Checkpoint Inhibitors In Lung Cancer Research Articles

Understanding Microbiome Effect on Immune Checkpoint Inhibition in Lung Cancer: Placing the Puzzle Pieces Together.

Over the past couple of years, human microbiome has received increasing attention as a regulator and predictor of response to the therapies of various diseases. It is speculated that manipulating gut microbiome can modify response to cancer immunotherapies as well. Through this review, we have critically analyzed our current understanding of gut microbiome as a modulator of immunotherapies in lung cancer, explained conflicting data, evaluated current gaps and extrapolated our present knowledge to generate directions for future investigations.

Abstract A09: Impaired HLA Class I antigen processing and presentation as a mechanism of acquired Rrsistance to immune checkpoint inhibitors in lung cancer

Abstract Immune checkpoint inhibitors (ICIs) including programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) antagonist antibodies for lung tumors mark a new era of cancer therapeutics harnessing a patient’s immune system to induce durable antitumor responses. Despite their impressive activity in some patients, challenges remain as most tumors exhibit primary or acquired resistance (AR) to ICIs, and the biologic mechanisms for resistance are poorly understood. Using a collection of 14 ICI-resistant lung cancer samples, we investigated whether alterations in genes encoding components of the HLA Class I antigen processing and presentation machinery or interferon signaling pathways play a role in AR to PD-1 or PD-L1 antagonistic antibodies. Although we did not detect any recurrent mutations or copy number changes in our AR cohort, we noted one case of an acquired homozygous loss of B2M that resulted in lack of HLA class I expression on the cell surface in both the patient’s tumor sample and the corresponding patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. To test if B2m expression confers sensitivity to ICIs in vivo, we used a CRISPR-mediated approach to knockout B2m in an ICI-sensitive, murine lung cancer cell line and transplanted the cells into syngeneic, immunocompetent mice. We found that the B2m knockout tumors were resistant to ICI therapy in contrast to the wild type tumors. Furthermore, RNA-seq analysis of a subset of the samples in the acquired resistance to ICI cohort revealed an inflammatory tumor microenvironment with significant upregulation of the inhibitory receptors LAG-3 and PD-1 in tumor-infiltrating T cells at ICI resistance. Overall, these findings provide a novel system for the evaluation and screening of candidate genes for their ability to mediate AR to ICIs in vivo. Moreover, they also provide evidence for the disruption of HLA Class I antigen processing and presentation as a mechanism for escape from ICIs in lung cancer and provide information on the immune microenvironment in ICI-resistant tumors. Citation Format: Katherine Hastings, Scott Gettinger, Choi Jungmin, Anna Truini, Ila Datar, Ryan Sowell, Anna Wurtz, Weilai Dong, Guoping Cai, Mary Ann Melnick, Joseph Schlessinger, Sarah Goldberg, Anne Chiang, Ignacio Melero, Jackeline Agorreta, Luis Montuenga, Richard Lifton, Soldano Ferrone, Paula Kavathas, David Rimm, Susan Kaech, Kurt Schalper, Roy Herbst, Katerina Politi. Impaired HLA Class I antigen processing and presentation as a mechanism of acquired Rrsistance to immune checkpoint inhibitors in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A09.

Response to checkpoint inhibition in lung cancer with molecular driver alterations.

e21071Background: Checkpoint inhibitors are widely used in NSCLC. While there is evidence that EGFR mutation driven tumours respond poorly to checkpoint inhibition, little is known about the sensit...

Emerging biomarkers for immune checkpoint inhibition in lung cancer.

Immune checkpoint inhibition with anti-PD-1 therapy has been notably successful in non-small cell lung cancer (NSCLC) and changed standard practice in multiple settings. However, despite some durable benefits seen, the majority of unselected patients with NSCLC fail to respond to checkpoint inhibitors. Patient selection is crucial and will become even more important in the development of combination therapies with immune checkpoint inhibitors. PD-L1 expression by immunohistochemistry (IHC) has emerged as the most commonly used clinical biomarker of response and overall tumor mutational burden (TMB) is being explored as a clinical biomarker. However, both are hampered by being imperfect predictors of response and both can be dynamic during the course of illness. In this review, we will discuss the development of PD-L1 expression as a biomarker as well as the ongoing emergence of other genomic and proteomic markers that can help refine our use of immunotherapies to maximize benefit in the most patients.

