Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies

Walsh, Robert J.; Soo, Ross A.

doi:10.1177/1758835920937902

Cited by 63 publications

(62 citation statements)

References 154 publications

(222 reference statements)

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“…131 In a Chinese study, the TMB was analysed in NSCLC patients receiving anti-PD-1/PD-L1 treatment; the mPFS was significantly longer at 10.6 months in the high TMB group compared with just 3.9 months in the low TMB group (p = 0.0007), and the mOS was 21.0 months in the high TMB group and just 11.6 months in the low TMB group (p = 0.0126). 132 The circulating tumour DNA (ctDNA)-related TMB was also assessed in NSCLC patients who received anti-PD-1 or anti-PD-L1 therapy; 133 however, higher ctDNA-related TMBs were obviously related to shorter mOS and mPFS, which indicated that a higher ctDNA TMB Therapeutic Advances in Medical Oncology 13 16 journals.sagepub.com/home/tam reflected worse clinical outcomes. 134 Another group detected TMB in plasma through bloodbased cell-free DNA (cfDNA), and they were able to successfully identify NSCLC patients whose PFS was significantly improved after anti-PD-L1 therapy.…”

Section: Tmbmentioning

confidence: 99%

The progress and challenge of anti-PD-1/PD-L1 immunotherapy in treating non-small cell lung cancer

Mei

Liu

et al. 2021

Ther Adv Med Oncol

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The use of programmed cell-death protein 1 (PD-1)/programmed cell-death ligand 1 (PD-L1) inhibitors is the standard therapy for the first-line or second-line treatment of patients with non-small-cell lung cancer (NSCLC). In contrast to current traditional treatments such as chemotherapy or radiotherapy, anti-PD-1 and anti-PD-L1 treatments can directly attenuate tumour-mediated exhaustion and effectively modulate the host anti-tumour immune response in vivo. In addition, compared with traditional therapy, PD-1/PD-L1 inhibitor monotherapy can significantly prolong survival without obvious side effects in the treatment of advanced NSCLC. Ideally, several biomarkers could be used to monitor the safety and effectiveness of anti-PD-1 and anti-PD-L1 treatments; however, the current lack of optimal prognostic markers remains a widespread limitation and challenge for further clinical applications, as does the possibility of immune-related adverse events and drug resistance. In this review, we aimed to summarise the latest progress in anti-PD-1/anti-PD-L1 treatment of advanced NSCLC, worldwide, including in China. An exploration of underlying biomarker identification and future challenges will be discussed in this article to facilitate translational studies in cancer immunotherapy.

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Section: Tmbmentioning

confidence: 99%

The progress and challenge of anti-PD-1/PD-L1 immunotherapy in treating non-small cell lung cancer

Mei

Liu

et al. 2021

Ther Adv Med Oncol

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“…However, mechanisms of primary and acquired resistance largely limit the activity of these drugs, with a very low fraction of patients experiencing a prolonged response [ 89 ]. In this respect, several mechanisms of resistance to ICIs treatment have been identified and, among those associated with genetic variants of tumor cells, there are alterations of HLA , β2-microglobulin and LKB1 genes, c-Myc copy number gain, KRAS mutations, and deletions of chromosomal regions with consequent neoantigens loss [ 90 ].…”

Section: Use Of Ngs-based Cfdna Testing To Track the Acquired Resimentioning

confidence: 99%

Next Generation Sequencing-Based Profiling of Cell Free DNA in Patients with Advanced Non-Small Cell Lung Cancer: Advantages and Pitfalls

Abate

Frezzetti

Maiello

et al. 2020

Cancers

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Lung cancer (LC) is the main cause of death for cancer worldwide and non-small cell lung cancer (NSCLC) represents the most common histology. The discovery of genomic alterations in driver genes that offer the possibility of therapeutic intervention has completely changed the approach to the diagnosis and therapy of advanced NSCLC patients, and tumor molecular profiling has become mandatory for the choice of the most appropriate therapeutic strategy. However, in approximately 30% of NSCLC patients tumor tissue is inadequate for biomarker analysis. The development of highly sensitive next generation sequencing (NGS) technologies for the analysis of circulating cell-free DNA (cfDNA) is emerging as a valuable alternative to assess tumor molecular landscape in case of tissue unavailability. Additionally, cfDNA NGS testing can better recapitulate NSCLC heterogeneity as compared with tissue testing. In this review we describe the main advantages and limits of using NGS-based cfDNA analysis to guide the therapeutic decision-making process in advanced NSCLC patients, to monitor the response to therapy and to identify mechanisms of resistance early. Therefore, we provide evidence that the implementation of cfDNA NGS testing in clinical research and in the clinical practice can significantly improve precision medicine approaches in patients with advanced NSCLC.

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“…In secondary resistance, patients relapse after a period of initial response as a consequence of the appearance of tumor evasion mechanisms. Primary resistance to IT accounts for 7–27% of first-line treatment and 20–44% of second-line treatment in patients with lung cancer [ 81 ]. According to the KEYNOTE-001 trial results, approximately 25% of patients treated with ICIs could develop secondary resistance [ 82 ].…”

Section: Resistance To Immune Checkpoints In Lung Cancer Immunothementioning

confidence: 99%

Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy

Boyero

Sánchez-Gastaldo

Alonso

et al. 2020

Cancers

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After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field. The appearance of immunotherapy, especially immune checkpoint inhibitors, has improved both the overall survival and quality of life of patients, many of whom are diagnosed late when classical treatments are ineffective. Despite these unprecedented results, a high percentage of patients do not respond initially to treatment or relapse after a period of response. This is due to resistance mechanisms, which require understanding in order to prevent them and develop strategies to overcome them and increase the number of patients who can benefit from immunotherapy. This review highlights the current knowledge of the mechanisms and their involvement in resistance to immunotherapy in lung cancer, such as aberrations in tumor neoantigen burden, effector T-cell infiltration in the tumor microenvironment (TME), epigenetic modulation, the transcriptional signature, signaling pathways, T-cell exhaustion, and the microbiome. Further research dissecting intratumor and host heterogeneity is necessary to provide answers regarding the immunotherapy response and develop more effective treatments for lung cancer.

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Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies

Cited by 63 publications

References 154 publications

The progress and challenge of anti-PD-1/PD-L1 immunotherapy in treating non-small cell lung cancer

The progress and challenge of anti-PD-1/PD-L1 immunotherapy in treating non-small cell lung cancer

Next Generation Sequencing-Based Profiling of Cell Free DNA in Patients with Advanced Non-Small Cell Lung Cancer: Advantages and Pitfalls

Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy

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