Biomarkers of resistance to immune checkpoint inhibitors in non-small-cell lung cancer: myth or reality?

Pourmir, Ivan; Gazeau, Benoit; Basile, Hortense de Saint; Fabre, Elizabeth

doi:10.20517/cdr.2020.14

Cited by 3 publications

(10 citation statements)

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“…Over past decades the advancement in high-throughput sequencing technology has increased the numbers of prognostic markers and therapeutic targets [27][28][29]. This development has contributed to understanding the oncogenesis of lung cancer and revolutionized the personalized treatment [27].…”

Section: Genetic Background Of Immunotherapy Failurementioning

confidence: 99%

“…This development has contributed to understanding the oncogenesis of lung cancer and revolutionized the personalized treatment [27]. To date, tumor PD-L1 expression and tumor mutation burden have emerged as the predictive biomarkers for ICIs in NSCLC; however, both seem to be imperfect tools [27,29]. PD-L1 expression, which states the point of ICIs binding, has various clinically approved cut-off scores and IHC tests that may be impacted by methodological variabilities [28].…”

Section: Genetic Background Of Immunotherapy Failurementioning

confidence: 99%

“…PD-L1 expression, which states the point of ICIs binding, has various clinically approved cut-off scores and IHC tests that may be impacted by methodological variabilities [28]. Similarly, TMB, which affects the rate of neoantigens production and increases the probability of triggering an adaptive immune response [27,29], may be affected by analytical factors and different sequencing genome coverage and depth applied by whole exome sequencing (WES) or targeted sequencing (TS) approaches [28]. Moreover, TMB cannot predict the immunogenicity driven by synonymous alterations, such as copy number alterations (CNAs) and frameshift indels (small insertions and deletions) that are also considered as a highly immunogenic mutational classes, increasing numbers of neoantigens associated with the sensitivity to ICIs [28,[30][31][32].…”

Section: Genetic Background Of Immunotherapy Failurementioning

confidence: 99%

“…Within the first two months of ICIs' administration, 40-50% of patients experience the failure of treatment that is clinically manifested by progression or even hyperprogression of the primary tumor or metastases [8,34,35]. This intrinsic resistance is regulated by different aberrations in oncogenes and suppressor genes' that affect the immune response by amending cytokines' profile and immune cells' composition rendering tumor cells resistance or sensitivity to ICIs [18,29].…”

Section: Genetic Background Of Immunotherapy Failurementioning

confidence: 99%

See 3 more Smart Citations

Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

Błach

Wojas‐Krawczyk

Nicoś

et al. 2021

IJMS

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Immune checkpoint inhibitors (ICIs) have a huge impact on clinical treatment results in non-small cell lung cancer (NSCLC). Blocking antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) or CTLA-4 (cytotoxic T cell antigen 4) have been developed and approved for the treatment of NSCLC patients. However, a large number of patients develop resistance to this type of treatment. Primary and secondary immunotherapy resistance are distinguished. No solid biomarkers are available that are appropriate to predict the unique sensitivity to immunotherapy. Knowledge of predictive markers involved in treatment resistance is fundamental for planning of new treatment combinations. Scientists focused research on the use of immunotherapy as an essential treatment in combination with other therapy strategies, which could increase cancer immunogenicity by generating tumor cells death and new antigen release as well as by targeting other immune checkpoints and tumor microenvironment. In the present review, we summarize the current knowledge of molecular bases underlying immunotherapy resistance and discuss the capabilities and the reason of different therapeutic combinations.

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Section: Genetic Background Of Immunotherapy Failurementioning

confidence: 99%

Section: Genetic Background Of Immunotherapy Failurementioning

confidence: 99%

Section: Genetic Background Of Immunotherapy Failurementioning

confidence: 99%

Section: Genetic Background Of Immunotherapy Failurementioning

confidence: 99%

See 2 more Smart Citations

Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

Błach

Wojas‐Krawczyk

Nicoś

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…ICIs are the first-line treatment for non-small cell lung cancer (NSCLC) with positive PD-L1 expression ( Ettinger et al, 2019 ). However, only 20% to 30% of NSCLC patients are sensitive to anti–PD-1/PD-L1 therapy, and most patients experience resistance to immunotherapy ( Pourmir et al, 2020 ). Acquired resistance is defined as disease progression within 6 months after a period of clinical benefit ( Remon et al, 2020 ; Sharma et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Clinical Perspectives to Overcome Acquired Resistance to Anti–Programmed Death-1 and Anti–Programmed Death Ligand-1 Therapy in Non-Small Cell Lung Cancer

