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Cited by 1,445Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

Open access
Yi, Ming, Zheng, Xiaoli, Niu, Mengke, Zhu, Shuangli, Ge, Hong, Wu, Kongming·2022·Molecular Cancer
DOI 10.1186/s12943-021-01489-2PMC PMC8780712
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Abstract

Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes mechanisms and clinical advances of combining PD-1/PD-L1 blockade with chemotherapy, radiotherapy, angiogenesis inhibitors, other immune checkpoints, targeted therapy, STING agonists, bispecific antibodies, FMT, epigenetic/metabolic modulators, cytokines, and CAR-T cells. It argues that combination strategies can boost multiple steps of the cancer-immunity cycle and improve response, but individualized selection and better predictive biomarkers are needed.

Key findings

  • Ten α-PD-1 antibodies (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, avelumab) have been approved for various cancers, yet low response rates remain a major problem.
  • Several combinations improve outcomes in trials: relatlimab plus nivolumab showed PFS 10.1 vs. 4.6 months (HR 0.75) in advanced melanoma; tiragolumab plus atezolizumab improved ORR (OR 2.57, 95% CI 1.07–6.14) and PFS (HR 0.57, 95% CI 0.37–0.90) in PD-L1-positive NSCLC; niraparib plus pembrolizumab had ORR 56.3% in PD-L1-high advanced NSCLC.
  • Toxicity can limit combinations: TATTON reported 22% interstitial lung disease with osimertinib plus durvalumab, and CheckMate-370 reported 38% severe hepatic toxicities with nivolumab plus crizotinib.
  • Only combinations of α-PD-1/PD-L1 with chemotherapy, angiogenesis inhibitors, or α-CTLA-4 are approved by the FDA or NMPA; most other combinations remain preclinical or in clinical trials.

Methods

  • Narrative review of published preclinical and clinical literature on α-PD-1/PD-L1-based combination strategies.
  • Synthesizes mechanisms, approved indications, and clinical trial results across many cancer types, with tables listing selected trials and bispecific/bifunctional antibodies.
  • No primary patient data, systematic search strategy, or meta-analysis is reported.

Limitations

  • The paper states that many positive preclinical findings have not been validated clinically, that optimal preclinical models are a challenge, and that only a few combinations are approved.
  • It states that combination therapy increases irAE risk and healthcare cost, and that optimal dosage, timing, sequence, and predictive biomarkers remain unclear.
  • Evident from the text: this is a narrative review without a described systematic search or quantitative synthesis, so selection and interpretation of cited trials may be subject to bias.

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

Integrity signals

Registry

Crossref · 10.1186/s12943-021-01489-2

Cites

350 of 350 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 376 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    PD-1 signaling suppresses T cell functions, including activation, proliferation, and cytokine production.

    “As a result, PD-1 signaling suppresses T cell functions, including activation, proliferation, and cytokine production [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Premisecitation

    PD-1 signaling is commonly hijacked by cancer cells to escape immune surveillance.

    “Programmed cell death 1 (PD-1) signaling is commonly hijacked by cancer cells to escape immune surveillance [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Premisecitation

    5-fluorouracil, doxorubicin, gemcitabine, and docetaxel reduced circulating myeloid-derived suppressor cells (MDSCs) in mouse models.

    “although 5-fluorouracil, doxorubicin, gemcitabine, and docetaxel reduced circulating myeloid-derived suppressor cells (MDSCs) in mouse models [42–45]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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  • Premisecitation

    Accumulating evidence indicates that chemotherapy, radiotherapy, angiogenesis inhibitor, STING agonist, FMT, epigenetic modulators, or other immunomodulators could synergize α-PD-1/PD-L1, by enhancing cancer antigen release, APC function, or effector activity.

    “Accumulating evidence indicates that chemotherapy, radiotherapy, angiogenesis inhibitor, stimulator of interferon genes (STING) agonist, fecal microbiota transplantation (FMT), epigenetic modulators, or other immunomodulators could synergize α-PD-1/PD-L1, by enhancing cancer antigen release, APC function, or effector activity [22–31].”
    Quote in the paperSubstantial claim0 of 10 sources checked
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  • Premisecitation

    Paclitaxel promoted tumor-associated macrophage (TAM) repolarization from M2-like to M1-like phenotype.

    “Moreover, paclitaxel promoted tumor-associated macrophage (TAM) to repolarize from M2-like to M1-like phenotype [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims. 72
  • Classified as probably not a substantial claim. 22

  • May combine two claims.

    Interpretationreasoning

    These combination strategies simultaneously boost multiple processes in the cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment.

    “These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Strengthening these positive elements might boost the cancer-immune cycle, drive the transformation from cold to hot tumors, and improve the response to α-PD-1/PD-L1 therapies.

    “Correspondingly, strengthening these positive elements might boost the cancer-immune cycle, drive the transformation from cold to hot tumors, and improve the response to α-PD-1/PD-L1 therapies [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    Apart from immunogenic cell death, chemotherapy could directly eliminate immune suppressor cells and enhance the functions of effector cells, especially when administered at a dose below the maximum-tolerated dose.

    “Apart from immunogenic cell death, chemotherapy could directly eliminate immune suppressor cells and enhance the functions of effector cells, especially administrated at the dose below maximum-tolerated dose [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Some cytotoxic chemotherapeutic drugs such as anthracycline and oxaliplatin could induce immunogenic cell death and stimulate antitumor immune response.

    “Besides, some cytotoxic chemotherapeutic drugs such as anthracycline and oxaliplatin could induce immunogenic cell death and stimulate antitumor immune response [33, 34].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    The ATP-P2RX7 signaling recruits DCs into the tumor bed; the CRT-CD91 axis promotes DC to engulf cancer antigens; the HMGB1-TLR4 pathway facilitates optimal cancer antigen presentation.

    “The ATP-P2RX7 signaling recruits DCs into the tumor bed; the CRT-CD91 axis promotes DC to engulf cancer antigens; the HMGB1-TLR4 pathway facilitates the optimal cancer antigen presentation [36].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chemotherapy retards tumor growth mainly by arresting the cell cycle, inhibiting DNA replication, disturbing cell metabolism, or suppressing microtubule assembly.

    “Chemotherapy retards tumor growth mainly by arresting cell cycle, inhibiting DNA replication, disturbing cell metabolism, or suppressing microtubule assembly [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Gotwals P, Cameron S, Cipolletta D, Cremasco V, Crystal A, Hewes B, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer. 2017;17:286–301. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    For non-responders, PD-1 signaling is not the speed-limiting rheostat of the cancer-immunity cycle, and it is insufficient to revive antitumor immunity by blocking PD-1 or PD-L1.

