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Cited by 750Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

The Next Decade of Immune Checkpoint Therapy

Open access
Sharma, Padmanee, Siddiqui, Bilal A., Anandhan, Swetha, Yadav, Shalini S., Subudhi, Sumit K., Gao, Jianjun, Goswami, Sangeeta, Allison, James P.·2021·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-1680
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Abstract

Immune checkpoint therapy (ICT) can provide durable clinical responses and improve overall survival. However, only subsets of patients with specific tumor types respond to ICT. Thus, significant challenges remain, including understanding pathways of resistance, optimizing patient selection, improving management of immune-related adverse events, and identifying rational therapeutic combinations. These challenges will need a focused approach encompassing both clinical and basic research, with the integration of reverse translational studies. This integrated approach will lead to identification of potential targets for subsequent clinical trials, which will guide decisions as we develop novel combination strategies to maximize efficacy and minimize toxicities for patients. Significance: ICTs induce durable antitumor responses for subsets of patients with cancer. Recent evidence suggests that rational combinatorial strategies can improve response by overcoming primary and adaptive resistance mechanisms, although these may carry an increased risk of immune-mediated toxicities. This review surveys the current understanding of mechanisms of response and resistance to ICTs and active areas of investigation, and proposes a path forward to improving efficacy and minimizing toxicities through better patient selection and rational combinations.

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Crossref · 10.1158/2159-8290.cd-20-1680

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Claims the paper makes

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  • Findingown data

    Analysis of the immune microenvironment of five tumor types revealed that immune checkpoint therapy-sensitive and therapy-resistant tumor types have distinct immune microenvironments.

    “Analysis of the immune microenvironment of five different tumor types, including those that respond relatively well to ICT and those that do not, revealed that ICT-sensitive and ICT-resistant tumor types have distinct immune microenvironments.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Rational combinatorial strategies can improve response by overcoming primary and adaptive resistance mechanisms.

    “Recent evidence suggests that rational combinatorial strategies can improve response by overcoming primary and adaptive resistance mechanisms, although these may carry an increased risk of immune-mediated toxicities.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Only subsets of patients with specific tumor types respond to immune checkpoint therapy.

    “However, only subsets of patients with specifi c tumor types respond to ICT.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Rational combinatorial strategies may carry an increased risk of immune-mediated toxicities.

    “Recent evidence suggests that rational combinatorial strategies can improve response by overcoming primary and adaptive resistance mechanisms, although these may carry an increased risk of immune-mediated toxicities.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The CD8 T-cell population is diverse rather than uniform.

    “CD8 T cells are typically regarded as a uniform population with cytotoxic function; however, recent studies have highlighted the diversity of the CD8 T-cell population (5)(6)(7)(8)(9).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Khan, 2019, TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion, Nature source

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    • cites [6] Scott, 2019, TOX is a critical regulator of tumour-specific T cell differentiation, Nature source

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    • cites [7] Chen, 2019, TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision, Immunity source

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  • May combine two claims. 45
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    Premisecitation

    Immune checkpoint therapy can produce durable clinical responses and improve overall survival in some patients with cancer.

    “Immune checkpoint therapy (ICT) can provide durable clinical responses and improve overall survival.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Leach, 1996, Enhancement of antitumor immunity by CTLA-4 blockade, Science source

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    Premisecitation

    T-cell activation requires two primary signals: a TCR signal through CD3 and a CD28 costimulatory signal through B7.

    “To activate or turn T cells “on,” both the TCR signal via CD3 (signal 1) and the CD28 costimulatory signal via B7 interactions (signal 2) are required (Fig. 1A).”
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    • cites [2] Sharma, 2015, The future of immune checkpoint therapy, Science source

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    Premisecitation

    Certain CD4 T cells can have cytotoxic function.

