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Cited by 2,027Angiogenesis and VEGF in CancerCancer Immunotherapy and BiomarkersLymphatic System and Diseases

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

Open access
Fukumura, Dai, Kloepper, Jonas, Amoozgar, Zohreh, Duda, Dan G., Jain, Rakesh K.·2018·Nature Reviews Clinical Oncology
DOI 10.1038/nrclinonc.2018.29PMC PMC5921900
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Abstract

Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.

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Crossref · 10.1038/nrclinonc.2018.29

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  • Premisecitation

    An adequate level of oxygen is required for many drugs and immune cells to kill cancer cells.

    “an adequate level of oxygen is required for many drugs and immune cells to kill cancer cells7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

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  • Premisenone given

    Elevated levels of proangiogenic factors such as VEGF and angiopoietin 2 cause the vascular abnormalities seen in tumours.

    “These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2)”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Vascular normalization can convert the intrinsically immunosuppressive tumour microenvironment to an immunosupportive one.

    “convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Normalizing components of the tumour microenvironment could improve outcomes for patients treated with standard and emerging anticancer therapies.

    “normalizing components of the TME could improve the outcomes of patients treated with standard and emerging anticancer therapies, including chemotherapeutics, radiation, molecularly targeted agents, and immunotherapeutics8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Palucka, A. K. & Coussens, L. M. The basis of oncoimmunology. Cell 164, 1233–1247 (2016). source

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  • Premisecitation

    The recruited immunosuppressive cells include immature dendritic cells, regulatory T cells, myeloid-derived suppressor cells and pro-tumour tumour-associated macrophages.

    “These cells include immature dendritic cells (DCs), regulatory T (Treg) cells, myeloid-derived suppressor cells (MDSCs), and tumour-associated macrophages (TAMs) with pro-tumour phenotypes.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

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    • cites [17] Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011). source

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    • cites [18] Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44 (2011). source

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    • cites [19] Chang, A. L. et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res. 76, 5671–5682 (2016). source

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    • cites [20] Raman, D., Baugher, P. J., Thu, Y. M. & Richmond, A. Role of chemokines in tumor growth. Cancer Lett. 256, 137–165 (2007). source

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  • May combine two claims. 59
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    Most patients with cancer do not benefit from immunotherapy, and 50-80% of patients with tumours for which immune-checkpoint inhibitors are indicated do not benefit from these drugs.

    “However, 50–80% of patients with tumours for which immune-checkpoint inhibitors are indicated do not benefit from these drugs”
    • Also stated in: § Abstract · plain
      “Currently, however, the majority of patients with cancer do not derive benefit from these treatments.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Table S1

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  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationcitation

    The tumour microenvironment, characterized by hypoxia, low pH and high interstitial fluid pressure, can reduce the effectiveness of virtually all anticancer therapies, including immunotherapy.

    “Our hypothesis is that the tumour micro-environment (TME) — characterized by hypoxia, a low pH, and a high interstitial fluid pressure — can reduce the effectiveness of virtually all types of anticancer therapies, including immunotherapy6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013). source

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    Premisecitation

    This vascular abnormality promotes tumour progression by impairing perfusion, which causes tumour hypoxia and low intratumoural pH.

    “this abnormality promotes tumour progression by impairing perfusion, which results in tumour hypoxia and a low pH intratumourally7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

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    Premisenone given

    CD8+ cytotoxic T lymphocytes can home to tumours, but multiple factors in the tumour microenvironment often render them dysfunctional or limit their penetration into the tumour.

    “while CD8+ cytotoxic T lymphocytes (CTLs) can also home to tumours, multiple factors present in the TME often render these cells dysfunctional and/or limit their penetration into the tumour (FIGS 1,2)”
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    • cites FIGS 1,2

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    Interpretationreasoning

    Combining antiangiogenic therapies with immunotherapies might increase the effectiveness of immunotherapy and reduce the risk of immune-related adverse effects.

    “combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion.

    “Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

      Not checked in the free run.

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    Premisecitation

    Each component of the tumour microenvironment is abnormal and heterogeneous compared with nonmalignant tissues, and this abnormality fuels tumour progression and treatment resistance.

    “each component of the TME is abnormal and heterogeneous, and this abnormality fuels tumour progression and treatment resistance6,7”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013). source

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    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

      Not checked in the free run.

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    Premisecitation

    VEGF promotes angiogenesis that produces an aberrant tumour vasculature, leading to hypoxia and low pH, which in turn fosters local and systemic immunosuppression.