Lee

et al. 2021

Molecules and Cells

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Immune checkpoint inhibitors have changed the paradigm of treatment options for non-small cell lung cancer (NSCLC).Monoclonal antibodies targeting programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have gained wide attention for their application, which has been shown to result in prolonged survival. Nevertheless, only a limited subset of patients show partial or complete response to PD-1 therapy, and patients who show a response eventually develop resistance to immunotherapy. This article aims to provide an overview of the mechanisms of acquired resistance to anti-PD-1/PD-L1 therapy from the perspective of tumor cells and the surrounding microenvironment. In addition, we address the potential therapeutic targets and ongoing clinical trials, focusing mainly on NSCLC.

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Immunological markers for predicting the response to immunotherapy in non-small cell lung cancer

et al. 2022

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Itroduction. Immune checkpoint inhibitors have become the standard of care for patients with advanced non-small cell lung cancer. However, despite the determination of programmed death-ligand 1 expression in clinical practice, which determines the effectiveness of therapy, up to 80 % of patients with non-small cell lung cancer do not respond to treatment.The study objective – investigation of the prognostic role of clinical and immunological markers during immune checkpoint inhibitor monotherapy in ≥2 lines in patients with advanced non-small cell lung cancer.Materials and methods. The study included 45 patients with advanced non-small cell lung cancer receiving programmed cell death 1 / programmed death-ligand 1 inhibitors in monotherapy in 2 and subsequent lines (Group 1), as well as 30 patients with advanced non-small cell lung cancer receiving first-line chemotherapy (Group 2). All patients from 2 groups did not have autoimmune diseases before starting treatment. The determination of autoantibodies, β-2-microglobulin, neopterin, interleukin 6, interleukin 18 and the allelic variant of HLA-DRB1 in patients in the Group 1 was carried out 2 months after the start of therapy, and in the Group 2 – before the start of the next chemotherapy cycle.Results. In Group 1, the presence of EGFR / ALK mutations is an independent predictor of shorter progression-free survival (p = 0.018). Also, in the univariate analysis, neutrophil-lymphocyte ratio <5 before immune checkpoint inhibitors (p = 0.009) and the appearance of immune-related adverse events (p = 0.038) are associated with long-term progressionfree survival. In Group 1, β-2-microglobulin was lower in patients with a response duration of ≥6 months than with a progression <6 months: 1.7 mg / L and 2.9 mg / L, respectively (p <0.0001). Patients receiving immune checkpoint inhibitors with a β-2-microglobulin level ≥2.5 mg / L have a shorter progression-free survival than patients with a marker value <2.5 mg / L: 168 days and the value is not reached, respectively (p = 0.017). In response duration ≥6 months neopterin value was lower than in disease progression: 8.6 nmol / l and 13.4 nmol / L, respectively (p <0,0001). Progression-free survival was lower in patients with neopterin ≥12 nmol / L than patients with neopterin <12 nmol / L: median was 164 days and the value was not reached, respectively (p = 0.0007). Based on the results of multivariate analysis, β-2-microglobulin ≥2.5 mg / L (p = 0.006) and neopterin ≥12 nmol / L (p = 0.027) were independent predictors of shorter progression-free survival. Low levels of interleukin 6 and interleukin 18, as well as antibodies to thyroperoxidase, are associated with a response of ≥6 months. HLA-DRB1*03 was associated with a duration of response of ≥6 months, as well as a longer progression-free survival compared with other allelic variants. The levels of β-2-microglobulin, neopterin, interleukin 6, interleukin 18 were higher in patients in Group 1 than in patients in Group 2 (p <0.0001).Conclusion. Immunological markers can serve as promising prognosis markers in patients with advanced non-small cell lung cancer during immunotherapy.

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Biomarkers of resistance to immune checkpoint inhibitors in non-small-cell lung cancer: myth or reality?

Cited by 3 publications

References 83 publications

Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

Clinical Perspectives to Overcome Acquired Resistance to Anti–Programmed Death-1 and Anti–Programmed Death Ligand-1 Therapy in Non-Small Cell Lung Cancer

Immunological markers for predicting the response to immunotherapy in non-small cell lung cancer

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