    “Although CD4 T cells are known as helper cells, accumulating evidence suggests a cytotoxic function demonstrated by certain CD4 T cells (4).”
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    • cites [4] Śledzińska, 2020, Regulatory T cells restrain interleukin-2- and Blimp-1-dependent acquisition of cytotoxic function by CD4(+) T cells, Immunity source

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    Premisecitation

    In early studies, anti-CTLA4 antibody prevented CTLA4 from engaging B7, prolonging T-cell responses and eradicating cancer cells.

    “In early studies, an anti-CTLA4 antibody prevented CTLA4 from engaging B7, leading to prolonged T-cell responses and eradication of cancer cells (1).”
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    • cites [1] Leach, 1996, Enhancement of antitumor immunity by CTLA-4 blockade, Science source

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    Premisecitation

    Anti-CTLA4 expands CD4 effector T cells, increasing the Teff/Treg ratio in responding tumors.

    “In general, anti-CTLA4 expands CD4 effector T cells (Teff) with subsequent increase in the Teff/ Treg ratio in responding tumors (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Quezada, 2006, CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells, J Clin Invest source

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    Premisecitation

    PD-1 interacts with SHP2 to dephosphorylate signaling molecules downstream of the TCR and inhibit IL2 production and T-cell proliferation.

    “PD-1 interacts with an SHP2 tyrosine phosphatase domain, leading to dephosphorylation of signaling molecules downstream of the TCR and inhibiting TCR-mediated activation of IL2 production and T-cell proliferation (13).”
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    • cites [13] Okazaki, 2007, PD-1 and PD-1 ligands: from discovery to clinical application, Int Immunol source

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    Premisecitation

    Preclinical models show that PD-1 blockade causes tumor rejection by reinvigorating exhausted CD8 T cells expressing PD-1, LAG3, and TIM3 and by expanding CD8 T cells.

    “Preclinical models demonstrated that PD-1 blockade results in tumor rejection through reinvigoration of exhausted CD8 T cells that express PD-1, LAG3, and TIM3 and expansion of CD8 T cells, a hallmark of response to anti-PD-1 therapy (16).”
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    • cites [16] Im, 2016, Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy, Nature source

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    Premisecitation

    In vivo administration of anti-CTLA4 enhanced the antitumor effect of tumor-infiltrating T cells, causing regression of established tumors and long-lived immunity in tumor models.

    “Similarly, the in vivo administration of anti-CTLA4 antibodies enhanced the antitumor effect of tumor-infiltrating T cells, leading to regression of established tumors and long-lived immunity in tumor models (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Leach, 1996, Enhancement of antitumor immunity by CTLA-4 blockade, Science source

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    Premisenone given

    Anti-PD-1/PD-L1 does not appear to expand clonal diversity or promote T-cell trafficking into tumors.

    “Anti-PD-1/PD-L1 also does not appear to expand clonal diversity nor promote T-cell trafficking into tumors.”
    Quote in the paperNot a substantial claim

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    Premisenone given

    Anti-CTLA4 primarily functions in T-cell priming and expands clonal diversity.

    “Anti-CTLA4 primarily functions in T-cell priming and expands clonal diversity.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Prostate cancer is predominantly resistant to immune checkpoint therapy because of low mutation burden, few antigens for T-cell recognition, and scarce tumor-infiltrating T cells.

    “As a result of a low number of mutations, and therefore few antigens for T-cell recognition, as noted by scarce tumor-infiltrating T cells, prostate cancer has been predominantly resistant to treatment with ICT (100-102).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [100] Kwon, 2014, Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial, Lancet Oncol source

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    • cites [101] Beer, 2017, Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer, J Clin Oncol source

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    • cites [102] Antonarakis, 2020, Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study, J Clin Oncol source

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

    Premisenone given

    Immune-related adverse events can affect any organ, most commonly the skin, gastrointestinal tract, and endocrine system.

    “The irAEs can affect any organ, most commonly skin, gastrointestinal tract, and endocrine system (including the thyroid, adrenal, and pituitary glands).”
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    Premisecitation

    Ipilimumab was the first immune checkpoint therapy approved by the FDA, in 2011 for metastatic melanoma, based on phase III trials showing improved overall survival compared with vaccine or chemotherapy.