    “Fourth, VEGF promotes angiogenesis that results in an aberrant tumour vasculature, leading to hypoxia and a low pH in the TME, which in turn fosters immunosuppression both locally (FIG. 2) and systemically (FIG. 3), as discussed above21,27,28”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Huang, Y. H., Goel, S., Duda, D. G., Fukumura, D. & Jain, R. K. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 73, 2943–2948 (2013). source

      Not checked in the free run.

    • cites [27] Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012). source

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    • cites [28] Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005). source

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    Premisecitation

    High-dose or long-term antiangiogenic therapy causes massive vessel pruning and increases immunosuppression in tumour models.

    “preclinical evidence indicates that high-dose and/or long-term antiangiogenic therapy causes massive vessel pruning and increases immunosuppression in tumour models37–40”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [37] Rahbari, N. N. et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl Med. 8, 360ra135 (2016). source

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    • cites [38] Jung, K. et al. Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer. Proc. Natl Acad. Sci. USA 114, 10455–10460 (2017). source

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    • cites [39] Jung, K. et al. Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J. Clin. Invest. 127, 3039–3051 (2017). source

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    • cites [40] Chen, Y. et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61, 1591–1602 (2015). source

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    Premisecitation

    VEGF directly inhibits cytotoxic T lymphocyte trafficking, proliferation and effector function.

    “First, increased VEGF directly inhibits CTL trafficking, proliferation, and effector function22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015). source

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    Premisecitation

    Bevacizumab reduces the incidence of brain metastasis in a mouse model of non-small-cell lung cancer, and when combined with carboplatin and paclitaxel it is associated with reduced frequency of brain metastases as first relapse in patients with this disease.

    “targeting of VEGF with bevacizumab has been shown to reduce the incidence of brain metastasis in a mouse model of non-small-cell lung cancer (NSCLC), and when combined with carboplatin and paclitaxel, is associated with a reduced frequency of brain metastases as a site of first relapse in patients with this disease42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Ilhan-Mutlu, A. et al. Bevacizumab prevents brain metastases formation in lung adenocarcinoma. Mol. Cancer Ther. 15, 702–710 (2016). source

      Not checked in the free run.

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    Premisecitation

    VEGF inhibits dendritic cell maturation and antigen presentation, hampering T cell activation and diminishing the T cell-mediated anticancer immune response.

    “Second, VEGF inhibits DC maturation and antigen presentation, thus hampering T cell activation and, consequently, diminishing the T cell-mediated anticancer immune response23,24”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Gabrilovich, D. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92, 4150–4166 (1998). source

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    • cites [24] Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1267 (1996). source

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    Premisecitation

    Inhibition of VEPTP inhibited extravasation of metastatic breast cancer cells into the lungs and subsequent metastatic foci formation, and extended survival in animal models of mammary cancer when added to adjuvant doxorubicin chemotherapy.

    “inhibition of vascular endothelial protein tyrosine phosphatase (VEPTP; also known as PTPRβ), which sustains endogenous activation of TIE2, also inhibited extravasation of metastatic breast cancer cells into the lungs and subsequent metastatic foci formation, and thus extended survival durations, in animal models of mammary cancer when added to adjuvant doxorubicin chemotherapy49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Goel, S. et al. Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J. Natl Cancer Inst. 105, 1188–1201 (2013). source

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    Premisecitation

    VEGF and ANG2 might cooperate to induce tumour immunosuppression, and this effect might depend on their relative levels in the tumour microenvironment.

    “Experimental data indicate that VEGF and ANG2 might cooperate to induce tumour immunosuppression and that this effect might be dependent on the relative levels of these cytokines in the TME35–37”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [35] Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476–4481 (2016). source

      Not checked in the free run.

    • cites [36] Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470–4475 (2016). source

      Not checked in the free run.

    • cites [37] Rahbari, N. N. et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl Med. 8, 360ra135 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ANG2 increases leukocyte-endothelial interactions by upregulating adhesion molecules, thereby facilitating recruitment of myeloid-derived suppressor cells, regulatory T cells and TIE2-expressing monocytes.

