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Cited by 1,353Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Immune Checkpoint Inhibitors in Cancer Therapy

Open access
Shiravand, Yavar, Khodadadi, Faezeh, Kashani, Seyyed Mohammad Amin, Hosseini-Fard, Seyed Reza, Hosseini, Shadi, Sadeghirad, Habib, Ladwa, Rahul, O’Byrne, Ken +1 more·2022·Current Oncology
DOI 10.3390/curroncol29050247PMC PMC9139602
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Abstract

The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small lung cancer. The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab). Unfortunately, not all patients respond favourably to these drugs, highlighting the role of biomarkers such as Tumour mutation burden (TMB), PDL-1 expression, microbiome, hypoxia, interferon-γ, and ECM in predicting responses to ICIs-based immunotherapy. The current study aims to review the literature and updates on ICIs in cancer therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes FDA-approved immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4 and discusses biomarkers for predicting response. It reports that only 20–40% of patients benefit and reviews resistance, immune-related adverse events, and combination strategies.

Key findings

  • Three FDA-approved ICI categories are covered: PD-1 inhibitors (nivolumab, pembrolizumab, cemiplimab), PD-L1 inhibitors (atezolizumab, durvalumab, avelumab), and the CTLA-4 inhibitor ipilimumab; only 20–40% of patients benefit, motivating predictive biomarkers.
  • Biomarkers discussed include PD-L1 expression, TMB, MSI/dMMR, microbiome, hypoxia, IFN-γ, and ECM; TMB ≥10 mut/Mb is considered high and linked to improved survival in some tumor types, and KEYNOTE-158 found pembrolizumab effective in cancers with TMB ≥10 mut/Mb.
  • Selected trial results include atezolizumab vs docetaxel in POPLAR (HR = 0.54; p = 0.014), atezolizumab plus nab-paclitaxel reducing risk of progression or death by 40% in PD-L1-positive TNBC, and durvalumab median OS of 16.3 months vs chemotherapy 12.9 months vs durvalumab/tremelimumab 11.9 months in PD-L1 ≥25% NSCLC.
  • Toxicities include CTLA-4 blockade dose-dependent adverse events in more than 70% of patients, increased treatment-related mortality with higher dose (10 mg/kg) CTLA-4 inhibitors, fatigue in 16–37% of PD-1 inhibitor recipients and 12–24% of PD-L1 inhibitor recipients, and cemiplimab fatigue 27.0% and diarrhea 23.5%.

Methods

  • Narrative literature review of ICIs in cancer therapy, covering mechanisms, FDA approvals, clinical trials, and biomarkers; no primary patient cohort or new experimental data are reported.
  • Synthesizes published clinical and preclinical studies, including trials such as KEYNOTE-024, KEYNOTE-048, KEYNOTE-158, CHECKMATE 040/142, POPLAR, IMpassion130, PACIFIC, MYSTIC, JAVELIN Merkel 200, and Study 111/KEYNOTE-146.
  • Main analysis is descriptive/qualitative synthesis; no systematic search protocol or meta-analysis is reported.

Limitations

  • Stated: there is limited data regarding ICI safety in children; the role of systemic immunity in these modalities is not fully known; and more work is needed to uncover mechanisms of response across tumor types.
  • Stated: unpredictable off-target effects on critical organs may pose life-threatening risks to children whose organs are less mature.
  • Evident: as a narrative review, it does not report systematic search/selection criteria, risk-of-bias assessment, or quantitative pooling, so findings depend on the cited literature and selected trials.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/curroncol29050247

Cites

147 of 147 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 67 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The FDA recently approved pembrolizumab as the first tissue-agnostic/site-agnostic drug for treatment of patients with mismatch repair deficient/metastatic microsatellite instability-high (dMMR/MSI-H).