    “Ipilimumab (anti-CTLA4) was the first ICT to gain FDA approval in 2011 for the treatment of metastatic melanoma, on the basis of phase III trials demonstrating improvements in overall survival compared with vaccine or chemotherapy (37,38).”
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    • cites [37] Hodi, 2010, Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med source

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    • cites [38] Robert, 2011, Ipilimumab plus dacarbazine for previously untreated metastatic melanoma, N Engl J Med source

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    Premisereasoning

    CTLA4 inhibits signal 2, whereas PD-1/PD-L1 inhibits signal 1.

    “Therefore, whereas CTLA4 inhibits signal 2 (CD28-B7), PD-1/PD-L1 inhibits signal 1 (TCR).”
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    Premisecitation

    Human prostate cancers have few tumor-infiltrating T cells, minimal to no PD-1 or PD-L1 expression, and lack significant clinical benefit with anti-PD-1 monotherapy.

    “Previous studies on human prostate cancers demonstrated few tumor-infiltrating T cells, with minimal to no expression of PD-1 or PD-L1, and lack of significant clinical benefit with anti-PD-1 monotherapy in patients with metastatic prostate cancer (104, 105).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [104] Antonarakis, 2019, Pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: updated analysis of KEYNOTE-199, J Clin Oncol source

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    • cites [105] Gao, 2017, VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer, Nat Med source

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    Premisecitation

    CTLA4 binds B7-1 and B7-2 on antigen-presenting cells with higher affinity than CD28, competitively inhibiting CD28 costimulation and dampening T-cell signaling.

    “It bears structural homology to CD28 and binds to B7-1 (CD80) and B7-2 (CD86) molecules on APCs with higher affinity than CD28, leading to competitive inhibition of costimulatory CD28 signaling, thereby dampening T-cell signaling (10,11).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Alegre, 1996, Regulation of surface and intracellular expression of CTLA4 on mouse T cells, J Immunol source

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    • cites [11] Takahashi, 2000, Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4, J Exp Med source

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    Combined blockade of CTLA4 and PD-1/PD-L1 yields higher response rates than either monotherapy in melanoma, hepatocellular carcinoma, renal cell carcinoma, non-small cell lung cancer, malignant pleural mesothelioma, and MSI-H/dMMR colorectal cancer.

    “Multiple clinical trials with combined blockade of CTLA4 and PD-1/PD-L1 demonstrated higher response rates than either monotherapy, in different cancer types including melanoma ( 54, 55 ), hepatocellular carcinoma ( 56 ), renal cell carcinoma (RCC; refs.57, 58 ), NSCLC ( 59 ), malignant pleural mesothelioma ( 60 ), and colorectal cancer (MSI-H/dMMR; ref. 61 ).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [54] Larkin, 2015, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, N Engl J Med source

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    • cites [55] Larkin, 2019, Five-year survival with combined nivolumab and ipilimumab in advanced melanoma, N Engl J Med source

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    • cites [56] Yau, 2020, Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial, JAMA Oncol source

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    Premisecitation

    Approximately 20% of patients who received ipilimumab achieved long-term survival greater than three years, with some patients surviving 10 years.

    “Indeed, approximately 20% of patients who received ipilimumab achieved long-term survival greater than three years, with survival of 10 years noted for some patients (38,42).”
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    • cites [38] Robert, 2011, Ipilimumab plus dacarbazine for previously untreated metastatic melanoma, N Engl J Med source

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    • cites [42] Schadendorf, 2015, Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma, J Clin Oncol source

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    Premisecitation

    Anti-CTLA4 predominantly affects CD4 T cells, increasing the frequency of ICOS-expressing Th1 CD4 T cells.