    “First, ANG2 increases leukocyte–endothelial interactions via upregulation of adhesion molecules, thereby facilitating the recruitment of MDSCs29, Treg cells30, and TIE2-expressing monocytes that induce immunosuppression31”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Scholz, A. et al. Angiopoietin-2 promotes myeloid cell infiltration in a β2-integrin-dependent manner. Blood 118, 5050–5059 (2011). source

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    • cites [30] Coffelt, S. B. et al. Angiopoietin 2 stimulates TIE2-expressing monocytes to suppress T cell activation and to promote regulatory T cell expansion. J. Immunol. 186, 4183–4190 (2011). source

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    • cites [31] De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005). source

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    Premisecitation

    In other mouse tumour models, anti-ANG2 therapy prevents metastasis by inhibiting tumour cell dissemination to tumour-draining lymph nodes and distant tissues, and inhibits growth of established metastatic lesions.

    “In other mouse tumour models, anti-ANG2 therapy has been shown to prevent metastasis through the inhibition of tumour cell dissemination to tumour-draining lymph nodes and distant tissues47,48, and has therapeutic inhibitory effects on the growth of established metastatic lesions47”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011). source

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    • cites [48] Park, J. S. et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell 30, 953–967 (2016). source

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    Premisecitation

    Multiple molecular and physical mechanisms contribute to vascular dysfunction in tumours, with the chief mechanism being an imbalance between proangiogenic and antiangiogenic signalling.

    “Multiple molecular and physical mechanisms contribute to vascular dysfunction in tumours7,60; chief among them is the imbalance of signalling mediated by proangiogenic versus antiangiogenic molecules28”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

      Not checked in the free run.

    • cites [60] Jain, R. K., Martin, J. D. & Stylianopoulos, T. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 16, 321–346 (2014). source

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    • cites [28] Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The normalization process is transient and reversible, depends on tumour and dose, and lasts around 1 week in mice and possibly a few months in humans.

    “The normalization process is transient and reversible, in a tumour-dependent and dose-dependent manner, and lasts for around 1 week in mice and possibly for a few months in humans7,62,63,67”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

      Not checked in the free run.

    • cites [62] Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

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    • cites [63] Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007). source

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    • cites [67] Batchelor, T. T. et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28, 2817–2823 (2010). source

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

    Premisenone given

    Renal cell carcinoma is a highly VEGF-dependent tumour.

    “While RCC is a highly VEGF-dependent tumour”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    In 2001, the authors proposed that restoring the angiogenic balance with judicious doses of antiangiogenic agents would transiently produce tumour vessels with structural and functional phenotypes closer to those of nonmalignant tissues, a state called normalized.

    “In 2001, we proposed to restore this balance using judicious doses of antiangiogenic agents and suggested that this strategy would transiently give rise to tumour vessels with structural and functional phenotypes closer to those of the vessels of nonmalignant tissues — a state we referred to as ‘normalized’ (REF. 61)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001). source

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  • May combine two claims.

    Premisecitation

    Only transient vascular normalization has been observed with anti-VEGF therapies; the normalization window might be short, lasting days to weeks, and depends on the tumour and the dose of anti-VEGF agent.

    “A major challenge with anti-VEGF therapies is that only transient vascular normalization has been observed62; the window of normalization might be of short duration (days to weeks) and is dependent on the tumour and dose of anti-VEGF agent used27”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012). source

      Not checked in the free run.

    • cites [62] Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical data indicate that anti-VEGF therapy results in vascular normalization via pruning of immature blood vessels with poor pericyte coverage and via active pericyte recruitment.

    “Preclinical data indicate that anti-VEGF therapy results in vascular normalization via pruning of immature blood vessels, which have poor pericyte coverage, and via active pericyte recruitment62,69”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

      Not checked in the free run.

    • cites [69] Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731–3736 (2004). source

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    Premisereasoning

    During carcinogenesis, this balance typically tips towards angiogenesis, and vessels become chronically immature and abnormal.

    “During carcinogenesis, however, this balance typically tips towards angiogenesis, and the vessels become chronically immature and abnormal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Anti-VEGF therapy combined with chemotherapy improves survival in the metastatic setting across several solid tumour types, but was inefficacious in all phase III adjuvant trials to date.

    “while anti-VEGF therapy in combination with chemotherapy has been associated with improved patient survival in the metastatic setting across a number of solid tumour types, such treatment was found to be inefficacious in all phase III trials performed in the adjuvant setting to date6”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In preclinical studies, vascular-normalizing doses of anti-VEGF agents convert the immunosuppressive tumour microenvironment to an immunosupportive one and improve the outcome of vaccine-based anticancer immunotherapy.