    “For the non-responders, PD-1 signaling is not the speed-limiting rheostat of cancer-immunity cycle, and it is insufficient to revive antitumor immunity by blocking PD-1 or PD-L1 [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. source

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  • May combine two claims.

    Interpretationreasoning

    Removing these negative factors could enhance the therapeutic effect of α-PD-1/PD-L1 and relieve drug resistance.

    “Logically, removing these negative factors could enhance the therapeutic effect of α-PD-1/PD-L1 and relieve drug resistance.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Chemotherapy-mediated MDSC depletion remains to be further verified in cancer patients.

    “Therefore, the chemotherapy-mediated MDSC depletion remains further verification in cancer patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Radiotherapy promoted T cell infiltration, increased the number of TILs, and expanded TCR repertoire in the TME.

    “Firstly, radiotherapy promoted T cell infiltration, increased the number of TILs, and expanded T-cell receptor (TCR) repertoire in the TME [72, 73].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • May combine two claims.

    Interpretationreasoning

    Generally, pembrolizumab has a great advantage in chemoimmunotherapy, with a broad range of indications.

    “Generally, pembrolizumab has a great advantage on chemoimmunotherapy, with a broad range of indications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Radiotherapy not only eliminates local lesions but also stimulates the systemic antitumor immune response (abscopal effects).

    “Consequently, radiotherapy not only eliminates local lesions but also stimulates the systemic antitumor immune response (also known as abscopal effects) [71].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    Radiotherapy could induce immunogenic cell death and enhance antitumor immune response.

    “Like some chemotherapeutic drugs, radiotherapy could induce immunogenic cell death and enhance antitumor immune response [70].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Radiotherapy increased the MHC-I on tumor cells and relieved resistance to α-PD-1/PD-L1.

    “Thirdly, radiotherapy increased the MHC-I on tumor cells and relieved resistance to α-PD-1/PD-L1 (Fig. 1b) [75].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    Radiotherapy upregulated the expression of PD-L1 on tumor cells, which can be utilized by additional α-PD-1/PD-L1.

    “Secondly, radiotherapy upregulated the expression of PD-L1 on tumor cells, which can be utilized by additional α-PD-1/PD-L1 [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    VEGF could inhibit the maturation of DC, induce the exhaustion of T cells, promote the proliferation of Tregs, and increase the ratio of MDSCs.

    “Secondly, VEGF could inhibit the maturation of DC, induce the exhaustion of T cells, promote the proliferation of Tregs, and increase the ratio of MDSCs [90–93].”
    Quote in the paperSubstantial claim0 of 4 sources checked
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    Premisecitation

    Angiogenesis inhibitor blocks proangiogenic pathways, promotes vessel normalization, improves tumor perfusion and oxygenation, restores the hypoxic TME, and enhances drug delivery.

    “Angiogenesis inhibitor blocks these proangiogenic pathways, promotes vessel normalization, improves tumor perfusion and oxygenation, restores the hypoxic TME, and enhances drug delivery [100, 101].”
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    Premisecitation

    ANGPT2 recruits Tie-2-expressing monocytes, enhances the differentiation towards M2-like macrophages, and upregulates the expression of IL-10.

    “Thirdly, despite without direct influence on T cells, ANGPT2 recruits Tie-2-expressing monocytes, enhances the differentiation towards M2-like macrophages, and upregulates the expression of IL-10 [94–97].”
    Quote in the paperSubstantial claim0 of 4 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ipilimumab is the first approved α-CTLA-4 drug, initially used for advanced melanoma.

    “Ipilimumab (developed by Bristol-Myers Squibb) is the first approved α-CTLA-4 drug, initially used for advanced melanoma [127].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Angiogenesis inhibitor reshapes the TME: promoting T cell infiltration and DC maturation, enhancing the differentiation towards M1-like macrophage, decreasing the ratio of Treg and MDSC, and alleviating hypoxia-induced PD-L1.

    “Also, angiogenesis inhibitor reshapes the TME: promoting T cell infiltration and DC maturation, enhancing the differentiation towards M1-like macrophage, decreasing the ratio of Treg and MDSC, and alleviating hypoxia-induced PD-L1 (Fig. 1c) [93, 102–105].”
    Quote in the paperSubstantial claim0 of 5 sources checked
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    Premisecitation

    CTLA-4 is primarily expressed on activated T cells and Tregs, as a negative regulator for T cell activation.

    “CTLA-4 is primarily expressed on activated T cells and Tregs, as a negative regulator for T cell activation [121].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Tremelimumab is a human IgG2 monoclonal antibody targeting CTLA-4, which has entered phase 3 clinical trials.

    “Tremelimumab is a human IgG2 monoclonal antibody (developed by AstraZeneca) targeting CTLA-4, which has entered phase 3 clinical trials [139].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    EGFR is a member of the ErbB family that drives the initiation and development of multiple types of cancers.

    “EGFR is a member of ErbB family driving the initiation and development of multiple types of cancers [181].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    The results of some clinical trials were unsatisfactory, and no additional benefit was brought by tremelimumab plus durvalumab, compared to durvalumab monotherapy or standard chemotherapy.

    “The results of some clinical trials were unsatisfactory, and no additional benefit was brought by tremelimumab plus durvalumab, compared to durvalumab monotherapy or standard chemotherapy [140, 142, 144].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [140] Goldman JW, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22:51–65. source

      Not checked in the free run.

    • cites [142] Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21:1574–88. source

      Not checked in the free run.

    • cites [144] Ferris RL, Haddad R, Even C, Tahara M, Dvorkin M, Ciuleanu TE, et al. Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study. Ann Oncol. 2020;31:942–50. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preliminary data showed that co-stimulatory molecule agonists plus α-PD-1/PD-L1 were well-tolerated, supporting further investigation in advanced solid tumors.

    “The preliminary data showed that these combination strategies were well-tolerated, supporting further investigation in advanced solid tumors [177–180].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [177] Patel MR, Naing A III, HAB, Lin C-C, Curigliano G, Thistlethwaite F, et al. A phase 1/2 open-label study of KY1044, an anti-ICOS antibody with dual mechanism of action, as single agent and in combination with atezolizumab, in adult patients with advanced malignancies. J Clin Oncol. 2021. https://doi.org/10.1200/JCO.2021.39.15_suppl.2624. source

      Not checked in the free run.

    • cites [178] Weiss SA, Djureinovic D, Jessel S, Krykbaeva I, Zhang L, Jilaveanu L, et al. A phase I study of APX005M and Cabiralizumab with or without Nivolumab in patients with melanoma, kidney Cancer, or non-small cell lung Cancer resistant to anti-PD-1/PD-L1. Clin Cancer Res. 2021;27:4757–67. source

      Not checked in the free run.