    “Anti-CTLA4 predominantly affects CD4 T cells, with multiple studies identifying increased frequency of a Th1 subset of CD4 T cells that express inducible costimulator (ICOS) as a result of anti-CTLA4 therapy (17)(18)(19).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Carthon, 2010, Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial, Clin Cancer Res source

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    • cites [18] Liakou, 2008, CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients, Proc Natl Acad Sci U S A source

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    • cites [19] Chen, 2009, Anti-CTLA-4 therapy results in higher CD4 +ICOS hi T cell frequency and IFNγ levels in both nonmalignant and malignant prostate tissues, Proc Natl Acad Sci U S A source

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    Premisecitation

    Phase III data show overall survival and/or progression-free survival benefit for immune checkpoint therapy plus chemotherapy in non-small cell lung cancer, small cell lung cancer, triple-negative breast cancer, bladder cancer, and head and neck squamous cell carcinoma.

    “Toward this end, combinations of ICTs with concurrent and/or sequential chemotherapy are under extensive investigation, with phase III clinical data demonstrating overall survival and/or progression-free survival benefi t in NSCLC ( 63-66 ), small cell lung cancer ( 51,52 ), triple-negative breast cancer ( 67 ), bladder cancer ( 53 ), and head and neck squamous cell carcinoma ( 68 ).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [63] Gandhi, 2018, Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer, N Engl J Med source

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    • cites [64] Paz-Ares, 2018, Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer, N Engl J Med source

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    • cites [65] Socinski, 2018, Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC, N Engl J Med source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Anti-PD-1/PD-L1 antibodies predominantly affect exhausted CD8 T cells.

    “Anti-PD-1/PD-L1 antibodies predominantly affect exhausted CD8 T cells.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Maintenance immune checkpoint therapy provides clinical benefit in non-small cell lung cancer, extensive-stage small cell lung cancer, and bladder cancer, leading to FDA approvals.

    “Clinical benefi t with maintenance ICT in specifi c settings was demonstrated in patients with nonsmall cell lung cancer (NSCLC; ref.50 ), extensive-stage small cell lung cancer ( 51,52 ), and bladder cancer ( 53 ), leading to FDA approvals in these tumor types.”
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    • cites [50] Antonia, 2017, Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer, N Engl J Med source

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    • cites [51] Horn, 2018, First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer, N Engl J Med source

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    • cites [52] Paz-Ares, 2019, Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial, Lancet source

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  • May combine two claims.

    Interpretationreasoning

    Anti-CTLA4 increases CD28 signaling and thereby raises EZH2 expression on T cells.

    “Anti-CTLA4 increases CD28 signaling, thereby leading to increased EZH2 expression on T cells.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Low tumor mutational burden does not prevent effective antigen responses, and high tumor mutational burden does not guarantee response to immune checkpoint therapy.

    “In addition, low TMB does not preclude generation of effective antigen responses, nor does high TMB guarantee response to ICT (130-132).”
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    • cites [130] Cristescu, 2018, Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy, Science source

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    • cites [131] Subudhi, 2020, Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer, Sci Transl Med source

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    • cites [132] Braun, 2020, Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma, Nat Med source

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    Premisecitation

    Phagocytosis, which is needed to clear tumor cells, also appears to drive M2 macrophage differentiation that suppresses immune responses and limits further cell death.

    “Interestingly, the process of phagocytosis, which is required for clearing tumor cells, also seems to play a role in driving M2 differentiation in an attempt to suppress immune responses and avoid further cell death (114), indicating the complexity of how immune responses are regulated.”
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    • cites [114] Asare, 2020, LC3-associated phagocytosis (LAP): a potentially influential mediator of efferocytosis-related tumor progression and aggressiveness, Front Oncol source

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    Premisecitation

    Posttreatment tumor samples showed that soft-tissue metastases were infiltrated by Th1 cells, whereas bone metastases were infiltrated by Th17 cells.

    “Immune monitoring data of posttreatment tumor samples collected from patients indicated that soft-tissue metastases were infiltrated by Th1 cells, whereas bone metastases were infiltrated by Th17 cells (110).”
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    • cites [110] Jiao, 2019, Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy, Cell source

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    Premisecitation

    VISTA is an inhibitory checkpoint highly expressed on myeloid cells and moderately expressed on T cells.