    “we subsequently showed in preclinical studies that vascular-normalizing doses of anti-VEGF agents also convert the immunosuppressive TME to an immunosupportive one and improve the outcome of vaccine-based anticancer immunotherapy27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Concomitant blockade of ANG2 and VEGF extends both the normalization window and survival benefit compared with inhibition of either pathway alone, partly by reprogramming the immunosuppressive tumour microenvironment.

    “concomitant blockade of ANG2 and VEGF extends both the window of normalization and the survival benefit compared with inhibition of either pathway alone, in part, by reprogramming the immunosuppressive TME35,36”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476–4481 (2016). source

      Not checked in the free run.

    • cites [36] Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470–4475 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High ANG2 pathway activation led to lymph node invasion and metastasis in breast cancer models, and high ANG2 expression in patients with breast cancer correlates with metastatic disease.

    “studies in which a high level of ANG2 pathway activation led to lymph node invasion and metastasis in breast cancer models (Supplementary Table S5), and of studies showing that high levels of ANG2 expression in patients with breast cancer correlate with the presence of metastatic disease50–52”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [50] Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8, 696–706 (2014). source

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    • cites [51] Imanishi, Y. et al. Angiopoietin-2 stimulates breast cancer metastasis through the α5β1 integrin-mediated pathway. Cancer Res. 67, 4254–4263 (2007). source

      Not checked in the free run.

    • cites [52] Sfiligoi, C. et al. Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int. J. Cancer 103, 466–474 (2003). source

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    • cites Supplementary Table S5

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  • May combine two claims.

    Premisecitation

    Dual VEGF-ANG2 inhibition was more efficacious than anti-VEGF therapy alone in breast cancer models, reducing metastatic dissemination and formation of micrometastatic nodules.

    “Dual VEGF–ANG2 inhibition was also more efficacious in breast cancer models than anti-VEGF therapy alone, with a reduce frequency of metastatic dissemination and thus decreased formation of micrometastatic nodules54”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Kienast, Y. et al. Ang-2–VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin. Cancer Res. 19, 6730–6740 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A better understanding of VEGF and ANG2 signalling interactions might offer strategies to prevent and treat metastasis and to increase the effectiveness of immunotherapy, including immune checkpoint blockade.

    “Thus, a better understanding of the interactions between VEGF and ANG2 signalling might offer novel strategies to prevent and treat metastasis and increase the effectiveness of other therapeutic approaches such as immunotherapy, including ICB.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In models of resistance to anti-VEGF therapy, ANG2 promoted endothelial CCL2 and ICAM1 expression in metastases and recruited tumour-promoting TIE2− CCR2+ macrophages.

    “ANG2 promoted the upregulation of endothelial CCL2 and ICAM1 expression in metastases and, in turn, promoted the recruitment and adhesion of tumour-promoting TIE2− CCR2+ macrophages53”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Srivastava, K. et al. Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26, 880–895 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pre-treatment levels of circulating VEGF are prognostic for treatment outcome in different solid tumour settings but are not predictive of anti-VEGF therapy outcome.

    “pre-treatment levels of circulating VEGF are prognostic for treatment outcome in different solid tumour settings, but are not predictive of anti-VEGF therapy outcome79”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Hegde, P. S. et al. Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Clin. Cancer Res. 19, 929–937 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High-dose sorafenib caused increased hypoxia and SDF1-mediated recruitment of immunosuppressive cells such as regulatory T cells and M2-like macrophages in a mouse model of advanced hepatocellular carcinoma; CXCR4 blockade prevented this shift, inhibited tumour growth and metastasis, and improved survival of sorafenib-treated mice.

    “blockade of VEGF signalling using high doses of the multi-target, pan-VEGFR TKI sorafenib caused increased hypoxia and the stromal cell-derived factor 1 (SDF1)-mediated recruitment of immunosuppressive cells, such as Treg cells and M2-like macrophages, in a mouse model of advanced-stage hepatocellular carcinoma (HCC); blockade of the SDF1 receptor C-X-C-chemokine receptor 4 (CXCR4) prevented this”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Chen, Y. et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61, 1591–1602 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumours inevitably develop resistance to anti-VEGF agents, and one key mediator of resistance is the hypoxia induced by exposure to these drugs.

    “tumours inevitably develop resistance to anti-VEGF agents, and one key mediator of resistance is the hypoxia induced by exposure to these drugs7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment-resistant cancer stem cells are hypothesized to reside in the hypoxic niche, and excessive antiangiogenic therapy can cause hypoxia and thereby support these cells.