    • cites [179] Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, Rasco DW, et al. Phase Ib study of Utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with Pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res. 2017;23:5349–57. source

      Not checked in the free run.

    • cites [180] Piha-Paul SA, Geva R, Tan TJ, Lim DW, Hierro C, Doi T, et al. First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas. J Immunother Cancer. 2021;9:e002863. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the phase 2 study NCT03563716, tiragolumab (α-TIGIT) plus atezolizumab showed an improvement in ORR (OR:2.57, 95%CI:1.07-6.14) and PFS (HR:0.57; 95%CI 0.37-0.90) in PD-L1 positive NSCLC, relative to placebo plus atezolizumab.

    “In addition, in the phase 2 study NCT03563716, tiragolumab (α-TIGIT) plus atezolizumab showed an improvement in ORR (OR:2.57, 95%CI:1.07–6.14) and PFS (HR:0.57; 95%CI 0.37–0.90) in PD-L1 positive NSCLC, relative to placebo plus atezolizumab [167].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] Rodriguez-Abreu D, Johnson ML, Hussein MA, Cobo M, Patel AJ, Secen NM, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020. https://doi.org/10.1200/JCO.2020.38.15_suppl.9503. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dual blockade of TIM-3 and PD-1/PD-L1 dramatically enhanced antitumor immune response and retarded tumor growth in murine tumor models.

    “Dual blockade of TIM-3 and PD-1/PD-L1 dramatically enhanced antitumor immune response and retarded tumor growth in murine tumor models [157].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207:2187–94. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PD-1/PD-L1 blockade followed by osimertinib led to a higher incidence rate of irAE, while osimertinib followed by PD-1/PD-L1 blockade decreased the risk of irAE.

    “PD-1/PD-L1 blockade followed by osimertinib led to a higher incidence rate of irAE, while osimertinib followed by PD-1/PD-L1 blockade decreased the risk of irAE [194].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [194] Schoenfeld AJ, Arbour KC, Rizvi H, Iqbal AN, Gadgeel SM, Girshman J, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30:839–44. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpressed ALK fusion protein increased PD-L1 level, promoting apoptosis of tumor-infiltrating T cells.

    “Overexpressed ALK fusion protein increased PD-L1 level, promoting the apoptosis of tumor-infiltrating T cells [201].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201] Hong S, Chen N, Fang W, Zhan J, Liu Q, Kang S, et al. Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients. Oncoimmunology. 2016;5:e1094598. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the phase 1 trial CheckMate-012, nivolumab combined with erlotinib showed potent and durable antitumor activity in EGFR-mutated NSCLC patients, with tolerable adverse events and no grade 4/5 adverse event reported.

    “In the phase 1 trial CheckMate-012, nivolumab combined with erlotinib showed potent and durable antitumor activity in EGFR-mutated NSCLC patients, with tolerable adverse events (no grade 4/5 adverse event reported) (Table 6) [189].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Gettinger S, Hellmann MD, Chow LQM, Borghaei H, Antonia S, Brahmer JR, et al. Nivolumab plus Erlotinib in patients with EGFR-mutant advanced NSCLC. J Thorac Oncol. 2018;13:1363–72. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A retrospective analysis showed that co-expression of PD-L1 and CD8 was rare in ALK-arranged tumors, which might contribute to the lower response rate to α-PD-1/PD-L1.

    “A retrospective analysis showed that the co-expression of PD-L1 and CD8 was rare in ALK-arranged tumors, which might contribute to the lower response rate to α-PD-1/PD-L1 [200].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Liu SY, Dong ZY, Wu SP, Xie Z, Yan LX, Li YF, et al. Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer. Lung Cancer. 2018;125:86–92. source

      Not checked in the free run.

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

    Premisecitation

    Upon ligand engagement, EGFR homodimerizes or heterodimerizes.

    “Upon the engagement with its ligands (such as epidermal growth factor, transforming growth factor-alpha, amphiregulin), EGFR would be homodimerized or heterodimerized [182].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17:53. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In NCT02013219, no pneumonitis and no dose-limiting toxicity were reported.

    “No pneumonitis and dose-limiting toxicity were reported in this study [190].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Rudin C, Cervantes A, Dowlati A, Besse B, Ma B, Costa D, et al. P3.02c-046 safety, clinical activity and biomarker results from a phase Ib study of Erlotinib plus Atezolizumab in advanced NSCLC. J Thorac Oncol. 2017. https://doi.org/10.1016/j.jtho.2016.11.1841. source

      Not checked in the free run.

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

    Premisecitation

    ALK-TKI has dramatically prolonged the survival of ALK-arranged patients.

    “ALK-TKI has dramatically prolonged the survival of ALK-arranged patients [198].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [198] Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, et al. First-line Lorlatinib or Crizotinib in advanced ALK-positive lung Cancer. N Engl J Med. 2020;383:2018–29. source

      Not checked in the free run.

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

    Premisecitation

    The constitutively activated ALK fusion gene promotes cancer development by initiating MAPK, PI3K-Akt, JAK-STAT, and PLCγ pathways.

    “The constitutively activated ALK fusion gene promotes cancer development by initiating some oncogenic pathways including MAPK, PI3K-Akt, JAK-STAT, and PLCγ [197].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Golding B, Luu A, Jones R, Viloria-Petit AM. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer. 2018;17:52. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ALK inhibition induced immunogenic cell death in ALK-arranged cancer cells and conferred protection against tumor rechallenge in the mouse model.

    “Besides, ALK inhibition induced immunogenic cell death in ALK-arranged cancer cells and conferred the protection of tumor rechallenge in the mouse model [202].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Petrazzuolo A, Perez-Lanzon M, Martins I, Liu P, Kepp O, Minard-Colin V, et al. Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects. Cell Death Dis. 2021;12:713. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    In the active state, RAS triggers several downstream pathways including MAPK and PI3K-AKT.

    “In active state, RAS triggers several downstream pathways including MAPK and PI3K-AKT [209].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [209] Roskoski R Jr. Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS. Pharmacol Res. 2021;172:105806. source

      Not checked in the free run.

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

    Premisecitation

    EML4-ALK fusion is the most common ALK arrangement variant in NSCLC patients.

    “EML4-ALK fusion is the most common ALK arrangement variant in NSCLC patients [196].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Katayama R, Lovly CM, Shaw AT. Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin Cancer Res. 2015;21:2227–35. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Atezolizumab plus alectinib and avelumab plus lorlatinib had a manageable safety profile, indicating that hepatotoxicity might be ALK-TKI specific.