    “FDA recently approved the pembrolizumab as first tissue-agnostic/site-agnostic drug for treatment of patients with mismatch repair deficient/metastatic microsatellite instability—high (dMMR/MSI-H) [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Le, 2017, Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Science source

      Not checked in the free run.

  • Premisecitation

    Nivolumab is a first-in-class fully human IgG4 monoclonal antibody inhibitor that suppresses PD-1 activity by selectively targeting and blocking the interaction between PD-L1 and PD-L2 and the PD-1 receptor.

    “Nivolumab (BMS-936558, ONO-4538, or MDX1106, trade name Opdivo; Bristol-Myers Squibb, Princeton, NJ, USA) is a first-in-class fully human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) inhibitor that suppresses PD-1 activity through selectively targeting and blocking the interaction between ligands (PD-L1 and PD-L2) and PD-1 receptor [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Rizvi, 2015, Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial, Lancet Oncol. source

      Not checked in the free run.

  • Premisecitation

    In patients with recurrent NSCLC tumours expressing medium or high levels of PD-L1, atezolizumab demonstrated a statistically significant survival advantage in comparison with docetaxel (HR = 0.54; p = 0.014) in a randomized phase II trial (POPLAR).

    “Patients with recurrent NSCLC tumours, expressing medium or high levels of PD-L1, Atezolizumab demonstrated a statistically significant survival advantage in comparison with docetaxel (HR = 0.54; p = 0.014) in a randomized phase II trial (POPLAR) [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Park, 2018, 136PD_PR 3-year survival and duration of response in randomized phase II study of atezolizumab (atezo) vs docetaxel (doc) in 2L+ NSCLC (POPLAR), J. Thorac. Oncol. source

      Not checked in the free run.

  • Premisecitation

    Atezolizumab improved progression-free survival in patients with metastatic breast cancer based on the Phase 3 IMpassion130 trial.

    “These trial results demonstrated that Atezolizumab improved progression-free survival in patients with metastatic breast cancer.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Kaplan, 2022, Treatments on the Horizon: Breast Cancer Patients with Central Nervous System Metastases, Curr. Oncol. Rep. source

      Not checked in the free run.

  • Premisecitation

    ICIs work by reinvigorating the host immune system to fight tumour cells, in contrast to traditional therapeutic strategies.

    “In contrast to traditional therapeutic strategies, ICIs work by reinvigorating the host immune system to fight tumour cells [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Cai, 2021, Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases, Front. Genet. source

      Not checked in the free run.

  • May combine two claims. 24
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    Both tumour and immune cells can express PD-L1, which is a useful biomarker in predicting response to anti-PD-1/PD-L1 antibodies in some patients with different types of cancer.

    “Both tumour and immune cells can express PD-L1 which is a useful biomarker in predicting response to anti-PD-1/PD-L1 antibodies in some patients with different types of cancer [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Doroshow, 2021, PD-L1 as a biomarker of response to immune-checkpoint inhibitors, Nat. Rev. Clin. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pembrolizumab is a humanized IgG4 mAb that disrupts the PD-1/PD-L1 pathway.

    “Pembrolizumab (Keytruda, Merck) is another humanized IgG4 mAb that disrupts the PD-1/PD-L1 pathway [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Liebl, 2019, Identification of responders to immune checkpoint therapy: Which biomarkers have the highest value?, J. Eur. Acad. Dermatol. Venereol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with metastatic CSCC, cemiplimab has exhibited remarkable anticancer activity with a reasonable safety profile.

    “In patients with metastatic CSCC, Cemiplimab has exhibited remarkable anticancer activity with a reasonable safety profile [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Migden, 2020, Cemiplimab in locally advanced cutaneous squamous cell carcinoma: Results from an open-label, phase 2, single-arm trial, Lancet Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cemiplimab is a fully humanized IgG4 mAb that inhibits the interaction of the PD-1 receptor with its ligands and is used to treat patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are ineligible for curative resection or radiotherapy.

