Anti-HVEM mAb therapy improves antitumoral immunity bothin vitroandin vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors

Abstract

AbstractBackgroundTNFRF-14/HVEM is the ligand for BTLA and CD160 negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis.MethodsWe developed C57BL/6 mouse models co-expressing human huBTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands.ResultsHere, we show that the anti-HVEM18-10 mAb increases primary human αß-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cellsin vitro(TRANS-activity). Anti-HVEM18-10 synergizes with anti-PD-L1 mAb to activate T cells in the presence of PDL-1 positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1 negative cells. In order to better understand HVEM18-10 effectin vivoand especially disentangle its CIS and TRANS effects, we developed a knock-in (KI) mouse model expressing human BTLA (huBTLA+/+) and a KI mouse model expressing both human BTLA and human HVEM (huBTLA+/+/huHVEM+/+(DKI)).In vivopre-clinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM+ tumor growth. In the DKI model, anti-HVEM 18-10 treatment induces a decrease of exhausted CD8+T cells and regulatory T cells and an increase of Effector memory CD4+T cells within the tumor. Interestingly, mice which completely rejected tumors (± 20%) did not develop tumors upon re-challenge in both settings, therefore showing a marked T cell-memory phenotype effect.ConclusionsAltogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (anti-PD1/anti-PDL-1/anti-CTLA-4).