    “Conversely, some other combination strategies such as atezolizumab plus alectinib and avelumab plus lorlatinib had a manageable safety profile, indicating the hepatotoxicity might be ALK-TKI specific [205, 206].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [205] Kim D-W, Gadgeel SM, Gettinger SN, Riely GJ, Oxnard GR, Mekhail T, et al. Safety and clinical activity results from a phase Ib study of alectinib plus atezolizumab in ALK+ advanced NSCLC (aNSCLC). J Clin Oncol. 2018. https://doi.org/10.1200/JCO.2018.36.15_suppl.9009. source

      Not checked in the free run.

    • cites [206] Shaw AT, Lee S-H, Ramalingam SS, Bauer TM, Boyer MJ, Costa EC, et al. Avelumab (anti–PD-L1) in combination with crizotinib or lorlatinib in patients with previously treated advanced NSCLC: phase 1b results from JAVELIN lung 101. J Clin Oncol. 2018. https://doi.org/10.1200/JCO.2018.36.15_suppl.9008. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EGFR-TKI could promote T cell infiltration, decrease the ratios of tumor-infiltrating Treg and M2-like macrophage, and improve responsiveness to α-PD-1/PD-L1 in EGFR-mutated models.

    “Recent studies demonstrated that EGFR-TKI could promote T cell infiltration, decrease the ratios of tumor-infiltrating Treg and M2-like macrophage, and improve the responsiveness to α-PD-1/PD-L1 in EGFR-mutated models [17, 187].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Bai X, Yi M, Jiao Y, Chu Q, Wu K. Blocking TGF-β signaling to enhance the efficacy of immune checkpoint inhibitor. Onco Targets Ther. 2019;12:9527–38. source

      Not checked in the free run.

    • cites [187] Sugiyama E, Togashi Y, Takeuchi Y, Shinya S, Tada Y, Kataoka K, et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Sci Immunol. 2020;5:eaav3937. source

      Not checked in the free run.

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

    Premisecitation

    ALK is a receptor tyrosine kinase belonging to the insulin receptor superfamily.

    “ALK is a receptor tyrosine kinase belonging to insulin receptor superfamily [195].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene. 1997;14:439–49. source

      Not checked in the free run.

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

    Premisecitation

    Mutated KRAS is a well-established driver gene of NSCLC, colorectal cancer, and pancreatic cancer.

    “Mutated KRAS is a well-established driver gene of NSCLC, colorectal cancer, and pancreatic cancer [208].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] Hamarsheh S, Groß O, Brummer T, Zeiser R. Immune modulatory effects of oncogenic KRAS in cancer. Nat Commun. 2020;11:5439. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In tumor cells, RAS mutations disturb the switch between GTP-bound and GDP-bound states, locking RAS in the GTP-bound state and leading to hyperactive downstream pathways and tumor growth.

    “In tumor cells, mutations in RAS disturb this switch between GTP-bound state and GDP-bound state. As a result, RAS is locked in GTP-bound state, leading to the hyperactive downstream pathways and tumor growth [209, 210].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [209] Roskoski R Jr. Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS. Pharmacol Res. 2021;172:105806. source

      Not checked in the free run.

    • cites [210] Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19:533–52. source

      Not checked in the free run.

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

    Premisecitation

    RAS is a small G protein that toggles between a GTP-bound active state and a GDP-bound inactive state.

    “RAS is a small G protein, toggling between GTP-bound state (active) and GDP-bound state (inactive).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Roskoski R Jr. Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS. Pharmacol Res. 2021;172:105806. source

      Not checked in the free run.

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

    Premisecitation

    Phosphorylation of the cytoplasmic tyrosine kinase domain of EGFR triggers activation of PI3K-AKT and MAPK pathways.

    “Then, the cytoplasmic tyrosine kinases domain of EGFR is phosphorylated, triggering the activation of PI3K-AKT and MAPK pathways [182].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer. 2018;17:53. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CDK4/6 inhibitors promoted NF-κB activation, increased T cell chemoattractant and PD-L1 level, and prevented PD-L1 degradation in cancer cells.

    “CDK4/6 inhibitors promoted NF-κB activation, increased T cell chemoattractant and PD-L1 level, and prevented PD-L1 degradation in cancer cells [244].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [244] Lelliott EJ, McArthur GA, Oliaro J, Sheppard KE. Immunomodulatory effects of BRAF, MEK, and CDK4/6 inhibitors: implications for combining targeted therapy and immune checkpoint blockade for the treatment of melanoma. Front Immunol. 2021;12:661737. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PARP inhibitor modulates the TME and promotes the antitumor immune response.

    “Besides synthetic lethal effect, PARP inhibitor (PARPi) modulates the TME and promotes the antitumor immune response [223].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [223] Stewart RA, Pilié PG, Yap TA. Development of PARP and immune-checkpoint inhibitor combinations. Cancer Res. 2018;78:6717–25. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the phase 1 study NCT02660034, pamiparib plus tislelizumab was well-tolerated, and 20% of patients with advanced solid tumors achieved an objective response at a median follow-up of 8.3 months.

    “In the phase 1 study NCT02660034, pamiparib plus tislelizumab was well-tolerated, and 20% of patients with advanced solid tumors achieved an objective response at a median follow-up of 8.3 months [226].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [226] Friedlander M, Meniawy T, Markman B, Mileshkin L, Harnett P, Millward M, et al. Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. Lancet Oncol. 2019;20:1306–15. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CDK4/6 inhibitors upregulated NFAT activity and elevated effector gene expression in T cells.

    “Besides, CDK4/6 inhibitors upregulated NFAT activity and elevated effector gene expression in T cells [244].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [244] Lelliott EJ, McArthur GA, Oliaro J, Sheppard KE. Immunomodulatory effects of BRAF, MEK, and CDK4/6 inhibitors: implications for combining targeted therapy and immune checkpoint blockade for the treatment of melanoma. Front Immunol. 2021;12:661737. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PARPi activates the cGAS-STING pathway in cancer cells and increases T cell recruitment.

    “Firstly, PARPi activates cGAS-STING pathway in cancer cells and increases T cell recruitment [224].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [224] Pantelidou C, Sonzogni O, De Oliveria TM, Mehta AK, Kothari A, Wang D, et al. PARP inhibitor efficacy depends on CD8(+) T-cell recruitment via Intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast Cancer. Cancer Discov. 2019;9:722–37. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutant FGFR signaling might be related to poor response to α-PD-1/PD-L1, and FGFR inhibitor synergized with α-PD-1/PD-L1 in FGFRmut models.