    “Cemiplimab (Libtayo®, Regeneron Pharmaceuticals/Sanofi) is considered a fully humanized IgG4 mAb that inhibits the interaction of the PD-1 receptor with its ligands and is used to treat patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are ineligible for curative resection or radiotherapy (approved by FDA in September 2018, and by the European Medicines Agen”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Argenziano, 2022, Identifying candidates for immunotherapy with cemiplimab to treat advanced cutaneous squamous cell carcinoma: An expert opinion, Ther. Adv. Med. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Biomarkers such as TMB, PD-L1 expression, microbiome, hypoxia, interferon-γ, and ECM are related to immunotherapy outcomes and can predict responses to ICIs.

    “Tumour mutational burden (TMB), PDL-1 expression, microbiome, hypoxia, interferon-γ, extracellular matrix (ECM) and molecular and cellular characterization within the tumour microenvironment (TME) are all related to immunotherapy outcomes [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Monkman, 2021, Understanding the tumor microenvironment for effective immunotherapy, Med. Res. Rev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 2010, Brahmer et al. demonstrated clinical activity of MDX-1106 in patients with various tumour types such as colorectal cancer, renal cell cancer, melanoma, NSCLC, and castration refractory prostate cancer.

    “In 2010, Brahmer et al. demonstrated clinical activity of MDX-1106 in patients with various tumour types such as colorectal cancer, renal cell cancer, melanoma, NSCLC, and castration refractory prostate cancer [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Brahmer, 2010, Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates, J. Clin. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A phase III study (KEYNOTE-048) demonstrated that pembrolizumab compared to chemotherapy has remarkably improved overall survival in recurrent/metastatic HNSCC patients with PD-L1 combined positive score (CPS) ≥20, and its combinations with chemotherapy were more efficacious compared to chemotherapy in R/M HNSCC patients with PD-L1 CPS ≥1.

    “A phase III study (KEYNOTE-048) date demonstrated that Pembrolizumab compared to chemotherapy has remarkably improved OS in recurrent/metastatic (R/M) HNSCC patients with PD-L1 combined positive score (CPS) ≥20 and its combinations with chemotherapy was more efficacious compared to chemotherapy in R/M HNSCC patents with PD-L1 CPS ≥1, proposing c [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Burtness, 2019, Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study, Lancet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Nivolumab was approved by the FDA in 2014 and 2015 for the treatment of melanoma and renal cell carcinoma, respectively.

    “Nivolumab was approved by the FDA in 2014 and 2015 for the treatment of melanoma and renal cell carcinoma, respectively (Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The FDA approved nivolumab in 2015 for the treatment of squamous cell lung cancer (SCLC) and NSCLC.

    “Furthermore, the FDA approved nivolumab in 2015 for the treatment of squamous cell lung cancer (SCLC) and NSCLC [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Kazandjian, 2016, FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy, Oncologist source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The US FDA has approved three categories of immune checkpoint inhibitors: PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and a CTLA-4 inhibitor (Ipilimumab).

    “The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab).”
    • Also stated in: § 1. Introduction · plain
      “Three different groups of ICIs, including PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab) have been approved by the US Food and Drug Administration (FDA) for the treatment of various types of cancer [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Liebl, 2019, Identification of responders to immune checkpoint therapy: Which biomarkers have the highest value?, J. Eur. Acad. Dermatol. Venereol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Avelumab is a completely human IgG1 monoclonal antibody that binds to PD-L1, thereby inhibiting PD-L1 and PD-1 interactions, which could lead to T cell mediated antitumour responses.

    “Avelumab (MSB0010718C) is another completely human IgG1 monoclonal antibody, binding to PD-L1, thereby inhibiting PD-L1 and PD-1 interactions. This could lead to T cells mediated antitumour responses as well as [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Collins, 2019, Product review: Avelumab, an anti-PD-L1 antibody, Hum. Vaccines Immunother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pembrolizumab induces complete and robust responses in a tumour-agnostic manner, targeting the immune system rather than the tumour cell itself.