    “Treatment-resistant cancer stem cells are hypothesized to reside in the hypoxic niche, and excessive antiangiogenic therapy can cause hypoxia and thereby support these cells73”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Conley, S. J. et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl Acad. Sci. USA 109, 2784–2789 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Therapeutic agents targeting the ANG2-TIE2 axis can lead to tumour regression in several subcutaneous and orthotopic mouse models, and many of these agents have advanced to clinical trials.

    “Therapeutic agents that target the ANG2–TIE2 axis can lead to tumour regression in a number of subcutaneous and orthotopic mouse models (Supplementary Table S7); many of these agents have been advanced to testing in clinical trials (Supplementary Table S8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Supplementary Table S7

      Not checked in the free run.

    • cites Supplementary Table S8

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The window of vessel normalization ends when an excessive number of vessels are pruned or when tumours switch to alternative angiogenic pathways or alternative mechanisms of blood vessel recruitment such as vessel co-option.

    “The window of vessel normalization ends when an excessive number of vessels are pruned, or when tumours switch to the use of alternative angiogenic pathways or alternative mechanisms of blood vessel recruitment, such as vessel co-option56,62”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Griveau, A. et al. A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment. Cancer Cell (in press).

      Not checked in the free run.

    • cites [62] Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dual VEGF-ANG2 blockade can provide tumour control in some preclinical models, but the degree of benefit and mechanism appear context-dependent.

    “This dual blockade approach can provide tumour control in some preclinical models, although the degree of benefit and the underlying mechanism of action seem to be context-dependent31,32,80,89.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [31] De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005). source

      Not checked in the free run.

    • cites [32] Holopainen, T. et al. Effects of angiopoietin-2-blocking antibody on endothelial cell-cell junctions and lung metastasis. J. Natl Cancer Inst. 104, 461–475 (2012). source

      Not checked in the free run.

    • cites [80] Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603 (2008). source

      Not checked in the free run.

    • cites [89] Liu, C., Workman, C. J. & Vignali, D. A. Targeting regulatory T cells in tumors. FEBS J. 283, 2731–2748 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The immune-evasive mechanism of PD-L1 upregulation after A2V could be counteracted by concomitant anti-PD-1 antibody treatment, improving tumour control.

    “this immune-evasive mechanism could be counteracted by concomitant treatment with an anti-PD-1 antibody, resulting in improved tumour control16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl Med. 9, eaak9670 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dual anti-VEGF-ANG2 therapy with A2V upregulates adhesion molecules during the window of vascular normalization and facilitates accumulation of anticancer T cells within multiple tumour types in mice.

    “Dual anti-VEGF–ANG2 therapy with A2V has been shown to upregulate the expression of adhesion molecules during the window of vascular normalization and can thereby facilitate the accumulation of anticancer T cells within multiple types of tumours in mice16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl Med. 9, eaak9670 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A2V treatment improved the anticancer activity of T cells, with increased IFNγ production and increased CD69 expression on CTLs compared with anti-ANG2 or anti-VEGF monotherapy.

    “the anticancer activity — an important determinant of durable tumour control — of the T cells was improved, with increased production of IFNγ and increased expression of the activation marker CD69 on CTLs with this treatment compared with the results of monotherapy with neutralizing antibodies to either ANG2 or VEGF alone16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl Med. 9, eaak9670 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Combining antiangiogenic and immunotherapy agents is likely to increase biological complexity and may increase the risk of toxicities, particularly immune-related adverse events such as autoimmune colitis.

    “these therapies have complex biological effects, and combining them is likely to further increase this complexity; an increased risk of toxicities, particularly immune-related adverse events such as autoimmune colitis5, might ensue.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Nishino, M., Ramaiya, N. H., Hatabu, H. & Hodi, F. S. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat. Rev. Clin. Oncol. 14, 655–668 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The extent of vessel normalization varies with tumour type, treatment duration, and drug dosage, and closure of the normalization window is marked by adaptive tumour resistance and immunosuppression.

    “The extent of normalization varies with tumour type, as well as with the duration of treatment and the dosage of drug, and closure of the normalization window is marked by the development of adaptive tumour resistance and immunosuppression7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The generalizability of reciprocal regulation of tumour vessel normalization and immunostimulatory reprogramming is supported by analyses of large transcriptomic databases in human tumours, but experimental studies were limited to breast cancer models.