    “Mutant FGFR signaling might be related to the poor response to α-PD-1/PD-L1, and FGFR inhibitor synergized with α-PD-1/PD-L1 in FGFRmut models [234].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [234] Palakurthi S, Kuraguchi M, Zacharek SJ, Zudaire E, Huang W, Bonal DM, et al. The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity. Cancer Immunol Res. 2019;7:1457–71. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the phase 1/2 study KEYNOTE-162, niraparib plus pembrolizumab was tolerable, with considerable antitumor efficacy in recurrent ovarian carcinoma (ORR 18%; DCR 65%).

    “Moreover, in the phase 1/2 study KEYNOTE-162, niraparib plus pembrolizumab was tolerable, with a considerable antitumor efficacy in recurrent ovarian carcinoma (ORR: 18%; DCR: 65%) [228].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Konstantinopoulos PA, Waggoner S, Vidal GA, Mita M, Moroney JW, Holloway R, et al. Single-arm phases 1 and 2 trial of Niraparib in combination with Pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019;5:1141–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    c-MET signaling upregulated PD-L1 expression, and c-MET inhibitor impaired intrinsic and IFN-γ-induced PD-L1 expression.

    “c-MET signaling upregulated PD-L1 expression, and c-MET inhibitor impaired intrinsic and IFN-γ-induced PD-L1 expression [239–241].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [239] Saigi M, Alburquerque-Bejar JJ, Mc Leer-Florin A, Pereira C, Pros E, Romero OA, et al. MET-oncogenic and JAK2-inactivating alterations are independent factors that affect regulation of PD-L1 expression in lung Cancer. Clin Cancer Res. 2018;24:4579–87. source

      Not checked in the free run.

    • cites [240] Balan M, Mier y Teran E, Waaga-Gasser AM, Gasser M, Choueiri TK, Freeman G, et al. Novel roles of c-met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J Biol Chem. 2015;290:8110–20. source

      Not checked in the free run.

    • cites [241] Martin V, Chiriaco C, Modica C, Acquadro A, Cortese M, Galimi F, et al. Met inhibition revokes IFNγ-induction of PD-1 ligands in MET-amplified tumours. Br J Cancer. 2019;120:527–36. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Erdafitinib plus α-PD-1 broadened the TCR repertoire and increased T cell fraction, contributing to superior antitumor efficacy.

    “The combination of erdafitinib (FGFR inhibitor) and α-PD-1 broadened the TCR repertoire and increased T cell fraction, contributing to the superior antitumor efficacy [234].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [234] Palakurthi S, Kuraguchi M, Zacharek SJ, Zudaire E, Huang W, Bonal DM, et al. The combined effect of FGFR inhibition and PD-1 blockade promotes tumor-intrinsic induction of antitumor immunity. Cancer Immunol Res. 2019;7:1457–71. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RAS and its downstream pathways participate in cancer immune escape by negatively regulating MHC-I expression on cancer cells, increasing cell-intrinsic PD-L1 level, and elevating immune suppression-associated cytokine production.

    “Recent studies have shown that RAS and its downstream pathways participated in cancer immune escape: negatively regulating MHC-I expression on cancer cells, increasing the cell-intrinsic PD-L1 level, elevating immune suppression-associated cytokine production [211, 212].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [211] Dennison L, Mohan AA, Yarchoan M. Tumor and systemic Immunomodulatory effects of MEK inhibition. Curr Oncol Rep. 2021;23:23. source

      Not checked in the free run.

    • cites [212] Nishida N. Role of oncogenic pathways on the Cancer immunosuppressive microenvironment and its clinical implications in hepatocellular carcinoma. Cancers (Basel). 2021;13:3666. source

      Not checked in the free run.

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

    Premisecitation

    Activated c-MET signaling triggers downstream MAPK, PI3K-AKT, RAC1, and FAK pathways.

    “Activated c-MET signaling triggers downstream MAPK, PI3K-AKT, RAC1, and FAK pathways [238].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [238] Fu J, Su X, Li Z, Deng L, Liu X, Feng X, et al. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene. 2021;40:4625–51. source

      Not checked in the free run.

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

    Premisecitation

    CDK4/6 is an essential component of the cell cycle that cooperates with cyclin D to promote the G1/S transition.

    “Cyclin-dependent kinase 4/6 (CDK4/6) is an essential component of cell cycle, which cooperates with cyclin D to promote cell cycle G1/S transition [243].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] Xu H, Yu S, Liu Q, Yuan X, Mani S, Pestell RG, et al. Recent advances of highly selective CDK4/6 inhibitors in breast cancer. J Hematol Oncol. 2017;10:97. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interim results of phase 1/2 study NCT02393248 indicated that pemigatinib combined with pembrolizumab was tolerable, with a potent antitumor effect in FGFRmut patients.

    “The interim results of phase 1/2 study NCT02393248 indicated pemigatinib (FGFR inhibitor) combined with pembrolizumab therapy was tolerable, with a potent antitumor effect in FGFRmut patients [236].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [236] Gutierrez M, Subbiah V, Nemunaitis JJ, Mettu NB, Papadopoulos KP, Barve MA, et al. Safety and efficacy of pemigatinib plus pembrolizumab combination therapy in patients (pts) with advanced malignancies: results from FIGHT-101, an open-label phase I/II study. J Clin Oncol. 2020. https://doi.org/10.1200/JCO.2020.38.15_suppl.3606. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    STING recruits and phosphorylates TBK1, which further activates downstream IRF3 and upregulates IFN-I.

    “Then, STING recruits and phosphorylates TBK1, which further activates downstream IRF3 and upregulates IFN-I [257–259].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [257] Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013;153:1094–107. source

      Not checked in the free run.

    • cites [258] Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498:380–4. source

      Not checked in the free run.

    • cites [259] Jiang M, Chen P, Wang L, Li W, Chen B, Liu Y, et al. cGAS-STING, an important pathway in cancer immunotherapy. J Hematol Oncol. 2020;13:81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M7824 is a TGF-β × PD-L1 bifunctional protein that had potent antitumor activity in murine tumor models.

    “M7824 is a TGF-β × PD-L1 bifunctional protein, which had potent antitumor activity in murine tumor models (Fig. 2c) [278].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [278] Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018;10:eaan5488. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    STING agonist promotes immune cell infiltration and enhances the function of APC, NK, and T cells.

    “On the one hand, STING agonist promotes immune cell infiltration and enhances the function of APC, NK, and T cells [272–274].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [272] Nakamura T, Sato T, Endo R, Sasaki S, Takahashi N, Sato Y, et al. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation. J Immunother Cancer. 2021;9:e002852. source

      Not checked in the free run.

    • cites [273] Yi M, Niu M, Zhang J, Li S, Zhu S, Yan Y, et al. Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers. J Hematol Oncol. 2021;14:146. source

      Not checked in the free run.

