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

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.

GA201 (RG7160): a novel, humanized, glycoengineered anti-EGFR antibody with enhanced ADCC and superior in vivo efficacy compared with cetuximab.

PURPOSE: Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell-bound antibody and Fc receptors present on immune effector cells. EXPERIMENTAL DESIGN: We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcγRIIIA. RESULTS: In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low- and high-affinity variants of FcγRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan). CONCLUSIONS: These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors. Clin Cancer Res; 19(5); 1126-38. ©2012 AACR.

Clinical and Doppler ultrasonography data of a polyurethane vascular access graft for haemodialysis: a prospective study.

BACKGROUND: Absence of a permanent vascular access in most patients starting haemodialysis remains a cause of high morbidity and costs. This study obtained new clinical and colour Doppler ultrasound (CDU) data of a polyurethane vascular access graft (PVAG) proposing early post-operative cannulation. METHODS: Baseline characteristics were determined in 15 patients and the PVAGs were evaluated prospectively including first cannulation, patency and complications. CDU was used post-operatively and after 1 year for assessing graft morphology and access blood flow. RESULTS: PVAGs were cannulated at a median of 4 days post-operatively. The 1-year primary patency of the PVAG was 66.7%. During the 15 months observation three grafts thrombosed, one was replaced because of infection and one because of ischaemia. CDU measurements at the feeding brachial artery revealed a mean initial access volume flow of 773+/-89 ml/min, being significantly higher in patients without thrombosis compared to patients with thrombotic events (930+/-90 vs 375+/-143 ml/min, P<0.05). The initial inability to directly monitor PVAGs by CDU changed at sites of frequent centesis, where Doppler signals and luminal morphology could be evaluated in the follow up examination. CONCLUSIONS: The PVAG offers early access for urgent haemodialysis. CDU for access volume flow measurement at the feeding brachial artery contributes to predict access thrombosis. Direct non-invasive graft imaging is limited and the ultrasonographical changes in the polyurethane material enabling graft monitoring after repeated cannulation might indicate an injury of the graft with increased risk for access failure.