Active Immunotherapy Induces Antibody Responses That Target Tumor Angiogenesis

Abstract

The inhibition of VEGF signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that antiangiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding subjects. These reactions are characterized by disrupted tumor blood vessels in association with lymphocyte and granulocyte infiltrates and zonal areas of ischemic tumor necrosis. However, the mechanisms underlying this immune-mediated destruction of the tumor vasculature remain to be clarified. Here, we show that GM-CSF-secreting tumor cell vaccines and CTLA-4 blockade elicit a functionally important humoral reaction against multiple angiogenic cytokines. Antibodies to angiopoietin-1 and angiopoietin-2 block Tie-2 binding, downstream signaling, endothelial cell tube formation, and macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) production. Together, these results delineate an immunotherapy-induced host response that broadly targets the angiogenic network in the tumor microenvironment.

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

“…34 Antibody responses developed towards neovessels following immunization were instrumental to create ischemic tumor necrosis. 35 Hence, GM-CSF-engineered tumor vaccines combined with anti-CTLA4 engendered a co-ordinated cellular and humoral immunity associated with clinically significant tumor regressions in advanced solid cancers. 36 In such regressing tumor burdens, T cell infiltrates were juxtaposed to antibody-producing B cells in long-term responders.…”

“…Humoral reactivity was reported against proangiogenic cytokines such as angiopoietin-1 and -2 blocking the endothelial cell tube formation and/or macrophage inhibitory factor attenuating macrophage Tie-2 and MMP9 expression. 35 Likewise, antibodies against protein disulfide isomerases (PDI, ERp5, 37 ) or an accessory unit of the vacuolar H þ -ATPase complex 38 appeared of clinical significance. These data are in line with other observations, stating that the presence of tertiary lymphoid organogenesis (TLO), high endothelial venules (HEV) or germinal centers (GC) residing around the tumor nests are associated with good prognosis in breast carcinoma, non-small cell lung cancer and melanoma.…”

Angiopoietin-2 TIEs Up Macrophages in Tumor Angiogenesis

“…The pharmacologic inhibition of the SDF1/CXCR4 axis prevented their influx to irradiated tumors and inhibited postirradiation development of a functional tumor vasculature, resulting in abrogation of tumor relapse (33). A recent report showed that vaccination with irradiated, autologous tumor cells engineered to secrete granulocytemacrophage colony stimulating factor and antibody blockade of cytotoxic T lymphocyte-associated antigen-4 triggered a tumor vasculopathy in some long-term responding patients with solid cancer (53). These reactions were associated with important humoral reactions against multiple angiogenic cytokines, including ANG2.…”

Cell death in cancer therapy of lung adenocarcinoma

“…A survival benefit for ADC patients treated with a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), bevacizumab, combined with standard platinum based chemotherapy (carboplatin plus paclitaxel) was demonstrated, although accompanied by greatly increased toxicity (Sandler et al, 2006). However, combination of immunotherapies with anti-angiogenic agents has been reported to be effective and potentially beneficial for the clinical outcome of NSCLC patients (Schoenfeld et al, 2010) Potential combination therapy including agents targeting different tumor features, such as additional oncogenic aberrations, signaling from stromal cells, metabolic alterations and angiogenesis, as well as immunotherapy approaches to treat lung ADC (Fig. 2) are underway.…”