    • cites [274] Song Y, Liu Y, Teo HY, Hanafi ZB, Mei Y, Zhu Y, et al. Manganese enhances the antitumor function of CD8(+) T cells by inducing type I interferon production. Cell Mol Immunol. 2021;18:1571–4. source

      Not checked in the free run.

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

    Premisecitation

    SHP2 is an oncogenic protein belonging to the protein tyrosine phosphatases family.

    “SHP2 is an oncogenic protein belonging to protein tyrosine phosphatases family [250].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250] Song Z, Wang M, Ge Y, Chen XP, Xu Z, Sun Y, et al. Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies. Acta Pharm Sin B. 2021;11:13–29. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stimulated by cGAMP, STING changes from monomer to dimer and translocates from the ER to the perinuclear microsome.

    “Stimulated by cGAMP, STING changes from monomer to dimer and translocates from ER to perinuclear microsome.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [257] Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013;153:1094–107. source

      Not checked in the free run.

    • cites [258] Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498:380–4. source

      Not checked in the free run.

    • cites [259] Jiang M, Chen P, Wang L, Li W, Chen B, Liu Y, et al. cGAS-STING, an important pathway in cancer immunotherapy. J Hematol Oncol. 2020;13:81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phase 1 studies of M7824 were encouraging, and patients receiving M7824 had a higher ORR compared to previous data.

    “The results of phase 1 studies were encouraging, and patients receiving M7824 had a higher ORR, compared to previous data [303, 304].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [303] Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, et al. Phase I trial of M7824 (MSB0011359C), a Bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors. Clin Cancer Res. 2018;24:1287–95. source

      Not checked in the free run.

    • cites [304] Paz-Ares L, Kim TM, Vicente D, Felip E, Lee DH, Lee KH, et al. Bintrafusp Alfa, a Bifunctional fusion protein targeting TGF-β and PD-L1, in second-line treatment of patients with NSCLC: results from an expansion cohort of a phase 1 trial. J Thorac Oncol. 2020;15:1210–22. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Bispecific/bifunctional antibody simultaneously blocks two molecules with one drug, having a strategic advantage over combination therapy.

    “Bispecific/bifunctional antibody simultaneously blocks two molecules with one drug, having a strategic advantage over the combination therapy (Table 7) [277].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [277] Kontermann RE. Dual targeting strategies with bispecific antibodies. MAbs. 2012;4:182–97. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Combination therapy of STING agonist and α-PD-1/PD-L1 simultaneously boosts innate immunity and adaptive immunity, effectively overcoming resistance to immunotherapy.

    “The combination therapy of STING agonist and α-PD-1/PD-L1 simultaneously boosts innate immunity and adaptive immunity, effectively overcoming resistance to immunotherapy.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The cGAS-STING pathway is a cytosolic DNA sensing signaling pathway.

    “cGAS-STING pathway is a cytosolic DNA sensing signaling.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [257] Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013;153:1094–107. source

      Not checked in the free run.

    • cites [258] Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Röhl I, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498:380–4. source

      Not checked in the free run.

    • cites [259] Jiang M, Chen P, Wang L, Li W, Chen B, Liu Y, et al. cGAS-STING, an important pathway in cancer immunotherapy. J Hematol Oncol. 2020;13:81. source

      Not checked in the free run.

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

    Premisecitation

    DMXAA is the first STING agonist and failed in clinical trials.

    “Dimethyloxoxanthenyl acetic acid (DMXAA) is the first STING agonist which failed in the clinical trials [262].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [262] Lara PN Jr, Douillard JY, Nakagawa K, von Pawel J, McKeage MJ, Albert I, et al. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:2965–71. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Manganese is identified as a natural STING agonist and plays an important role in antitumor immunity.

    “Besides, manganese is also identified as a natural STING agonist, playing an important role in antitumor immunity [270, 271].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [270] Lv M, Chen M, Zhang R, Zhang W, Wang C, Zhang Y, et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020;30:966–79. source

      Not checked in the free run.

    • cites [271] Wang C, Guan Y, Lv M, Zhang R, Guo Z, Wei X, et al. Manganese increases the sensitivity of the cGAS-STING pathway for double-stranded DNA and is required for the host defense against DNA viruses. Immunity. 2018;48:675–87.e7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DMXAA is a mouse-specific STING agonist with a subtle influence on the human STING pathway.

    “Further investigation has identified that DMXAA is a mouse-specific STING agonist, with a subtle influence on human STING pathway [263, 264].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [263] Shih AY, Damm-Ganamet KL, Mirzadegan T. Dynamic structural differences between human and mouse STING Lead to differing sensitivity to DMXAA. Biophys J. 2018;114:32–9. source

      Not checked in the free run.

    • cites [264] Conlon J, Burdette DL, Sharma S, Bhat N, Thompson M, Jiang Z, et al. Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J Immunol. 2013;190:5216–25. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TGF-β is a well-studied immunoinhibitory cytokine that restrains immune cell infiltration, induces Treg differentiation, and hampers the functions of T cells, APCs, and NK cells.

    “TGF-β is a well-studied immunoinhibitory cytokine: restraining immune cell infiltration, inducing Treg differentiation, and hampering the functions of T cell, APC, and NK [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Bai X, Yi M, Jiao Y, Chu Q, Wu K. Blocking TGF-β signaling to enhance the efficacy of immune checkpoint inhibitor. Onco Targets Ther. 2019;12:9527–38. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperactivated TGF-β signaling was associated with poor response to α-PD-1/PD-L1, and blocking TGF-β significantly improved the efficacy of α-PD-1/PD-L1.

    “Hyperactivated TGF-β signaling was associated with the poor response to α-PD-1/PD-L1, and blocking TGF-β significantly improved the efficacy of α-PD-1/PD-L1 [299–302].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [299] Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018;554:538–43. source

      Not checked in the free run.

    • cites [300] Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8. source

      Not checked in the free run.

    • cites [301] Chen X, Wang L, Li P, Song M, Qin G, Gao Q, et al. Dual TGF-β and PD-1 blockade synergistically enhances MAGE-A3-specific CD8(+) T cell response in esophageal squamous cell carcinoma. Int J Cancer. 2018;143:2561–74. source

      Not checked in the free run.

    • cites [302] Kim BG, Malek E, Choi SH, Ignatz-Hoover JJ, Driscoll JJ. Novel therapies emerging in oncology to target the TGF-β pathway. J Hematol Oncol. 2021;14:55. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The safety and efficacy of α-PD-1/PD-L1 combined with IL-2 pathway agonist (NKTR-214/BEMPEG), PEGylated IL-10 (Pegilodecakin), IL-12 plasmid (Tavo), IL-15 agonist (ALT-803), or PEGylated IFN-α had been validated in cancer patients.