    “VISTA is an inhibitory checkpoint that is highly expressed on myeloid cells [including macrophages, dendritic cells (DC), monocytes, neutrophils], and moderately expressed on T cells (108).”
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    • cites [108] Lines, 2014, VISTA is an immune checkpoint molecule for human T cells, Cancer Res source

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    Premisecitation

    Personalized neoantigen vaccines have been shown to modulate T cells in the tumor microenvironment and enhance responses to immune checkpoint therapy in both cold glioblastoma and hot melanoma.

    “which have been shown to modulate T cells in the TME and enhance responses to ICT, including in both immunologically”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [133] Ott, 2020, A phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer, Cell source

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    • cites [134] Keskin, 2019, Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial, Nature source

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    • cites [135] Ott, 2017, An immunogenic personal neoantigen vaccine for patients with melanoma, Nature source

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    Premisecitation

    Substantial responses can occur in some patients with PD-L1-negative tumors, which shows the difficulty of using PD-L1 alone as a biomarker.

    “however, in other cases, substantial responses can be observed in some patients with PD-L1-negative tumors, which highlights the difficulty of using PD-L1 as a single biomarker (34,143,144).”
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    • cites [34] Topalian, 2012, Safety, activity, and immune correlates of anti-PD-1 antibody in cancer, N Engl J Med source

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    • cites [143] Rosenberg, 2016, Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial, Lancet source

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    • cites [144] Balar, 2017, Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial, Lancet source

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    Premisecitation

    Preclinical experiments showed high levels of IL6 and TGFβ in bone metastases compared with soft-tissue metastases, cytokines that skew T-cell responses toward Th17 instead of Th1.

    “Data from these experiments demonstrated high levels of IL6 and TGFβ in bone metastases as opposed to soft-tissue metastases, which are important cytokines for skewing T-cell response toward Th17 instead of Th1 (110).”
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    • cites [110] Jiao, 2019, Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy, Cell source

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    Premisecitation

    A GBM-specific CD73-high myeloid cell population was identified by comparing tumor-infiltrating lymphocytes from GBM with those from several other tumor types, and this population remains after anti-PD-1 treatment.

    “Comparison of tumor-infiltrating lymphocytes (TIL) from GBM and multiple other tumor types led to the identification of a GBM-specific CD73 hi myeloid cell population, which persists even after treatment with anti-PD-1 (112).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Goswami, 2020, Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma, Nat Med source

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    • Rests on an assumption: Immunologically cold tumors such as prostate cancer and glioblastoma multiforme have few tumor-infiltrating T cells but a higher frequency of immunosuppressive myeloid cells.

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    Premisecitation

    CD73 knockout mice showed improved survival with immune checkpoint therapy compared with control mice, indicating a direct role for CD73.

    “Preclinical studies with CD73 knockout mice showed improved survival with ICT compared with control mice, demonstrating a direct role for CD73 (112).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Goswami, 2020, Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma, Nat Med source

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    • Rests on an assumption: CD73 is an extracellular ectonucleotidase in the adenosine immunosuppressive pathway that inhibits T-cell activation and proliferation.

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    Premisecitation

    Tumor-infiltrating lymphocytes are under active investigation as a biomarker for selecting patients for immune checkpoint therapy, although definitions and thresholds vary significantly.

    “TILs are therefore under active investigation as a biomarker to guide selection of patients for treatment with ICT, although significant variability exists in definitions and thresholds (149, 150).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [149] Tumeh, 2014, PD-1 blockade induces responses by inhibiting adaptive immune resistance, Nature source

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    • cites [150] Loi, 2019, Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers, J Clin Oncol source

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    Premisecitation

    TMB plus a T cell-inflamed gene expression profile or TMB plus PD-L1 expression showed improved prediction performance compared with single biomarkers.

    “For example, TMB plus a T cell-inflamed geneexpression profile or TMB plus PD-L1 expression showed an improved prediction performance compared with single biomarkers (130).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Cristescu, 2018, Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy, Science source

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    Premisecitation

    PTEN loss is associated with increased PI3K-AKT signaling and correlates with CD8 T-cell exclusion and poor clinical responses to immune checkpoint therapy.