Response and adverse events to chemotherapy after prior checkpoint inhibition in lung cancer.

170 Background: Historically, responses to chemotherapy beyond the first line for lung cancer range from 5-10%. The effect of antecedent immunotherapy on the response and reaction to chemotherapy is not well-established, but the immunomodulatory effects of many chemotherapy agents may lead to synergistic effects including both improved responses and unique toxicities. Methods: We reviewed the charts of patients at our institution who received at least one dose of an anti-PD-1 agent (aPD-1) as monotherapy prior to June 1, 2017. Patients with a diagnosis of non-small cell lung cancer or small cell lung cancer who received subsequent chemotherapy were included for analysis. Charts were assessed for response to aPD-1, occurrence of immune-related adverse event (irAE) on aPD1, type of post-aPD-1 (PaPD-1) chemotherapy, PaPD-1 best response to chemotherapy, and occurrence of irAE during PaPD-1 chemotherapy. irAEs were assessed based on treating physician diagnoses. We tested the association between response and treatment characteristics using Fisher’s exact and Wilcoxon rank-sum tests. Results: A total of 40 patients met criteria for inclusion. Histology was NSCLC in 38 (95%) and SCLC in 2 (5%). Median age was 68 and mean number of lines of therapy prior to aPD-1 was 2.00 (95% CI, 1.72-2.28). PaPD-1 chemotherapies included paclitaxel (15%), docetaxel (28%), gemcitabine (23%), docetaxel-ramucirumab (7.5%), pemetrexed (2.5%) and platinum doublet (15%). The disease control rate to PaPD-1 chemotherapy was 35% and the ORR was 15% (0 complete responses, 6 partial responses). The response to PaPD-1 was not higher in taxane-containing regimens than in non-taxane-containing regimens (16% v. 13%, p = 0.99). Four (10%) patients were diagnosed with an irAE during their receipt of PaPD-1 chemotherapy. These PaPD-1 irAEs included dermatitis, colitis, and pneumonitis that responded to steroid therapy and occurred on various chemotherapy agents (gemcitabine, paclitaxel, docetaxel). Conclusions: In lung cancer, the response to chemotherapy beyond first line may be modestly higher when administered after aPD-1 therapy. Immune-related adverse events can occur during chemotherapy administered after aPD-1 therapy has been stopped.

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.

Can radiotherapy potentiate the effectiveness of immune checkpoint inhibitors in lung cancer?

Can radiotherapy potentiate the effectiveness of immune checkpoint inhibitors in lung cancer?

Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Lung Cancer

Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Lung Cancer

Checkpoint Blockade in Lung Cancer and Mesothelioma.

In the last decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors (CPIs), antibodies that unleash the antitumor immune response. After the success in melanoma, numerous clinical trials are being conducted investigating CPIs in lung cancer and mesothelioma. The programmed death protein (PD) 1-PD ligand 1/2 pathway and cytotoxic T lymphocyte-associated protein 4 are currently the most studied immunotherapeutic targets in these malignancies. In non-small cell lung cancer, anti-PD-1 antibodies have become part of the approved treatment arsenal. In small cell lung cancer and mesothelioma, the efficacy of checkpoint inhibition has not yet been proven. In this Concise Clinical Review, an overview of the landmark clinical trials investigating checkpoint blockade in lung cancer and mesothelioma is provided. Because response rates are around 20% in the majority of clinical trials, there is much room for improvement. Predictive biomarkers are therefore essential to fully develop the potential of CPIs. To increase efficacy, multiple clinical trials investigating the combination of cytotoxic T lymphocyte-associated protein 4 inhibitors and PD-1/PD ligand 1 blockade in lung cancer and mesothelioma are being conducted. Given the potential benefit of immunotherapy, implementation of current and new knowledge in trial designs and interpretation of results is essential for moving forward.

Immune Checkpoint Inhibitors in Lung Cancer: Imaging Considerations.