    “The safety and efficacy of α-PD-1/PD-L1 combined with IL-2 pathway agonist (NKTR-214/BEMPEG) [321], PEGylated IL-10 (Pegilodecakin) [322], IL-12 plasmid (Tavo) [323], IL-15 agonist (ALT-803) [324], or PEGylated IFN-α [325] had been validated in cancer patients.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [321] Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, et al. Bempegaldesleukin (NKTR-214) plus Nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 2020;10:1158–73. source

      Not checked in the free run.

    • cites [322] Naing A, Infante JR, Papadopoulos KP, Chan IH, Shen C, Ratti NP, et al. PEGylated IL-10 (Pegilodecakin) induces systemic immune activation, CD8(+) T cell invigoration and polyclonal T cell expansion in Cancer patients. Cancer Cell. 2018;34:775–91.e3. source

      Not checked in the free run.

    • cites [323] Algazi AP, Twitty CG, Tsai KK, Le M, Pierce R, Browning E, et al. Phase II trial of IL-12 plasmid transfection and PD-1 blockade in immunologically quiescent melanoma. Clin Cancer Res. 2020;26:2827–37. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PD-1 × PD-L1 and CD47 × PD-L1 bispecific antibodies had enhanced immunomodulatory properties and improved antitumor activity relative to monospecific PD-1 and PD-L1 antibodies.

    “Besides, PD-1 × PD-L1 (LY3434172) and CD47 × PD-L1 (IBI322) bispecific antibodies had enhanced immunomodulatory properties and improved antitumor activity, relative to monospecific PD-1 and PD-L1 antibodies [297, 298].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [297] Kotanides H, Li Y, Malabunga M, Carpenito C, Eastman SW, Shen Y, et al. Bispecific targeting of PD-1 and PD-L1 enhances T-cell activation and antitumor immunity. Cancer Immunol Res. 2020;8:1300–10. source

      Not checked in the free run.

    • cites [298] Wang Y, Ni H, Zhou S, He K, Gao Y, Wu W, et al. Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity. Cancer Immunol Immunother. 2021;70:365–76. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The EGFR×PD-L1 bispecific antibody had enhanced tumor specificity, reducing the risks of indiscriminate reactivation of antitumor T cells and severe treatment-related adverse events.

    “This antibody had an enhanced tumor specificity, reducing the risks of the indiscriminate reactivation of antitumor T cells and severe treatment-related adverse events [296].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [296] Koopmans I, Hendriks D, Samplonius DF, van Ginkel RJ, Heskamp S, Wierstra PJ, et al. A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint. Oncoimmunology. 2018;7:e1466016. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    YM101 promoted T cell infiltration, enhanced T cell function, impaired CAF activity, and induced macrophage polarization toward an M2-like phenotype.

    “Further investigation showed that YM101 promoted T cell infiltration, enhanced T cell function, impaired cancer-associated fibroblasts (CAF) activity, and induced macrophage polarization toward M2-like phenotype [279].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [279] Yi M, Zhang J, Li A, Niu M, Yan Y, Jiao Y, et al. The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1. J Hematol Oncol. 2021;14:27. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    c-MET×PD-1 bispecific antibodies simultaneously reversed c-Met-mediated cell proliferation and migration and enhanced T cell functions.

    “c-MET×PD-1 bispecific antibodies simultaneously reversed c-Met-mediated cell proliferation and migration and enhanced T cell functions [292–295].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [292] Yuan Q, Liang Q, Sun Z, Yuan X, Hou W, Wang Y, et al. Development of bispecific anti-c-met/PD-1 diabodies for the treatment of solid tumors and the effect of c-met binding affinity on efficacy. Oncoimmunology. 2021;10:1914954. source

      Not checked in the free run.

    • cites [293] Hou W, Yuan Q, Yuan X, Wang Y, Mo W, Wang H, et al. A novel tetravalent bispecific antibody targeting programmed death 1 and tyrosine-protein kinase met for treatment of gastric cancer. Investig New Drugs. 2019;37:876–89. source

      Not checked in the free run.

    • cites [294] Wu Y, Yu M, Sun Z, Hou W, Wang Y, Yuan Q, et al. Generation and characterization of a Bispecific antibody targeting both PD-1 and c-MET. Protein Pept Lett. 2018;24:1105–12. source

      Not checked in the free run.

    • cites [295] Sun ZJ, Wu Y, Hou WH, Wang YX, Yuan QY, Wang HJ, et al. A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer. Oncotarget. 2017;8:29067–79. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bispecific antibodies targeting PD-1/PD-L1 and co-stimulatory molecules augmented the functions of TILs and exerted powerful antitumor efficacy.

    “These bispecific antibodies augmented the functions of TILs and exerted a powerful antitumor efficacy [288–291].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [288] Geuijen C, Tacken P, Wang LC, Klooster R, van Loo PF, Zhou J, et al. A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade. Nat Commun. 2021;12:4445. source

      Not checked in the free run.

    • cites [289] Jeong S, Park E, Kim HD, Sung E, Kim H, Jeon J, et al. Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade. J Immunother Cancer. 2021;9:e002428. source

      Not checked in the free run.

    • cites [290] Zhai T, Wang C, Xu Y, Huang W, Yuan Z, Wang T, et al. Generation of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer. J Immunother Cancer. 2021;9:e002131. source

      Not checked in the free run.

    • cites [291] Vitale LA, He LZ, Thomas LJ, Wasiuk A, O'Neill T, Widger J, et al. Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy. Cancer Immunol Immunother. 2020;69:2125–37. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EGFR×PD-L1 bispecific antibody was developed for EGFR+ tumors, avoiding on-target/off-tumor binding to PD-L1 on nonmalignant cells.

    “Moreover, avoiding ‘on-target/off-tumor’ binding to PD-L1 on nonmalignant cells, EGFR×PD-L1 bispecific antibody was developed for EGFR+ tumors [296].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [296] Koopmans I, Hendriks D, Samplonius DF, van Ginkel RJ, Heskamp S, Wierstra PJ, et al. A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint. Oncoimmunology. 2018;7:e1466016. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Relative to widely used syngeneic murine models, humanized patient-derived models could provide a more precious efficacy evaluation.

    “Relative to widely used syngeneic murine models, humanized patient-derived models could provide a more precious efficacy evaluation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Although dozens of combination regimens exhibit potent antitumor activities in preclinical studies, some positive preclinical findings could not be validated in the clinic.

    “Although dozens of combination regimens exhibit potent antitumor activities in preclinical studies, some positive preclinical findings could not be validated in the clinic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The efficacy of CAR-T cell therapy is modest in most solid tumors, which is partly attributed to the immunosuppressive TME.