    “In addition, PTEN loss is also associated with increased signaling through the PI3K-AKT pathway and correlated with exclusion of CD8 T cells and poor clinical responses to ICT (124).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Peng, 2016, Loss of PTEN promotes resistance to T cell-mediated immunotherapy, Cancer Discov source

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  • May combine two claims.

    Interpretationreasoning

    Neoadjuvant immune checkpoint therapy allows T and B cells to access antigens present on tumor tissues, unlike adjuvant therapy given after tumor removal, which limits antigen encounter.

    “Administration of ICT in the neoadjuvant setting enables T and B cells to have access to the antigens that are present on tumor tissues, which is in contrast to adjuvant studies where ICT is given after tumor tissues have been removed, thereby limiting the amount of tumor antigens that T and B cells encounter.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The first combination neoadjuvant immune checkpoint therapy trial with anti-CTLA4 plus anti-PD-L1 in bladder cancer demonstrated clinical responses and a correlation of TLS with responses.

    “The trial also led to the first combination ICT neoadjuvant trial with anti-CTLA4 plus anti-PD-L1 in patients with bladder cancer, which demonstrated clinical responses and correlation of TLS with responses (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Gao, 2020, Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma, Nat Med source

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    Premisecitation

    Adjuvant immune checkpoint therapy has been successful in high-risk melanoma and led to FDA approval.

    “Nonetheless, adjuvant ICT has been successful in high-risk melanoma, which led to FDA approval (189-193).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [189] Eggermont, 2018, Adjuvant pembrolizumab versus placebo in resected stage III melanoma, N Engl J Med source

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    • cites [190] Eggermont, 2015, Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial, Lancet Oncol source

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    • cites [191] Weber, 2017, Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma, N Engl J Med source

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    • cites [192] Tarhini, 2020, Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609, J Clin Oncol source

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    • cites [193] Ascierto, 2020, Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial, Lancet Oncol source

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  • May combine two claims.

    Premisecitation

    The first bladder cancer immune checkpoint therapy trial provided data showing antitumor responses, leading to larger metastatic bladder cancer trials and subsequent FDA approval.

    “This study was also the first ICT trial in patients with bladder cancer, which provided critical data demonstrating antitumor responses in patients with bladder cancer, thereby leading to large clinical trials with ICT in patients with metastatic bladder cancer, with subsequent FDA approval.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Carthon, 2010, Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial, Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Many biomarkers correlate with response to immune checkpoint therapy, but many studies were retrospective and require prospective validation.

    “Although many of the biomarkers described above, including tumor-intrinsic and host-specific variables, correlate with response to ICTs, many of the studies have been retrospective and need further validation through prospective clinical trials.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TLS represent sites of interaction between multiple immune cell types and capture an ongoing antitumor response.

    “TLS represent sites of interactions between multiple immune cell types and capture an ongoing antitumor response (168).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Sautès-Fridman, 2019, Tertiary lymphoid structures in the era of cancer immunotherapy, Nat Rev Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The first neoadjuvant immune checkpoint therapy trial, conducted in 2006, provided safety data indicating that immune checkpoint therapy can be given before surgery.

    “The first neoadjuvant ICT trial was conducted in 2006 and provided safety data indicating that ICT can be given prior to surgery (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Carthon, 2010, Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial, Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Single biomarker strategies do not capture the dynamic and complex interaction between tumor and host immune system, so combinatorial biomarkers are essential to optimize patient selection.

    “There is growing recognition that single biomarker strategies do not incorporate the dynamic and complex interaction of the tumor and host immune system and that combinatorial biomarkers will be essential to optimize patient selection.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    That pipeline could allow more accurate prediction of effective antitumor responses than conventional methods.