The purpose of this article is to review the mechanisms of action of immune checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC), highlight imaging manifestations of common adverse events, and discuss new criteria for using imaging to assess unique treatment response patterns. Immune checkpoint inhibitor therapy is a breakthrough in cancer treatment that has shown unprecedented success when used for a variety of malignancies. In recent phase 3 clinical trials for NSCLC, monoclonal antibodies that target the programmed death-1 (PD-1) receptor and its ligand PD-L1 (i.e., the PD-1/PD-L1 axis) were associated with better overall survival in head-to-head comparisons with conventional cytotoxic chemotherapy. On the strength of the results of these trials, the PD-1 inhibitors nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab recently received regulatory approval by the U.S. Food and Drug Administration for the treatment of advanced NSCLC. Because of their unique mechanisms of action, these agents differ from conventional cytotoxic chemotherapy in both patterns of treatment response and treatment-related adverse events. Given the rapidly expanding clinical use of immune checkpoint inhibitors and the central role of radiology in the care of patients with lung cancer, it is important for radiologists to be familiar with these agents and their unique imaging findings.

Immune checkpoint inhibitors in lung cancer: an update

Immune checkpoint inhibitors in lung cancer: an update

Immune checkpoint inhibitors in lung cancer: current status and future directions.

Recently, the immune checkpoint inhibitors that target programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) have made a breakthrough in treating advanced non-small cell lung cancer (NSCLC) with the efficacy of approximately 20%; among which, nivolumab has acquired treatment indications in lung squamous cell carcinoma. The inhibitors targeting cytotoxic T lymphocyte associated antigen 4 (CTLA-4) are also undergoing clinical trials. Researches on immune checkpoint inhibitors have been rapidly implemented in a variety of different types of lung cancer, such as small cell lung cancer (SCLC) and locally advanced NSCLC, and these inhibitors began to be applied in combination with some established treatments, including chemotherapy, targeting therapy and radiotherapy. Undoubtedly, the immune checkpoint inhibitors have become a hot spot in the research and treatment of lung cancer. However, many problems wait to be solved, such as searching for ideal biomarkers, constituting the best criteria for curative effect evaluation, exploring different combination treatment models, and clearly understanding the mechanisms of primary or secondary drug resistance. Along with these problems to be successfully solved, the immune checkpoint inhibitors will have more broad applications in lung cancer therapy.

Computed Tomography Features of Lung Adenocarcinomas With Programmed Death Ligand 1 Expression

IntroductionThe development of immune checkpoint inhibitors against programmed death 1 has paved the way for a new era of treatment of lung cancer. Programmed death-ligand 1 (PD-L1) is expected to predict the response of immune checkpoint inhibitors in lung cancer. Predicting PD-L1 expression using a noninvasive method before immunotherapy would, therefore, help identify patients for whom immunotherapy can be successful. Patients and MethodsA total of 394 patients with resected lung adenocarcinoma who had undergone preoperative thin-section computed tomography (CT) were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and CT characteristics, including convergence, surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation. ResultsOf the 394 patients, 78 (19.8%) were positive and 316 (80.2%) were negative for PD-L1 expression. Univariate analysis demonstrated that PD-L1+ adenocarcinoma was significantly associated with the presence of convergence (P < .01), notching (P < .01), spiculation (P < .01), and cavitation (P < .01) and the absence of surrounding GGO (P < .01) compared with PD-L1− cases. On multivariate analysis, the presence of convergence (P < .01) and cavitation (P < .01) and the absence of surrounding GGO (P = .02) and air bronchogram (P = .03) were significantly associated with PD-L1 expression. ConclusionPD-L1+ adenocarcinoma cases showed convergence and cavitation more frequently than did PD-L1− cases. In contrast, surrounding GGO and air bronchogram were observed less frequently in PD-L1+ cases than in PD-L1− cases. These results will prove helpful in identifying PD-L1–expressing adenocarcinoma by CT before immunotherapy.

Immune Checkpoint Inhibitors in Lung Cancer – An Unheralded Opportunity?