    “Several studies have found that pembrolizumab induces complete and robust responses in a tumour-agnostic manner, targeting the immune system rather than the tumour cell itself [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Le, 2017, Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microsatellite unstable tumours categorized into MSI-low and MSI-high; MSI-high enhanced significantly the neoantigen load, leading to activating lymphocyte, thereby rendering tumour cells sensitive to ICIs.

    “Microsatellite unstable tumours have been categorized into two phenotypes namely MSI-low (MSI-L) and MSI-high (MSI-H) that the latter enhanced significantly the neoantigen load, leading to activating lymphocyte, thereby rendering tumour cells sensitive to ICIs [116].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Luchini, 2019, ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: A systematic review-based approach, Ann. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The study 111/KEYNOTE-146 trial showed that pembrolizumab plus lenvatinib resulted in a promising antitumour response as well as a manageable safety profile in patients with metastatic renal cell carcinoma who had been previously treated with ICI therapy.

    “Furthermore, the study 111/KEYNOTE-146 trial (NCT02501096) showed that Pembrolizumab plus lenvatinib, a VEGFR1/2/3 kinases inhibitor, resulted in a promising antitumour response as well as a manageable safety profile in patients with metastatic renal cell carcinoma (RCC) who have been previously treat with ICI therapy [129].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Lee, 2021, Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): A phase 1b/2 study, Lancet Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Zheng et al. reported dynamic alterations within gut microbiome in patients with HCC during their immunotherapy, and metagenomic sequencing data showed higher taxa in faecal samples of patients responding to immunotherapy compared to non-responders.

    “In recently published work, Zheng et al. reported some dynamic alterations within gut microbiome in patients with HCC during their immunotherapy. Moreover, metagenomic sequencing data showed higher taxa in faecal samples of patients, responding to immunotherapy compared to non-responders, highlighting the role of microbiome in regulating immune responses [123].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Zheng, 2019, Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma, J. Immunother. Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KEYNOTE-048 results showed that pembrolizumab improved overall survival in patients with R/M HNSCC as PD-L1 increases, demonstrating that PD-L1 expression is a demonstrator of response for ICIs.

    “Furthermore, KEYNOTE-048 results showed that Pembrolizumab improved OS in patients with R/M HNSCC as PD-L1 increases, demonstrating the role of the PD-L1 expression is a demonstrator of response for ICIs [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Burtness, 2019, Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study, Lancet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Combination therapy with other ICIs, chemotherapy, targeted agents, radiotherapy, and T-cell based therapies could improve ICI outcomes, particularly in patients who have not experienced a favourable response to ICI-based therapies.

    “It seems that combination therapy with other ICIs, chemotherapy, targeted agents, radiotherapy, and T- cell based therapies could improve ICI outcomes, particularly in patients who have not experienced a favourable response to ICI-based therapies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Melanoma patients treated with anti-PD-L1 had higher levels of Bifdobacterium longum, Collinsella aerofaciens, and Enterococcus faecium, highlighting the importance of the microbiome.

    “Furthermore, melanoma patients treated with anti-PD-L1 had higher levels of Bifdobacterium longum, Collinsella aerofaciens, and Enterococcus faecium, highlighting the importance of the microbiome [122].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Matson, 2018, The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KEYNOTE-024 trial revealed that a fixed dose of pembrolizumab (200 mg) was associated with improved overall survival and progression-free survival and lower treatment-related adverse events in NSCLC patients with PD-L1 tumour proportion score (TPS) ≥50% in comparison with chemotherapy.

    “KEYNOTE-024 trail revealed that a fixed dose of Pembrolizumab (200 mg) was associated with the improved OS and PFS and lower treatment-related adverse events in NSCLC patients with PD-L1 tumour proportion score (TPS) ≥50% in comparison with chemotherapy [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Reck, 2019, Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater, J. Clin. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMB ≥10 mut/Mb is considered high TMB (TMB-H), and it has been linked to improved survival in a variety of tumour types, including small cell lung cancer.

