Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo

Abstract

SummaryRecent basic and clinical studies have shown that the programmed death ligand (PD-L)/PD-1 pathway has a significant role in tumour immunity, and its blockade has a therapeutic potential against several human cancers. We hypothesized that anti-angiogeneic treatment might augment the efficacy of PD-1 blockade. To this end, we evaluated combining the blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2) in a murine cancer model using Colon-26 adenocarcinoma. Interestingly, simultaneous treatment with anti-PD-1 and anti-VEGFR2 monoclonal antibodies (mAbs) inhibited tumour growth synergistically in vivo without overt toxicity. Blocking VEGFR2 inhibited tumour neovascularization significantly, as demonstrated by the reduced number of microvessels, while PD-1 blockade had no impact on tumour angiogenesis. PD-1 blockade might promote T cell infiltration into tumours and significantly enhanced local immune activation, as shown by the up-regulation of several proinflammatory cytokine expressions. Importantly, VEGFR2 blockade did not interfere with T cell infiltration and immunological activation induced by PD-1 blockade. In conclusion, simultaneous blockade of PD-1 and VEGFR2 induced a synergistic in-vivo anti-tumour effect, possibly through different mechanisms that might not be mutually exclusive. This unique therapeutic strategy may hold significant promise for future clinical application.

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

“…Because dual therapy normalizes the vasculature, TAMs in dual therapy-treated tumors are adapted to an antitumor phenotype, as shown in our companion manuscript, and thus are able to affect survival positively. However, additional interventions may be necessary to decrease the MDSCs and further activate cytotoxic T lymphocytes-for example by immune checkpoint inhibition-to enhance antitumor adaptive immunity further (30,62,63). Taken together, our data warrant further studies to assess the therapeutic potential of the anti-VEGF/Ang-2 combination with novel immunotherapeutics in GBM (51,64).…”

Clinicopathological and prognostic significance of regulatory T cells in patients with non-small cell lung cancer: A systematic review with meta-analysis

“…VEGF/VEGFR pathway blockade did not eradicate all Tregs but simply restored their proportion to physiology levels. Therefore, it would be interesting to combine anti-angiogenic agents inhibiting VEGF/VEGFR pathway with other immunotherapeutic strategies [44, 45]. This approach would selectively suppress Tregs and avoid the depletion of effector T cells and minimize the occurrence of autoimmune mediated adverse effects correlated with a total of Treg depletion [43].…”

PD-1 and PD-L1 blockade in gastrointestinal malignancies

“…Combined blockade of PD-1 and VEGFR2 has a synergistic inhibitory effect in a colon adenocarcinoma murine mouse model [67]. Combined PD-1 or PD-L1 blockade with anti-angiogenic drugs are currently being investigated in humans in Phase I trials (NCT01633970, NCT02298959, Table 1 …”