    “that might enable prediction of effective antitumor responses with much higher accuracy than conventional methods”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [217] Wells, 2020, Key parameters of tumor epitope immunogenicity revealed through a consortium approach improve neoantigen prediction, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Responses to immune checkpoint therapies correlate with commensal gut flora, and responders and nonresponders appear to differ substantially in gut microbial diversity and composition.

    “Responses to ICTs have been correlated with commensal gut flora, and there appear to be substantial differences in the diversity and composition in patients who respond to ICT versus nonresponders (205,206).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [205] Matson, 2018, The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients, Science source

      Not checked in the free run.

    • cites [206] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Intratumoral delivery rather than systemic delivery of agents targeting innate immune cells may ensure tumor-specific antigen presentation, enable effective T-cell responses, and reduce systemic toxicities.

    “Therefore, intratumoral delivery rather than systemic delivery of agents to target innate immune cells may provide an avenue to ensure presentation of tumorspecific antigens, enable effective T-cell responses, and also reduce systemic toxicities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Longitudinal blood-based assays such as circulating tumor DNA are easier to implement and less invasive than longitudinal tumor biopsies.

    “In addition, integration of longitudinal blood-based assays such as circulating-tumor DNA (ctDNA; ref. 216), which are easier to implement and less invasive as opposed to longitudinal tumor biopsies, is under investigation as a method to monitor responses to ICT.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [216] Zhang, 2020, Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade, Cancer Discov source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The anti-CD137 antibody utomilumab was well tolerated but had limited efficacy.

    “and a second anti-CD137 antibody, utomilumab, was well tolerated but had limited efficacy (212).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [212] Segal, 2018, Phase i study of single-agent utomilumab (PF-05082566), a 4-1bb/cd137 agonist, in patients with advanced cancer, Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Studies of agonist antibodies reveal significant knowledge gaps about target protein expression, sequencing with immune checkpoint therapy, and choice of immune checkpoint agent.

    “These studies highlight significant knowledge gaps regarding the use of agonist antibodies in terms of understanding expression of the target proteins, sequencing of the agonist antibody with ICT and choice of ICT agent (anti-CTLA4 vs. anti-PD-1/PD-L1).”
    Quote in the paperSubstantial claim
49 of 49

  • The paper relies on this without support.

    Metastatic cancers remain incurable in most patients because conventional therapies that target tumor cells usually cannot provide a durable response.

    “Metastatic cancers remain incurable in most patients as conventional therapies that target tumor cells usually cannot provide a durable response.”

  • The paper relies on this without support.

    The immune microenvironment is unique to each tumor type and plays a critical role in response and resistance to immune checkpoint therapy.

    “The immune microenvironment is unique to each tumor type and plays a critical role in response and resistance to ICT.”

  • The paper relies on this without support.

    Interaction of tumor cells with the immune microenvironment guides the constitution and phenotypes of immune subpopulations.

    “Interaction of tumor cells with the immune microenvironment guides the constitution and phenotypes of immune subpopulations.”

  • The paper relies on this without support.

    Immunologically cold tumors such as prostate cancer and glioblastoma multiforme have few tumor-infiltrating T cells but a higher frequency of immunosuppressive myeloid cells.

    “Immunologically cold tumors, such as prostate cancer and glioblastoma multiforme (GBM), have few tumor-infiltrating T cells but higher frequency of immune-suppressive myeloid cells.”

  • The paper relies on this without support.

    CD73 is an extracellular ectonucleotidase in the adenosine immunosuppressive pathway that inhibits T-cell activation and proliferation.

    “CD73 is an extracellular ectonucleotidase that plays a role in the adenosine immunosuppressive pathway, inhibiting T-cell activation and proliferation.”

  • The paper relies on this without support.

    The functional and phenotypic states of immune subpopulations play an important role in determining response to immune checkpoint therapy.

    “As outlined previously, the functional and phenotypic states of immune subpopulations play an important role in determining response to ICT.”

  • The paper relies on this without support.

    A major challenge in immune checkpoint therapy is the lack of a robust predictive biomarker for optimal patient selection.

    “One of the major challenges in the field of ICT is the lack of a robust predictive biomarker for optimal patient selection.”