    “although the generalizability of the reciprocal regulation of tumour vessel normalization and immunostimulatory reprogramming is supported by analyses of large transcriptomic databases in human tumours, the experimental studies were limited to breast cancer models105.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ICB can have vessel-normalizing effects in preclinical models of breast tumours, although the kinetics of vascular normalization are unknown.

    “ICB can have vessel-normalizing effects in preclinical models of breast tumours105, although the kinetics of vascular normalization are unknown.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Anti-VEGF therapy induces dendritic cell maturation and inhibits T cell priming.

    “Anti-VEGF therapy is also known to induce DC maturation and thus inhibit the priming of T cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Loss of VEGF in T cells results in vessel normalization and improved chemotherapeutic response in mice.

    “loss of VEGF in T cells results in vessel normalization and an improved chemotherapeutic response in mice97.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Palazon, A. et al. An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32, 669–683.e5 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    On the basis of positive preclinical data, combinations of antiangiogenic therapies with immunotherapies are now being tested in multiple clinical trials, with promising outcomes reported for patients with RCC in a phase II trial.

    “On the basis of positive preclinical data, these combinations are now being tested in multiple clinical trials, with promising outcomes reported for patients with RCC in a phase II trial65 (TABLE 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Amin, A. et al. Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J. Immunother. Cancer 3, 14 (2015). source

      Not checked in the free run.

    • cites TABLE 2

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adding agents that target the ANG2-TIE2 pathway to VEGF pathway blockade appears to extend the window of vascular normalization and convert an immunosuppressive microenvironment into an immunostimulatory milieu.

    “The addition of agents that target the ANG2–TIE2 pathway to VEGF pathway blockade seems to extend the window of vascular normalization and convert an immunosuppressive micro-environment into an immunostimulatory milieu35,36”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476–4481 (2016). source

      Not checked in the free run.

    • cites [36] Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470–4475 (2016). source

      Not checked in the free run.

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

    Interpretationreasoning

    The contrast between ICB-induced oedema in brain tumours and ICB-induced vascular normalization in breast cancer models suggests that vascular effects depend on tumour location and/or type.

    “This observation contrasts with the vascular normalization induced by ICB in breast cancer models105 and suggests that the vascular effects are dependent on the tumour location and/or type — a possibility that needs to be further investigated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-PD-1 treatment alone conferred a survival benefit for only a small fraction of patients with glioblastoma and failed to improve outcomes in a randomized phase III trial.

    “anti-PD-1 treatment alone conferred a survival benefit for only a small fraction of patients with glioblastoma99 and failed to improve the outcomes of patients with this disease in a randomized phase III trial100.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [99] Reardon, D. A. et al. OS10. 3 Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143 [abstract]. Neuro-Oncol. 19 (Suppl. 3), iii21 (2017). source

      Not checked in the free run.

    • cites [100] Martins, I. Opdivo fails to demonstrate survival benefit in phase 3 brain cancer trial. Immuno-Oncology News https://immuno-oncologynews.com/2017/04/18/opdivo-fails-demonstrate-increased-survival-glioblastoma-multiforme-phase-3-study/ (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neither anti-VEGF therapy nor ICB seem to be effective in highly desmoplastic tumours such as pancreatic ductal adenocarcinoma, breast cancer, and cholangiocarcinoma, with the notable exception of desmoplastic melanomas, which respond to ICB.

    “Neither anti-VEGF therapy nor ICB seem to be effective in highly desmoplastic tumours, such as pancreatic ductal adenocarcinoma, breast cancer, and cholangiocarcinoma7,110 — with the notable exception of desmoplastic melanomas, which have been shown to respond to ICB111.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014). source

      Not checked in the free run.

    • cites [110] Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012). source

      Not checked in the free run.

    • cites [111] Eroglu, Z. et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553, 347–350 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High endothelial venules are specialized vascular units that facilitate recruitment and extravasation of naive T cells and promote their differentiation into CTLs.

    “HEVs are specialized vascular units, usually organized as tertiary lymphoid structures, which facilitate the recruitment and extravasation of naive T cells, and then promote the differentiation of these cells into CTLs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In these models, antiangiogenic treatment several days before immunotherapy increased T cell accumulation in tumours and anticancer efficacy compared with vaccination alone.

    “antiangiogenic treatment several days before immunotherapy, by either vaccination or adoptive cell transfer approaches, increased the accumulation of T cells within the tumour and thus increased anticancer efficacy compared with vaccination therapy alone27,96.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012). source

      Not checked in the free run.

