Novel immunotherapy for multiple solid cancers using an Anti-HVEM blocking monoclonal antibody
Authors: Galore-Haskel Gilli , Merhavi-Shoham Efrat , Shapiro Mika , Bareli Roni , Dror Naama , Seliktar-Ofir Sivan , Shamalov Katerina , Levy-Barda Adva , Hout-Siloni Goni , Schachter Jacob , Sadot Eran , Eitan Ram , Barshack Iris , Golan Shay , Feferman Yael , Yeoshoua Effi , Eyadat Saeb , Greenberg Eyal , Markel Gal 
Published: December 2024

AbstractINTRODUCTIONImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their efficacy remains limited. Therefore, there is a clear need for new anti-tumor agents. HVEM (Herpes Virus Entry Mediator) plays a regulatory role in immunity, making it a promising cancer therapeutic target.EXPERIMENTAL DESIGNWe have developed Anti-4CB1, a fully human HVEM-BTLA and HVEM-CD160 blocking mAb and tested its anti-tumor activity in variousin-vitro, ex-vivoandin-vivomodels, alone or in combination with Anti-PD1. Finally, we analyzed HVEM expression in serum samples and melanoma tumor tissues and its correlation with HVEM and PD1 blockade treatment response.RESULTSIn-vitroassays demonstrated enhanced melanoma cell killing by autologous TILs in the presence of Anti-4CB1. In addition, Anti-4CB1 significantly increased cytotoxicity by up to 233% in a variety ofex-vivocancer tissue samples of different indications. Notably, Anti-4CB1 demonstrated effectiveness in samples where Anti-PD1 was ineffective. In addition, significant anti-tumor activity at 10 mg/kg in combination with Anti-PD1 (TGI 95% p=0.0001) or at 25 mg/kg as monotherapy (TGI 50% p=0.0096) was demonstrated in a colon carcinoma transgenic mice model. Moreover, significant anti-tumor activity was observed in a mouse ImmunoGraft model (TGI 53% p=0.0102 as monotherapy). Finally, we demonstrated that HVEM expression correlated with response to Anti-HVEM and Anti-PD1 treatments.DISCUSSIONWe describe the development of Anti-4CB1, a fully human anti-HVEM mAb, blocking HVEM-BTLA and HVEM-CD160 human interactions and enhancing lymphocytes cytotoxicity against various cancer cellsex-vivo.In-vivo,Anti-4CB1 showed promising anti-tumor effects, particularly in combination with Anti-PD1, suggesting its therapeutic potential. Finally, HVEM expression may serve as a predictive marker for Anti-HVEM and Anti-PD1 treatments response, offering potential diagnostic utility in patient selection for these immunotherapies. These results support Anti-4CB1 potential as an anti-cancer therapeutic agent.Translational RelevanceThe discovery of immune checkpoint inhibitors (ICIs), marks a significant breakthrough in cancer therapy. However, despite the remarkable success of current ICIs targeting CTLA4 and PD1/PD-L1 pathways, a significant proportion of patients fail to respond or develop resistance. Therefore, the search for novel ICIs is crucial for advancing cancer immunotherapy. Anti-HVEM emerged as a promising candidate, as we demonstrate inex-vivoandin-vivomodels, its ability to block the HVEM-BTLA interaction, resulting in enhanced antitumor immune responses in solid tumors, alone or in combination with existing ICIs, to improve treatment outcomes. Moreover, the correlation between HVEM expression and treatment responses highlight its potential as an attractive target for biomarker-driven therapies. Investigating HVEM as an ICI offers a promising path to expand therapeutic options, personalize treatment approaches, address the evolving challenges in cancer immunotherapy and improve patient outcomes.