  • The paper relies on this without support.

    PD-L1 expression is dynamic because of multiple factors including T-cell responses and IFN-gamma signaling.

    “PD-L1 expression is dynamic due to multiple factors, including T-cell responses and IFNγ signaling.”

  • The paper relies on this without support.

    T-cell exclusion is a mechanism of resistance to immune checkpoint therapy, exemplified by cold tumors such as prostate and pancreatic cancer that have few T cells in the tumor microenvironment.

    “In the same vein, T-cell exclusion is a mechanism of resistance to ICT, exemplified by”

  • The paper relies on this without support.

    IFN-gamma is a key cytokine produced by activated T cells, natural killer cells, and NK T cells, and is critical for effective antitumor immunity.

    “IFNγ is a key cytokine produced by activated T cells, as well as natural killer (NK) and NK T cells, and is critical for effective antitumor immunity.”

  • The paper relies on this without support.

    Melanoma patients with loss-of-function mutations in JAK1 and JAK2 were resistant to anti-PD-1 therapy.

    “Also, patients with melanoma tumors harboring loss-of-function mutations in JAK1 and JAK2, downstream IFNγ signaling molecules, were resistant to anti-PD-1 therapy, highlighting the utility of IFNγ as a potential biomarker.”

  • The paper relies on this without support.

    IFN-gamma drives expression of PD-L1 and IDO1, which may suppress immune responses in the tumor microenvironment.

    “In addition, consistent with the yin and yang concept of immune responses, IFNγ drives expression of proteins such as PD-L1 and IDO1, which may act to suppress immune responses in the TME.”

  • The paper relies on this without support.

    Over the past decade, immune checkpoint therapy has become established as the fourth pillar of cancer therapy along with chemotherapy or targeted therapy, radiotherapy, and surgery.

    “Over the past decade, ICT has become established as the fourth pillar of cancer therapy, along with chemotherapy/ targeted therapy, radiotherapy, and surgery.”

  • The paper relies on this without support.

    Improved bioinformatics algorithms for neoantigen prediction will allow identification of more relevant therapeutic targets.

    “the development of better bioinformatics algorithms that help with neoantigen prediction will enable identification of more relevant therapeutic targets”
14 of 14

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?

  • Over the past decade, the cancer hallmark of immune evasion has gained importance, reflecting immunotherapy, especially ICIs targeting PD-1/PD-L1, becoming a backbone of cancer drug development across many malignancies.

    “Over the past decade this hallmark of cancer has acquired ever more importance, reflecting the fact that immunotherapy, in particular with ICIs targeting the interaction between PD-1 and PD-L1, has progressively become (one of) the backbone(s) of cancer drug development across a wide spectrum of distinct malignancies.250”

    From Meta-hallmarks of aging and cancer (2023) · cites this paper as [250]

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.

  • Anti-PD-L1 drugs are listed as anti-PD-1 combinations

    Minor

    The combinations described as involving anti-PD-1 include avelumab and atezolizumab. Elsewhere, the paper identifies both drugs as anti-PD-L1 antibodies.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Korman, 2017, Next-generation anti-CTLA-4 antibodies [abstract]

Cited by

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Related

Authors
Sharma, P., Siddiqui, B. A., Anandhan, S., Yadav, S. S., Subudhi, S. K., Gao, J., Goswami, S., & Allison, J. P.
Affiliations
The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Sharma, Padmanee
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-04-01
Volume
11
Issue
4
Pages
838-857
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-1680
OpenAlex
W3146935595
Cited by
750
References
229
Citations by year
2026: 87 · 2025: 145 · 2024: 181 · 2023: 156 · 2022: 138 · 2021: 41
FWCI
15.69
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
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, immune resistance mechanisms, adaptive resistance, patient selection, immune-related adverse events, combination immunotherapy, reverse translational research, cancer immunotherapy
MeSH terms
Immune Checkpoint Inhibitors, Forecasting, Humans, Neoplasms, Drug Discovery

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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