Application progress of dual immunotherapy and antibody drug conjugates in the treatment of advanced gastric cancer

WANG Jing-yuan; LIU Tian-shu

doi:10.19538/j.cjps.issn1005-2208.2024.10.20

Abstract：Immune evasion is a multi-factorial and multi-stage process,thus the efficacy of immune checkpoint inhibitors(ICIs)monotherapy is limited,promoting the emergence of combination therapies as a novel vital approach to enhance antitumor efficacy and improve survival results.Dual immune blockade therapies offer complementary mechanisms of antitumor action,but they also increase the risk of treatment-related adverse events.The introduction of bispecific antibodies(BsAbs)addresses this challenge to some extent,achieving a balance between efficacy and safety.However,both dual ICIs combination therapies and BsAbs have their limitations.Fixed drug pairings in dual ICI combinations and fixed antibody valency in bsAbs impose various restrictions on dosage,efficacy,and indications.Immunotherapy-related adverse effects,increased medical costs,and treatment regimen choices,remain areas requiring long-term exploration.Besides,the advent of antibody-drug conjugates(ADCs)has brought a revolutionary change to targeted therapy for gastric cancer.Beyond their highly specific target-binding properties,ADCs exhibit a unique"bystander effect",allowing them to remain effective in populations with low target expression,thereby broadening their range of application.However,factors such as antigen downregulation,loss,or mutation can prevent ADCs from binding to their targets,defects in internalization pathways or reduced expression of membrane transport proteins,the inability to disintegration of ADCs due to lysosomal proteolytic or acidification dysfunction,or decreased lysosomal membrane transport proteins may hinder the delivery of effector molecules to the cytoplasm,ultimately affecting the antitumor efficacy of ADCs.Reversing ADCs resistance remains a key area of future research.