A Vascular Endothelial Growth Factor Receptor-2 Inhibitor Enhances Antitumor Immunity through an Immune-Based Mechanism

Manning, Elizabeth A.; Ullman, John G.M.; Leatherman, James M.; Asquith, Justin M.; Hansen, Timothy R.; Armstrong, Todd D.; Hicklin, Daniel J.; Jaffee, Elizabeth M.; Emens, Leisha A.

doi:10.1158/1078-0432.ccr-07-0374

Cited by 181 publications

(154 citation statements)

References 41 publications

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“…In the mouse model of breast cancer, VEGFR2 blockade by neutralizing antibody inhibited tumor growth through the increase of CTL infiltration and activation [82]. Sunitinib also enhanced intratumoral infiltration of T lymphocytes in mouse models [77].…”

Section: Anti-vegf Treatment Could Promote Antitumor Immune Responsesmentioning

confidence: 98%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

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Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.

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Section: Anti-vegf Treatment Could Promote Antitumor Immune Responsesmentioning

confidence: 98%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

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“…In genetic studies, vascular normalization by deletion of Rgs5 increased T-cell infiltration into tumors and substantially improved survival after adoptive T-cell transfer in mice (9). Several preclinical studies have suggested that antiangiogenic therapy could increase tumor-infiltrating T cells (22)(23)(24)(25). However, no antiangiogenic agent has been shown to improve breast cancer vaccine therapy in a clinically relevant model of immune-tolerant breast cancer (23).…”

mentioning

confidence: 99%

“…Several preclinical studies have suggested that antiangiogenic therapy could increase tumor-infiltrating T cells (22)(23)(24)(25). However, no antiangiogenic agent has been shown to improve breast cancer vaccine therapy in a clinically relevant model of immune-tolerant breast cancer (23). Here, we evaluate the effects of treatment with different doses of an anti-VEGF receptor 2 (VEGFR2) antibody (DC101) and establish a combinational regimen that synchronizes T-cell activation with breast cancer vascular normalization.…”

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confidence: 99%

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

Huang

Yuan

Righi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

815

770

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The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4 + and CD8 + T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8 + T-cell-dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.

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“…A few experimental studies have shown that endogenous T cell infiltration is increased following anti-angiogenic agents [153][154][155], and one study has shown that the efficacy of DC101 treatment is dependent on both CD4 + and CD8 + T cells in a transplantable mammary tumor model [153]. As such, the need for more investigations into the role of immunosuppressive and adaptive immune cells is warranted to help guide the future clinical possibility of combining vascular-targeting agents with immunotherapy.…”

Section: Much Less Is Known About the Role Of Tregs And T Cells Durinmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

121

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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A Vascular Endothelial Growth Factor Receptor-2 Inhibitor Enhances Antitumor Immunity through an Immune-Based Mechanism

Cited by 181 publications

References 41 publications

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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