    “TMB ≥ 10 mut/Mb is considered as High TMB (TMB-H), and it has been linked to improved survival in a variety of tumour types, including small cell lung cancer (SCLC) [110].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Shao, 2020, Prevalence of High Tumor Mutational Burden and Association With Survival in Patients With Less Common Solid Tumors, JAMA Netw. Open source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lysyl oxidase (LOX) inhibits T cell migration to ECM and suppresses immune response; inhibiting LOX can increase T cell infiltration, thereby improving responses to ICI-based immunotherapy.

    “Furthermore, Lysyl oxidase (LOX) inhibits T cell migration to ECM and suppresses immune response. The KPC model was used to demonstrate that inhibiting LOX can increase T cell infiltration, thereby improving responses to ICI-based immunotherapy [142,143].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [142] Brassart, 2020, Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression, Front. Oncol. source

      Not checked in the free run.

    • cites [143] Vaquero, 2021, Author response: Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment, Elife source

      Not checked in the free run.

    • Rests on an assumption: Findings from preclinical mouse models of cancer are informative about human ICI responses.

  • May combine two claims.

    Premisecitation

    In a study by Bellmunt et al., 542 patients with advanced urothelial cancer were evaluated, and pembrolizumab had improved survival and fewer side effects than chemotherapy.

    “In a study conducted by Bellmunt et al., 542 patients with advanced urothelial cancer were evaluated, and it was found that Pembrolizumab had an improved survival and fewer side effects than chemotherapy [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Bellmunt, 2017, Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma, N. Engl. J. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Durvalumab is an FDA-approved immunotherapy that binds to PD-L1 with high affinity and specificity, thereby inhibiting its interactions with PD-1 and CD80.

    “Durvalumab (MEDI4736) is an FDA-approved immunotherapy, binding to PD-L1 with high affinity and specificity, thereby inhibiting its interactions to PD-1 and CD80 [68,69].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] Simeone, 2019, Treatment patterns and overall survival in metastatic non-small-cell lung cancer in a real-world, US setting, Futur. Oncol. source

      Not checked in the free run.

    • cites [69] Stewart, 2015, Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody, Cancer Immunol. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The CHECKMATE 142 study reported that nivolumab could provide a durable response in patients with dMMR/MSI-H metastatic colorectal cancer, proposing nivolumab as a new treatment option in these patients.

    “The CHECKMATE 142 study reported that Nivolumab could provide a durable response in patients with dMMR/MSI-H metastatic colorectal cancer, proposing Nivolumab as a new treatment option in these patients [117].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Overman, 2017, Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study, Lancet Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Toxicities correlated with PD-1/PD-L1 blockades were less severe compared to CTLA-4 inhibitors, and fatigue was the most common adverse event, occurring in 16-37% of patients receiving PD-1 inhibitor, and 12-24% of those who received PD-L1 inhibitor.

    “The toxicities corelated with PD-1/PD-L1 blockades were less severe compared to CTLA-4 inhibitors, and fatigue as the most common adverse event, occurring in 16–37% of patients receiving PD-1 inhibitor, and 12–24% of those who received PD-L1 inhibitor [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Naidoo, 2015, Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies, Ann. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 2020, the FDA announced that nivolumab plus ipilimumab have therapeutic benefits for adult patients with unresectable malignant pleural mesothelioma, and NSCLC (with tumour PD-L1 expression ≥1% and no EGFR/ALK aberrations) as a first-line treatment.