    • cites [96] Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial cells lining HEVs express ICAM1 and VCAM1 and facilitate homing and migration of immune cells to tumours.

    “The ECs lining HEVs are known to express ICAM1 and VCAM1, and thus facilitate homing and migration of immune cells to tumours98.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Allen, E. et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl Med. 9, eaak9679 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Tumours might escape anti-VEGF therapies mainly through alternative modes of vascularization and/or upregulation of alternative angiogenic pathways such as ANG2-TIE2 signalling.

    “Tumours might escape anti-VEGF therapies mainly through alternative modes of vascularization (such as vessel co-option) and/or upregulation of alternative angiogenic pathways (such as ANG2–TIE2 signalling).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ICBs are known to cause sometimes severe immune-related adverse events, which can often be resolved by discontinuing ICB therapy or reducing doses.

    “ICBs are known to cause sometimes severe immune-related adverse events. These toxicities can often be resolved by discontinuing ICB therapy or reducing the doses of the immune-checkpoint inhibitors used5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Nishino, M., Ramaiya, N. H., Hatabu, H. & Hodi, F. S. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat. Rev. Clin. Oncol. 14, 655–668 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The proposed combination strategy might require lower doses of immune-checkpoint inhibitors to confer immunostimulation and reduce toxicity risk.

    “the proposed combination strategy might require lower doses of immune-checkpoint inhibitors to confer immunostimulation but also to reduce the risk of toxicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Endocrine therapy for hormone-dependent tumours can reduce VEGF levels and normalize tumour vessels.

    “endocrine therapy for hormone-dependent tumours can also reduce VEGF levels and normalize tumour vessels118.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Jain, R. K. et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc. Natl Acad. Sci. USA 95, 10820–10825 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    ICB can dramatically prolong survival of patients who have durable responses, but has generally failed to improve outcomes of the remaining majority of patients, at the cost of substantial toxicities in many recipients.

    “ICB can dramatically prolong the survival of patients who have durable responses, but has generally failed to improve the outcomes of the remaining majority of patients, at the cost of substantial toxicities in many recipients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    Elevated levels of extracellular matrix molecules, including collagen I and hyaluronan, in desmoplastic tumours can compress blood vessels, impair their function, and result in hypoxia.

    “results from our laboratory have shown that the elevated levels of extracellular matrix molecules, including collagen I and hyaluronan, in such tumours can compress blood vessels, impairing their function and resulting in hypoxia94.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013). source

      Not checked in the free run.

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

    Premisecitation

    The microbiota is emerging as a determinant of responses to various anticancer therapies, including immunotherapy.

    “The microbiota is emerging as a determinant of responses to various anticancer therapies, including immunotherapy122–125.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [122] Roy, S. & Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat. Rev. Cancer 17, 271–285 (2017). source

      Not checked in the free run.

    • cites [123] Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018). source

      Not checked in the free run.

    • cites [124] Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018). source

      Not checked in the free run.

    • cites [125] Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased severity of adverse effects has been observed in obese versus nonobese mice following immunotherapy, but the mechanisms are not understood.

    “an increased severity of adverse effects has been observed in obese versus nonobese mice following immunotherapy115; however, the mechanisms underlying this increase are not understood.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Mirsoian, A. & Murphy, W. J. Obesity and cancer immunotherapy toxicity. Immunotherapy 7, 319–322 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Vascular normalization approaches might improve the development of anticancer immunity and decrease required doses of cytotoxic therapies, thereby reducing adverse effects of combinations incorporating immunotherapies.

    “vascular normalization approaches might not only improve the development of anticancer immunity, but also decrease the required doses of cytotoxic therapies and thus reduce the adverse effects of combinations incorporating immunotherapies.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Antiangiogenic drugs offer only a modest survival benefit of a few weeks to months, with rare durable responses.

    “Antiangiogenic drugs offer only a modest survival benefit of a few weeks to months, with rare durable responses.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Obesity is associated with an unfavourable prognosis across multiple types of cancer.

    “Obesity is associated with an unfavourable prognosis across multiple types of cancer114.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Fukumura, D., Incio, J., Shankaraiah, R. C. & Jain, R. K. Obesity and cancer: an angiogenic and inflammatory link. Microcirculation 23, 191–206 (2016). source

      Not checked in the free run.

65 of 65

  • The paper relies on this without support.

