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

Abstract

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.

Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model

“…While not reaching statistical significance, our data also revealed a trend toward increased CD8+ T-cell infiltration into the CNS following treatment with aflibercept, suggesting that vascular normalization could, in fact, promote immune cell infiltration. Importantly, the dose of VEGF inhibitor has been shown to modulate the level of immune cell infiltration, and may require further optimization for enhancing immunotherapeutic responses in our model [60]. Additionally, detailed characterizations of the effector functions of infiltrating immune cells, including alterations to cytotoxic function and immunosuppressive capacity, are underway.…”

“…The GL261-Quad cell line is engineered to express the model antigens human gp100 [25][26][27][28][29][30][31][32][33] , chicken OVA 257-264 , chicken OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] , and mouse alloantigen I-Ea [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] . Female 6-8-week-old C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME, USA) were inoculated by stereotactic injection of 6.0×10 4 -1.0×10 5 GL261 or GL261-Quad cells into the right striatum.…”

Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies

“…Multiple studies have demonstrated evidence of vessel normalization and increased therapeutic uptake. [22][23][24] There are also a series of studies that demonstrate the opposite effect of decreased uptake of therapeutic following anti-VEGF administration. 25 The notion that there is a therapeutic window based on dose and time likely explains these discrepant findings.…”

“…25 The notion that there is a therapeutic window based on dose and time likely explains these discrepant findings. 10,22,26 In our study, we used a relatively low human-equivalent dose of 5 mg/kg. Studies that demonstrate decreased tumor uptake of small molecule chemotherapeutics following bevacizumab administration and a lack of a survival benefit typically dose above 10 mg/ kg.…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…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.…”