L1 by inhibiting USP21 might be a potentially novel strategy for the treatment of lung cancer.

scholarly journals Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

2020 ◽  
Author(s):  
Jie Mei ◽  
Yun Cai ◽  
Rui Xu ◽  
Xuejing Yang ◽  
Weijian Zhou ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Survival Data ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Methylation Status ◽  
Low Grade Glioma ◽  
Immune Checkpoints ◽  
Low Grade ◽  
Programmed Death

AbstractBackgroundImmune checkpoints play crucial roles in immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been defined yet.MethodsA total of 514 LGG samples from TCGA dataset containing both PD-1, PD-L1 and PD-L2 expression, DNA methylation, and survival data were enrolled into our study. The clinical significance of PD-1/PD-Ls expression and methylation in LGG were explored. Besides, the correlation between PD-1/PD-Ls expression and methylation with the infiltration levels of tumor-infiltrating immune cells (TIICs) was assessed. Moreover, GO enticement analysis of PD-1/PD-Ls co-expressed genes was performed as well. R 3.6.2 and GraphPad Prism 8 were applied as main tools for the statistical analysis and graphical exhibition.ResultsPD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation status of PD-1/PD-Ls seemed to be various in different LGG subtypes. Besides, upregulated PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with worse survival in LGG patients. In addition, PD-1/PD-Ls expression was revealed to be positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration. Moreover, the PD-1/PDLs correlated gene profiles screening and Gene Ontology (GO) enrichment analysis uncovered that PD-1/PDLs and their positively correlated gene mainly participated in immune response related biological processes.ConclusionsHigh expression and hypo-methylation of PD-1/PD-Ls significantly correlated with unfavorable survival in LGG patients, suggesting LGG patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

scholarly journals Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3504
Author(s):  
Silvia Pesce ◽  
Sara Trabanelli ◽  
Clara Di Vito ◽  
Marco Greppi ◽  
Valentina Obino ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Tissue Damages ◽  
Innate Lymphocytes

Immune checkpoints refer to a plethora of inhibitory pathways of the immune system that play a crucial role in maintaining self-tolerance and in tuning the duration and amplitude of physiological immune responses to minimize collateral tissue damages. The breakdown of this delicate balance leads to pathological conditions, including cancer. Indeed, tumor cells can develop multiple mechanisms to escape from immune system defense, including the activation of immune checkpoint pathways. The development of monoclonal antibodies, targeting inhibitory immune checkpoints, has provided an immense breakthrough in cancer therapy. Immune checkpoint inhibitors (ICI), initially developed to reverse functional exhaustion in T cells, recently emerged as important actors in natural killer (NK)-cell-based immunotherapy. Moreover, the discovery that also helper innate lymphoid cells (ILCs) express inhibitory immune checkpoints, suggests that these molecules might be targeted on ILCs, to modulate their functions in the tumor microenvironment. Recently, other strategies to achieve immune checkpoint blockade have been developed, including miRNA exploiting systems. Herein, we provide an overview of the current knowledge on inhibitory immune checkpoints on NK cells and ILCs and we discuss how to target these innate lymphocytes by ICI in both solid tumors and hematological malignancies.

scholarly journals Challenge of immune-mediated adverse reactions in the emergency department

2019 ◽  
Vol 36 (6) ◽  
pp. 369-377 ◽  
Author(s):  
Gregory A Daniels ◽  
Angela D Guerrera ◽  
Donna Katz ◽  
Jayne Viets-Upchurch
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Adverse Reactions ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
High Dose ◽  
Clear Understanding ◽  
Immune Mediated ◽  
Multiple Drugs

Multiple drugs of a new class of cancer treatments called immune checkpoint inhibitors, which work by enabling the immune system to attack tumour cells, have been approved for a variety of indications in recent years. Immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 and programmed death-1, are part of the normal immune system and regulate immune activation. Treatment with inhibitors of these checkpoints can significantly improve response rates, progression-free survival and overall survival of patients with cancer; it can also result in adverse reactions that present similarly to other conditions. These immune-mediated adverse reactions (IMARs) are most commonly gastrointestinal, respiratory, endocrine or dermatologic. Although patients’ presentations may appear similar to other types of cancer therapy, the underlying causes, and consequently their management, may differ. Prompt recognition is critical because, with appropriate management, most IMARs resolve and patients can continue receiving immune checkpoint inhibitor treatment. Rarely, these IMARs may be life-threatening and escape detection from the usual evaluations in the emergency environment. Given the unusual spectrum and mechanism of IMARs arising from immune checkpoint inhibitors, emergency departmentED staff require a clear understanding of the evaluation of IMARs to enable them to appropriately assess and treat these patients. Treatment of IMARs, most often with high-dose steroids, differs from chemotherapy-related adverse events and when possible should be coordinated with the treating oncologist. This review summarises the ED presentation and management of IMARs arising from immune checkpoint inhibitors and includes recommendations for tools and resources for ED healthcare professionals.

Management of Pneumonitis and Neuropathy in Patients Receiving PD-1–Based Therapy for Non–Small-Cell Lung Cancer

2020 ◽  
Vol 16 (2_suppl) ◽  
pp. 4s-9s ◽  
Author(s):  
Marianne J. Davies ◽  
Anne C. Chiang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Advanced Lung Cancer ◽  
Small Cell Lung ◽  
Case Examples ◽  
Improved Outcomes ◽  
Programmed Death

Immunotherapy with programmed cell death-1 (PD-1) receptor and programmed death ligand 1 (PD-L1) inhibitors has improved outcomes for certain patients with advanced lung cancer. As use of these therapies has expanded in first-line settings, in patients with different histologies, and in combinations with chemotherapeutic and targeted agents, more patients with lung cancer may benefit from these therapies. However, with expanded use comes greater potential exposure to the immune-related adverse events (irAEs) associated with these immune checkpoint inhibitors (ICIs). This article uses two case examples to illustrate the presentation, evaluation, and management of pulmonary and neurologic symptoms in two patients receiving PD-1–based therapy for non–small-cell lung cancer. These cases illustrate the challenges associated with recognizing pneumonitis and neuropathy in patients receiving ICIs for lung cancer. Although pneumonitis and neuropathy are relatively rare irAEs, they can have devastating or even fatal outcomes if not promptly recognized and managed appropriately. Specific use of guideline-based, multidisciplinary management is emphasized, as illustrated in the Immuno-Oncology Essentials Care Step Pathways.

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