Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade

Abstract

Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma. Mechanistically, A2V promoted vascular regression, tumor necrosis, and antigen presentation by intratumoral phagocytes. A2V also normalized the remaining blood vessels and facilitated the extravasation and perivascular accumulation of activated, interferon-γ (IFNγ)-expressing CD8 cytotoxic T lymphocytes (CTLs). Whereas the antitumoral activity of A2V was, at least partly, CTL-dependent, perivascular T cells concurrently up-regulated the expression of the immune checkpoint ligand programmed cell death ligand 1 (PD-L1) in tumor endothelial cells. IFNγ neutralization blunted this adaptive response, and PD-1 blockade improved tumor control by A2V in different cancer models. These findings position immune cells as key effectors of antiangiogenic therapy and support the rationale for cotargeting angiogenesis and immune checkpoints in cancer therapy.

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…For example, radiation therapy given during the window of normalization, especially when hypoxia was alleviated in tumours, had outcomes superior to those achieved when radiation was delivered outside this window 62 . A number of preclinical and clinical studies from our own institution and others have also provided evidence in support of the validity of this hypothesis for a number of malignancies 16,63 . Our initial efforts focused on cytotoxic therapies 64 , but 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 immunotherapy 27 .…”

“…1), can control the trafficking of immune cells to the tumour by altering the expression of adhesion molecules, including the integrin ligands intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion protein 1 (VCAM1), on endothelial cells (ECs) and immune cells 10,14,15 . Tumour-associated ECs can also express the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1), which binds to PD-1 expressed on T cells and thereby suppresses their anticancer activity 16 (FIG. 2).…”

“…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-dependent 31,32,80,89 . For example, dual VEGF–ANG2 blockade prolonged survival compared with anti-VEGF or anti-ANG2 monotherapy in mouse models of glioblastoma 35,36 , melanoma 16 , pancreatic neuroendocrine tumours (PNETs) 16 , and metastatic 16,90 or early stage (resected) breast cancer 90 . By contrast, a survival benefit was not observed in a model of metastatic RCC (RENCA) with VEGF–ANG2-neutralizing therapy 90 .…”

Anti-Angiogenics: Current Situation and Future Perspectives

“…Besides VEGF, Ang-2 is an important player in angiogenesis. A bispecific antibody which binds both VEGF-A and Ang-2 showed a better effect as compared to single blockade in many preclinical models and synergized with PD-1 blockade [36,38].…”

Novel Therapeutic Strategies for Solid Tumor Based on Body’s Intrinsic Antitumor Immune System

“…The normalization of tumor vessels can alleviate local hypoxia, activate effector immune cells, and make anti-tumor drugs reach tumor sites to increase drug concentration in local positions. Therefore, proper anti-angiogenic treatment should be applied in combination with chemotherapy or anti-tumor immunotherapy [92].…”