    “However, the efficacy of CAR-T cell therapy is modest in most solid tumors, which is partly attributed to the immunosuppressive TME [340].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [340] Tian Y, Li Y, Shao Y, Zhang Y. Gene modification strategies for next-generation CAR T cells against solid cancers. J Hematol Oncol. 2020;13:54. source

      Not checked in the free run.

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

    Interpretationnone given

    Inappropriate combination treatments will expose patients to significantly higher toxicities.

    “Inappropriate combination treatments will expose patients to significantly higher toxicities.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Combination therapy increases the risk of irAEs and the cost of health care.

  • May combine two claims.

    Interpretationcitation

    Liquid biopsy could dynamically monitor the immune landscape of the TME and provide a real-time biomarker for guiding precision immunotherapy.

    “Considering the heterogeneity and evolution of tumors, liquid biopsy could dynamically monitor the immune landscape of the TME and provide a real-time biomarker for guiding precision immunotherapy [346].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [346] Zhang T, Agarwal A, Almquist RG, Runyambo D, Park S, Bronson E, et al. Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer. Biomark Res. 2021;9:14. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Combining these therapies with α-PD-1/PD-L1 simultaneously boosts multiple processes in the cancer-immunity cycle, reshapes the TME, and substantially promotes the transformation from non-inflamed to inflamed tumors.

    “Combining these therapies with α-PD-1/PD-L1 simultaneously boosts multiple processes in the cancer-immunity cycle, reshapes the TME, and substantially promotes the transformation from non-inflamed to inflamed tumors (Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    For patients with non-inflamed tumors, α-PD-1/PD-L1 monotherapy scarcely provides clinical benefits, and a personalized combination is needed to overcome drug resistance.

    “For patients with non-inflamed tumors, α-PD-1/PD-L1 monotherapy scarcely provides clinical benefits, and a personalized combination is needed to overcome drug resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CAR-T cell therapy provides numerous cancer-reactive T cells and overcomes MHC downregulation-mediated cancer immune evasion.

    “CAR-T cell therapy provides numerous cancer-reactive T cells and overcomes MHC downregulation-mediated cancer immune evasion [339].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [339] Yu S, Li A, Liu Q, Li T, Yuan X, Han X, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017;10:78. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Accumulated adenosine in the TME promotes cancer immune evasion, and A2AR blockade rescues immune cell function.

    “The accumulated adenosine in the TME promotes cancer immune evasion, and A2AR blockade rescues immune cell function [335, 336].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [335] Borodovsky A, Barbon CM, Wang Y, Ye M, Prickett L, Chandra D, et al. Small molecule AZD4635 inhibitor of a(2A)R signaling rescues immune cell function including CD103(+) dendritic cells enhancing anti-tumor immunity. J Immunother Cancer. 2020;8:e000417. source

      Not checked in the free run.

    • cites [336] Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J Immunother Cancer. 2018;6:57. source

      Not checked in the free run.

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

    Premisecitation

    CAR-T cells are genetically engineered T cells that could recognize and bind cancer antigen in an MHC-independent manner.

    “CAR-T cells are genetically engineered T cells, which could recognize and bind cancer antigen in an MHC-independent manner [339].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [339] Yu S, Li A, Liu Q, Li T, Yuan X, Han X, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017;10:78. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    With the development of next-generation α-PD-1/PD-L1 drugs such as bifunctional or bispecific antibodies, the indication of α-PD-1/PD-L1 therapies would be greatly extended, and more patients could benefit from updated α-PD-1/PD-L1 treatments.

    “Besides, with the development of next-generation α-PD-1/PD-L1 drugs such as bifunctional or bispecific antibodies, the indication of α-PD-1/PD-L1 therapies would be greatly extended, and more patients could benefit from the updated α-PD-1/PD-L1 treatments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This combination strategy protects CAR-T cells from immune exhaustion and optimizes CAR-T cell efficacy.

    “This combination strategy protects CAR-T cells from immune exhaustion and optimizes CAR-T cell efficacy.”
    Quote in the paperSubstantial claim
91 of 91

  • The paper relies on this without support.

    Resistance to α-PD-1/PD-L1 is related to the upregulation of other immune checkpoints.

    “The resistance to α-PD-1/PD-L1 is related to the upregulation of other immune checkpoints.”

  • The paper relies on this without support.

    At present, only combinations of α-PD-1/PD-L1 with chemotherapy, angiogenesis inhibitor, or α-CTLA-4 are approved by the FDA or NMPA.

    “At present, only combinations of α-PD-1/PD-L1 with chemotherapy, angiogenesis inhibitor, or α-CTLA-4 are approved by the FDA or NMPA.”

  • The paper relies on this without support.

    Combination therapy increases the risk of irAEs and the cost of health care.

    “Besides, combination therapy increases the risk of irAEs and the cost of health care.”

  • The paper relies on this without support.

    Cyclic dinucleotides have two main flaws: poor transmembrane capability and dependence on intratumor injection.

    “Generally, CDNs have two main flaws: poor transmembrane capability and depending on intratumor injection.”
4 of 4

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?

  • Combination therapies based on PD-1/PD-L1 blockade for a wide range of cancer types have been introduced and can improve patient survival.

    “Combination therapies based on PD-1/PD-L1 blockade for a wide range of cancer types have been introduced and can improve patient survival (20).”

    From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [20]

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Authors
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K.
Affiliations
  • Tongji Hospital (CN)
  • Zhengzhou University (CN)
Corresponding author
  • Ge, Hong
  • Wu, Kongming
ORCID
Venue
Molecular Cancer
Publisher
Springer Science and Business Media LLC
Published
2022-01-21
Volume
21
Issue
1
Pages
28-28
ISSN
1476-4598 (ISSN-L)
DOI
10.1186/s12943-021-01489-2
PMC
PMC8780712
OpenAlex
W4205454439
Semantic Scholar
f4e684bbde5e40b309cd839f9099a1ad8c26cf49
Cited by
1,445
References
350
Citations by year
2026: 224 · 2025: 417 · 2024: 430 · 2023: 266 · 2022: 107
FWCI
37.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81874120, 82073370)
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
PD-1/PD-L1 blockade, immune checkpoint inhibitors, combination cancer therapy, nivolumab, pembrolizumab, durvalumab, avelumab, bispecific antibodies, cancer immunotherapy, tumor microenvironment, cancer-immunity cycle, treatment resistance
MeSH terms
Clinical Studies as Topic, Immune Checkpoint Inhibitors, Antineoplastic Combined Chemotherapy Protocols, Combined Modality Therapy, Disease Susceptibility, Humans, Neoplasms, Prognosis, Biomarkers, Tumor, Treatment Outcome, Disease Management, Molecular Targeted Therapy, B7-H1 Antigen, 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 2026-10-10.

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

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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