    “In 2020, the FDA announced that Opdivo (nivolumab) plus Yervoy (ipilimumab) (given as intravenous injections) have therapeutic benefits for adult patients with unresectable malignant pleural mesothelioma (MPM), and NSCLC (with tumour PD-L1 expression ≥1% and no EGFR/ALK aberrations) as a first-line treatment [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Lisi, 2021, Clinical experience with CTLA-4 blockade for cancer immunotherapy: From the monospecific monoclonal antibody ipilimumab to probodies and bispecific molecules targeting the tumor microenvironment, Pharmacol. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ipilimumab is a human IgG1 mAb that inhibits the function of CTLA-4 and was first approved and recommended for the treatment of melanoma in 2011.

    “Ipilimumab (Yervoy) is a human IgG1 mAb that can inhibit the function of CTLA-4 and was first approved and recommended for the treatment of melanoma in 2011 [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Callahan, 2013, At the bedside: CTLA-4-and PD-1-blocking antibodies in cancer immunotherapy, J. Leukoc. Biol. source

      Not checked in the free run.

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  • The paper relies on this without support.

    Findings from preclinical mouse models of cancer are informative about human ICI responses.

    “In melanoma, prostate, and also PDA murine model, GMCSF cell-based vaccines combined with CTLA-4 inhibitor decreased tumour growth and restored the antitumor immunity [92,93,94].”
    “The KPC model was used to demonstrate that inhibiting LOX can increase T cell infiltration, thereby improving responses to ICI-based immunotherapy [142,143].”
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Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In current clinical practice, various biomarkers such as PD-L1 expression, tumor mutational burden (TMB), MSI, microbiome composition, hypoxia levels, IFN-γ levels, and extracellular matrix characteristics are utilized as prognostic indicators to predict the clinical response to immunotherapy among patients receiving ICIs.

    “In current clinical practice, various biomarkers such as PD-L1 expression, tumor mutational burden (TMB), MSI, microbiome composition, hypoxia levels, IFN-γ levels, and extracellular matrix characteristics are utilized as prognostic indicators to predict the clinical response to immunotherapy among patients receiving ICIs [162].”

    From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [162]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • SCLC is expanded in two different ways

    Minor

    The paper uses SCLC to mean both "squamous cell lung cancer" and "small cell lung cancer," making the abbreviation inconsistent.

1 of 1

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Authors
Shiravand, Y., Khodadadi, F., Kashani, S. M. A., Hosseini-Fard, S. R., Hosseini, S., Sadeghirad, H., Ladwa, R., O’Byrne, K., & Kulasinghe, A.
Affiliations
  • University of Naples Federico II (IT)
  • PES University (IN)
  • Shiraz University of Medical Sciences (IR)
  • Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
  • Kurdistan University of Medical Sciences (IR)
  • The University of Queensland (AU)
  • Princess Alexandra Hospital (AU)
  • Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
Corresponding author
Kulasinghe, Arutha
ORCID
Venue
Current Oncology
Publisher
MDPI AG
Published
2022-04-24
Volume
29
Issue
5
Pages
3044-3060
ISSN
  • 1198-0052 (ISSN-L)
  • 1718-7729
DOI
10.3390/curroncol29050247
PMC
PMC9139602
OpenAlex
W4226329559
Cited by
1,353
References
147
Citations by year
2026: 267 · 2025: 467 · 2024: 434 · 2023: 156 · 2022: 29
FWCI
33.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
Funders
National Health and Medical Research Council (1157741)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
immune checkpoint inhibitors, PD-1/PD-L1, CTLA-4, cancer immunotherapy, nivolumab, pembrolizumab, cemiplimab, durvalumab, avelumab, ipilimumab, predictive biomarkers, tumor mutational burden, PD-L1 expression, microbiome, tumor hypoxia, interferon-gamma, extracellular matrix, metastatic melanoma, renal cell carcinoma, head and neck cancer, non-small cell lung cancer
MeSH terms
Immune Checkpoint Inhibitors, Immune Checkpoint Proteins, Humans, Immunotherapy, Lung Neoplasms, Programmed Cell Death 1 Receptor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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