In the current study, we evaluated the antitumoral activity of bevacizumab an anti-VEGF monoclonal antibody in two NSCLC PDX in vivo in the presence or absence of human immune cells.
Two NSCLC PDX models were subcutaneously implanted into different mouse strains: NMRI-nude, CD34+-humanized NOG (huNOG), NOG and NOG-EXL both substituted with human monocytes by weekly iv injection. Animals were treated with control vehicle or bevacizumab. Tumor and lymphatic organs were harvested and flow cytometry as well as IHC analysis was performed. The serum levels of 40 human and 23 murine cytokines were determined using a Bioplex system.
In both tumor models, bevacizumab showed in the absence of human immune cells moderate antitumoral activity. The co-injection of human monocytes markedly enhanced the therapeutic effect in both NSCLC PDX. The effect human immune cells on antitumoral activity was similar in NOGs, NOG-EXL and huNOG. The injection of monocytes alone did not affect tumor growth. The TIL infiltrates were enhanced under treatment specifically in the NOG-EXL mice. In all treatment arms receiving bevacizumab the CD11b+ subpopulations were increased. The cytokine analyses revealed an upregulation of human cytokines under treatment with bevacizumab towards a pro-inflammatory micro-environment including IL-6, CCL24 and CXCL-1. Interestingly, also the murine host cells contributed to this pro-inflammatory reaction by upregulation of mouse IL-6, TNF-alpha, Eotaxin and others.
Monocytes have been reported to induce antibody-dependent cytotoxicity of tumor cells in the presence of antibodies like bevacizumab. Our results confirm these observations in a PDX based in vivo model.
Julia Schueler– Charles River
Nathalie Harrer– Boehringer Ingelheim RCV GmbH & Co KG
Anna Edinger– Charles River Research Services Germany GmbH
Cordula Tschuch– Charles River Research Services Germany GmbH
Eva Oswald– Charles River Research Services Germany GmbH
Wolfgang Sommergruber– Boehringer Ingelheim RCV GmbH & Co KG