Lung cancer remains the leading cause of cancer-related death worldwide, with non-small cell lung cancer accounting for 85% of the disease. Over 70% of patients present with locally advanced, non-resectable or metastatic disease and despite improvements in chemoradiotherapy regimens and the development of molecularly targeted agents, 5 year survival rates remain poor, with acquired resistance to novel targeted therapies becoming a growing concern. Currently there remains an unmet need in effectively treating and inducing durable responses in advanced disease. Targeting the immune system has, however, recently given hope of improving therapeutic outcomes for these patients. The notion that the immune system is capable of recognising and eliminating cancer cells is now a widely accepted phenomenon and growing evidence suggests lung cancer is an attractive target for such intervention. Recent success targeting the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis of immune checkpoint inhibition suggests a major immunotherapeutic advance in treating lung cancer and unheralded opportunity for such approaches to further improve outcome for patients.Currently there is considerable interest in combining anti-PD-1 or PD-L1 monoclonal antibodies with established standard of care therapies such as radiotherapy. Radiotherapy is known to be immunostimulatory and efforts are underway to combine and augment the efficacy of the immune checkpoint inhibitors further. This review outlines the interaction between lung cancer and the immune system, summarises current evidence supporting the use of monoclonal antibodies targeting the PD-1 axis in lung cancer and explores the potential of combining radiotherapy with immunotherapy to augment anti-tumour immune responses.

Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

2017;22:81-88 IMPLICATIONS FOR PRACTICE: Strategies targeting negative regulators (i.e., checkpoints) of the immune system have demonstrated significant antitumor activity across a range of solid tumors. In non-small cell lung cancer (NSCLC), programmed cell death protein-1 (PD-1) pathway inhibitors have entered routine clinical use because of the results from recent randomized studies demonstrating superiority against single-agent chemotherapy in previously treated patients. The present report provides an overview of immune checkpoint inhibitors in lung cancer for the practicing clinician, focusing on the rationale for immunotherapy, recent clinical trial data, and future directions.

肺癌に対する免疫Check Point阻害剤の有効性

肺癌に対する免疫Check Point阻害剤の有効性

MTE13.02 Basic Immunology for the Clinician

MTE13.02 Basic Immunology for the Clinician

Immune checkpoint inhibitors in lung cancer: past, present and future.

Inhibitory ligands on tumor cells and their corresponding receptors on T cells are collectively called immune checkpoint molecules and have emerged as druggable targets that harness endogenous immunity to fight cancer. Immune checkpoint inhibitors targeting CTLA-4, PD-1 and PD-L1 have been developed for the treatment of patients with non-small-cell lung cancer and other malignancies, with impressive clinical activity, durable responses and a favorable toxicity profile. This article reviews the development, current status and future directions for some of these agents. The efficacy and safety data for drugs such as ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab are reviewed, along with combination strategies and response evaluation criteria. The toxicity profiles and predictive biomarkers of response are also discussed.

Immunotherapy with checkpoint inhibitors for lung cancer: novel agents, biomarkers and paradigms.

Despite recent advances, prognosis of patients with advanced lung cancer remains dismal. Owing to a better understanding of the interactions between immune system and tumor cells, immunotherapy has emerged as a promising therapeutic strategy. After the recent approval of nivolumab and the promising results with other immune checkpoint inhibitors, combination strategies are now subject of intensive research. Notwithstanding these successes, immunotherapy still holds significant drawbacks. As the target shifts from tumor cells to the tumor microenvironment, treatment paradigms are changing and several improvements are needed for optimal use in clinical practice. Robust biomarkers for patient selection and a reliable way of evaluating treatment response are high priorities. Herein we review current data on immune checkpoint inhibitors for lung cancer treatment.

Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer.

Antibodies against immune checkpoints including CTLA-4, PD-1 and PD-L1 are increasingly being used in lung cancer. They are associated with novel, immune related toxicities not previously encountered with established treatments for lung cancer including colitis, hepatitis, rashes, neuropathies and other rarer immune mediated toxicities. Although generally these are low grade, there is a potential to be life threatening if not managed promptly. Early recognition of toxicity and institution of management algorithms are key to ensuring patient safety. We review the common toxicities and provide recommendations on their management.