    The effectiveness of immunotherapy depends on the accumulation and activity of immune effector cells within the tumour microenvironment.

    “Immunotherapy relies on the accumulation and activity of immune effector cells within the TME”

  • The paper relies on this without support.

    Findings from preclinical mouse tumour models about antiangiogenic and immunotherapy combinations are predictive of human cancer outcomes.

    “we subsequently showed in preclinical studies that vascular-normalizing doses of anti-VEGF agents also convert the immunosuppressive TME to an immunosupportive one and improve the outcome of vaccine-based anticancer immunotherapy27”

  • The paper relies on this without support.

    The success of immunotherapy relies on the recruitment, expansion, and effective anticancer activity of immune cells, especially CTLs, in the tumour microenvironment.

    “The success of immunotherapy relies on the recruitment, expansion, and effective anticancer activity of immune cells, especially CTLs, in the TME.”

  • The paper relies on this without support.

    T cell accumulation in tumours occurs through a multistep process involving interaction with adhesion molecules on endothelial cells and crossing endothelial barriers.

    “The accumulation of T cells occurs via a multistep process. First, T cells must interact with adhesion molecules, such as E-selectin, ICAM1, and VCAM1, expressed on the luminal surface of ECs lining blood vessels and must then cross the endothelial barriers.”
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?

  • High angiogenesis and the resulting abnormal vasculature and high interstitial pressure in the tumor microenvironment impair immune cell infiltration and penetrance of checkpoint inhibitors.

    “The high rates of angiogenesis in the tumor microenvironment and the resultant abnormal vasculature and high interstitial pressure within the tumor (Folkman, 1971) can impair the infiltration of immune cells and the penetrance of checkpoint inhibitors (Fukumura et al., 2018).”

    From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Fukumura et al., 2018

  • Combining anti-angiogenic antibodies with checkpoint inhibitors has shown promising results in enhancing anti-tumor immune response.

    “strategies to combine anti-angiogenic antibodies with checkpoint inhibitors have shown promising results in enhancing the anti-tumor immune response (Fukumura et al., 2018).”

    From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Fukumura et al., 2018

  • Hypoxia may affect immunotherapy.

    “If hypoxia affects antitumoral immune responses, it is justified to propose that hypoxia may affect immunotherapy as well [74].”

    From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [74]

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.

  • The scope of the ICB vessel-normalization experiments conflicts

    Minor

    One passage says the experiments included breast and other tumour models, while a later passage says the experimental studies were limited to breast cancer models.

  • Anti-VEGF treatment is said to both support and inhibit T-cell priming

    Minor

    The paper says VEGF inhibits dendritic-cell maturation and thereby hampers T-cell activation. Later, it says anti-VEGF therapy induces dendritic-cell maturation but consequently inhibits T-cell priming; that consequence conflicts with the earlier account.

2 of 2

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Related

Authors
Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G., & Jain, R. K.
Affiliations
  • Harvard University (US)
  • Centre Hospitalier Universitaire Vaudois (CH)
Corresponding author
Jain, Rakesh K.
ORCID
Venue
Nature Reviews Clinical Oncology
Publisher
Springer Science and Business Media LLC
Published
2018-03-06
Volume
15
Issue
5
Pages
325-340
ISSN
  • 1759-4774 (ISSN-L)
  • 1759-4782
DOI
10.1038/nrclinonc.2018.29
PMC
PMC5921900
OpenAlex
W2791328450
Semantic Scholar
f768a19ee78949540bebf9ae77628fd1f0f1f9c5
Cited by
2,027
References
190
Citations by year
2026: 258 · 2025: 270 · 2024: 283 · 2023: 305 · 2022: 310 · 2021: 265 · 2020: 195 · 2019: 113 · 2018: 27
FWCI
14.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Clinical Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
National Cancer Institute (R41CA213678, R01CA159258, R01CA096915, U01CA224348, P01CA080124, R35CA197743, R01CA208205, R01CA129371, P50CA165962)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Keywords
cancer immunotherapy, anti-angiogenic therapy, tumor immune evasion, tumor microenvironment, vascular endothelial growth factor, angiopoietin-2, immune checkpoint inhibitors, combination therapy, immune-related adverse events
MeSH terms
Humans, Immunotherapy, Neoplasms, Neovascularization, Pathologic, Angiogenesis Inhibitors, Vesicular Transport Proteins, Vascular Endothelial Growth Factor A, Tumor Microenvironment

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 2026-10-07.

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

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