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

• DOI: 10.1136/jitc-2022-006348
• Publication Date: 2023-05-25T17:15:37Z
• Authors: Clémence Demerlé; Laurent Gorvel; Marielle Mello; Sonia Pastor; Clara Degos; Ana Zarubica; Fabien Angelis; Frédéric Fiore; Jacques A Nunes; Bernard Malissen; Laurent Greillier; Geoffrey Guittard; Hervé Luche; Fabrice Barlesi; Daniel Olive
• Keywords: BTLA

Tumor necrosis factor superfamily member 14 (TNFRSF14)/herpes virus entry mediator (HVEM) is the ligand for B and T lymphocyte attenuator (BTLA) CD160-negative immune co-signaling molecules as well viral proteins. Its expression dysregulated with an overexpression in tumors a connection of adverse prognosis.We developed C57BL/6 mouse models co-expressing human (hu)BTLA huHVEM antagonistic monoclonal antibodies (mAbs) that completely prevent interactions HVEM its ligands.Here, we show anti-HVEM18-10 mAb increases primary αβ-T cells activity alone (CIS-activity) or presence HVEM-expressing lung colorectal cancer vitro (TRANS-activity). Anti-HVEM18-10 synergizes antiprogrammed death-ligand 1 (anti-PD-L1) to activate PD-L1-positive tumors, but sufficient trigger cell activation PD-L1-negative cells. In order better understand HVEM18-10 effects vivo especially disentangle CIS TRANS effects, knockin (KI) model expressing BTLA (huBTLA+/+) KI both huBTLA+/+/huHVEM+/+ (double (DKI)). preclinical experiments performed showed treatment was efficient decrease HVEM+ tumor growth. DKI model, induces exhausted CD8+ regulatory increase effector memory CD4+ within tumor. Interestingly, mice which rejected (±20%) did not develop on rechallenge settings, therefore showing marked cell-memory phenotype effect.Altogether, our validate promising therapeutic antibody use clinics monotherapy combination existing immunotherapies (antiprogrammed death protein 1/anti-PD-L1/anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4)).