Immune checkpoint inhibitors for advanced non-small cell lung cancer: emerging sequencing for new treatment targets

Aguiar, Pedro Nazareth; Mello, Ramon Andrade De; Barreto, Carmélia Maria Noia; Perry, Luke A; Penny-Dimri, Jahan C.; Tadokoro, Hakaru; Lopes, Gilberto

doi:10.1136/esmoopen-2017-000200

Cited by 34 publications

(30 citation statements)

References 62 publications

(151 reference statements)

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“…Evidence indicates that checkpoint inhibitor therapy can increase the 5-year survival of patients with advanced non-small-cell lung cancer (unrelated to silica exposure) by fourfold, emphasizing the benefit of such a treatment strategy. 93 , 94 …”

Section: Etiopathogenesis Of Silica-induced Lung Cancermentioning

confidence: 99%

Silicosis and lung cancer: current perspectives

Sato¹,

Shimosato²,

Klinman³

2018

LCTT

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“Silica” refers to crystalline particles formed by the combination of silicon with oxygen. Inhalation of silica particles promotes the development of pulmonary fibrosis that over prolonged periods increases the risk of lung cancer. The International Agency for Research on Cancer (IARC) classified crystalline silica as a human carcinogen in 1997. This categorization was questioned due to 1) the absence of dose–response findings, 2) the presence of confounding variables that complicated interpretation of the data and 3) potential selection bias for compensated silicosis. Yet, recent epidemiologic studies strongly support the conclusion that silica exposure increases the risk of lung cancer in humans independent of confounding factors including cigarette smoke. Based on this evidence, the US Occupational Safety and Health Administration (OSHA) lowered the occupational exposure limit for crystalline silica from 0.1 to 0.05 mg/m3 in 2013. Further supporting the human epidemiologic data, murine models show that chronic silicosis is associated with an increased risk of lung cancer. In animals, the initial inflammation induced by silica exposure is followed by the development of an immunosuppressive microenvironment that supports the growth of lung tumors. This work will review our current knowledge of silica-associated lung cancers, highlighting how recent mechanistic insights support the use of cutting-edge approaches to diagnose and treat silica-related lung cancer.

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Section: Etiopathogenesis Of Silica-induced Lung Cancermentioning

confidence: 99%

Silicosis and lung cancer: current perspectives

Sato¹,

Shimosato²,

Klinman³

2018

LCTT

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“…In this scenario, researchers are looking both at the short-term effects of ICI on the tumor viability (as assessed by histological analysis of the resected tumor), and at the long-term effects of ICIs on disease recurrence rates [ 17 ]. However, as promising as ICIs may seem for disease treatment, it is important to recall the following: (a) the overall response rates to ICI in NSCLC remain relatively low (15–50%); (b) the duration of response to ICIs is relatively limited (12 months) with “cure” remaining an unmet goal; and (c) the side effect profile of ICIs is significant and consequently many patients—especially those who are being treated with more than one ICI—withdraw treatment due to its associated autoimmune symptoms [ 18 , 19 , 20 ].…”

Section: Lung Cancer Staging and Treatmentmentioning

confidence: 99%

CXCR4 Based Therapeutics for Non-Small Cell Lung Cancer (NSCLC)

Wald

2018

JCM

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Lung cancer is the second most common malignancy. Unfortunately, despite advances in multimodality therapeutics for the disease, the overall five-year survival rate among newly diagnosed lung cancer patients remains in the range region of 15%. In addition, although immune checkpoint inhibitors are increasingly being incorporated into lung cancer treatment protocols, the proportion of patients that respond to these agents remains low and the duration of response is often short. Therefore, novel methodologies to enhance the efficacy of immunotherapy in lung cancer are highly desirable. Chemokines are small chemotactic cytokines that interact with their 7 transmembrane G-protein–coupled receptors, to guide immune cell trafficking in the body under both physiologic and pathologic conditions. Tumor cells highjack a small repertoire of the chemokine/chemokine receptor system and utilize it in a manner that benefits local tumor growth and distant spread. The chemokine receptor, CXCR4 is expressed in over 30 types of malignant tumors and, through interaction with its ligand CXCL12, was shown exert pleotropic pro-tumorigenic effects. In this review, the pathologic roles that CXCL12/CXCR4 play in lung cancer propagation are presented. Furthermore, the challenges and potential benefits of incorporating drugs that target CXCL12/CXCR4 into immune-based lung cancer therapeutic protocols are discussed.

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“…Pembrolizumab was already approved as the first-line agent in lung cancer with PDL1 expression of more than 50%. But, pembrolizumab was found effective in only less than half of the patients with a PDL1 expression of more than 50% [8,9]. Checkpoint inhibitors have become first-line therapy for most of the patients with metastatic disease, but there are a lot of controversies regarding ICIs [10].…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Lung Cancer: Role of Biomarkers and Combination Therapies

Maung

Ergin

Javed

et al. 2020

Cureus

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Lung cancer is the leading cause of cancer-related death worldwide, with a poor prognosis. Despite aggressive treatment, progression-free survival (PFS) and overall survival are limited. Recently, various kinds of immune checkpoint inhibitors (ICIs) have emerged for several cancers, targeting PD1, PDL1, and CTLA-4. ICIs have made a significant breakthrough in cancer and revolutionized the management of cancer including lung cancer. However, there are a lot of controversies regarding which group of patients is most suitable to be treated with ICIs in terms of monotherapy, combination, and predictive biomarkers. We reviewed various kinds of studies, such as meta-analysis, randomized control trials, multi-center cohort studies, and case-control studies from PubMed written in English from the last five years. ICIs have significant benefits in the overall survival compared with traditional chemotherapy. Patients with a higher level of PDL1 expression and high tumor mutational burden (TMB) have a higher response rate, and those with EGFR-/ALK-were better than those with EGFR+/ALK+. The patient who responded to immunotherapy completely can still maintain the efficacy after two years of treatment. Neoadjuvant immunotherapy in patients with resectable non-small cell lung cancer resulted in a 45% major pathology response (MPR) and 40% downstaging. Combined therapy (ICIs + chemotherapy) was better than chemotherapy alone, irrespective of PD-L1 expression. A combination of ICIs such as CTLA-4 and PD-1/PD-L1 improved PFS as well. Radiochemotherapy ahead of ICIs is promising as well. However, ICIs combined with EGFR/ALK-TKI (tyrosine kinase inhibitor) are not suggested for the time being. PDL1 expression, TMB, and EGFR/ALK mutations are promising predictive biomarkers. Gut microbiota, galectin-3, and intensity of CD8 cell infiltration are other potential predictive biomarkers. These are very important in the future management of lung cancers as they can prevent unnecessary toxicities and cost of treatment.

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Immune checkpoint inhibitors for advanced non-small cell lung cancer: emerging sequencing for new treatment targets

Cited by 34 publications

References 62 publications

Silicosis and lung cancer: current perspectives

Silicosis and lung cancer: current perspectives

CXCR4 Based Therapeutics for Non-Small Cell Lung Cancer (NSCLC)

Immune Checkpoint Inhibitors in Lung Cancer: Role of Biomarkers and Combination Therapies

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