Anti-VEGF antibody enhances the antitumor effect of CD40

Abstract

As its central immunomodulatory effects, CD40 induces interleukin (IL)-12-dependent antitumor immune responses; as its local protumor effects, CD40 induces the expression of vascular endothelial growth factor (VEGF) that promotes tumor angiogenesis and growth. Therefore, using a previously established tumor model in mouse, we examined if the antitumor functions of CD40 are self-limited by VEGF induction. We observed that as the tumor mass grew during day 6 to day 18, VEGF expression in the tumor peaked with concomitant decrease in expressions of CD40 and IL-12 but not of IL-10. Among the angiogenic factors, VEGF-B, VEGFR-1, VEGFR-2, angiopoietin-1 and Tie2 expressions decreased, whereas the expressions of angiopoietin-2 and angiopoietin-3 increased with tumor growth. As significant changes in the expressions of these factors were observed on day 6, we treated the tumor-bearing mice with the agonistic anti-CD40 antibody or neutralizing anti-VEGF antibody-alone or in combination-from the fifth day after the injection of tumor cells. The anti-VEGF antibody significantly enhanced the antitumor effects of the anti-CD40 antibody, as observed through increased survival of the mice, accompanied by reduced angiogenesis and angiopoietin-2 expression but higher T-cell proliferation in response to tumor antigens, increased interferon-c production and tumor cell cytotoxicity and higher levels of tumor antigen-specific serum IgM, IgG1 and IgG2a, indicating B-cell activation. Thus, our data show for the first time that the combined treatment with an agonistic anti-CD40 antibody and a neutralizing anti-VEGF antibody, which increases antitumor immune response or reduces local angiogenesis, respectively, is a novel antitumor strategy.

Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment

“…In line with this, several reports have shown benefits of repressing VEGF-signaling in the tumor microenvironment during immunotherapy. Antibody targeting of VEGF/VEGFR2 signaling increases the efficacy of adoptive T-cell therapy of established B16 melanomas [36] and has been demonstrated to enhance the antitumor effect of agonistic CD40-antibodies after subcutaneous injection of RM-1 prostate cancer cells [37]. …”

Agonistic CD40 Antibodies in Cancer Treatment

“…Drugs that target VEGF/VEGFR signaling and/or Ang2 decrease tumor vascularity and reduce the immunosuppressive effects mediated by these factors. Anti-angiogenic therapies have been combined with CD40 agonists and appear to be superior to either class of drugs alone [83]. In a recently reported preclinical study, CD40 agonism was combined with antibodies to VEGFA or Ang2.…”

Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy

“…Several clinical studies (NCT03439891, NCT03277924, NCT03616691, and NCT03074513) are evaluating the efficacy of antiangiogenic therapy in combination with immune checkpoint blockade (1,2,26,28,29). Anti-CD40 immunotherapy (3-6, 30, 31) might represent a complementary approach to immune checkpoint inhibitors for combination with angiogenesis inhibitors (32). In this study, we show that combination of agonistic CD40 antibodies with dual VEGFA/Ang2 blockade enhances antitumor responses in mouse cancer models through synergistic gene regulation and the induction of an immune permissive tumor microenvironment characterized by proinflammatory (M1-like) macrophage activation, vascular normalization, and improved infiltration and spatial localization of effector T cells.…”