From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer

Abstract

Current Therapeutic modalities provide no survival advantage to gastric cancer (GC) patients. Targeting the human epidermal growth factor receptor-2 (HER-2) is a viable therapeutic strategy against advanced HER-2 positive GC. Antibody-drug conjugates, small-molecule tyrosine kinase inhibitors (TKIs), and bispecific antibodies are emerging as novel drug forms that may abrogate the resistance to HER-2-specific drugs and monoclonal antibodies. Chimeric antigen receptor-modified T cells (CAR-T) targeting HER-2 have shown considerable therapeutic potential in GC and other solid tumors. However, due to the high heterogeneity along with the complex tumor microenvironment (TME) of GC that often leads to immune escape, the immunological treatment of GC still faces many challenges. Here, we reviewed and discussed the current progress in the research of anti-HER-2-CAR-T cell immunotherapy against GC.

Targeting HER2 in Gastroesophageal Adenocarcinoma: Molecular Features and Updates in Clinical Practice

“…It requires a meticulous balancing of CAR T-cell activation to stimulate cytokine secretion but avoid cytokine storm. Moreover, considering the heterogeneity of HER2 expression and the immunosuppressive tumour microenvironment, genetic research should focus on designing CAR T cells with enhanced anti-tumour activity and ability to target multiple antigens, and on reversing the immunosuppressive tumour microenvironment, for example by associating PD-L1 or PD-1 inhibitors [79].…”

“…The heterogeneity of gastric cancer cells has limited the development of CAR-T cells in the treatment of GEA. Although HER2-targeted CAR-Ts have been successfully explored in other tumours, the evidence in GEA is only preclinical [79].…”

HER2+ advanced gastric cancer: Current state and opportunities (Review)

“…HER-2-targeting CAR-T cells for AGC are currently been investigated to develop strategies to reduce drug resistance and improve therapeutic effect ( Fig. 4 ) ( 143 ). In another study, a novel type of genetically modified human CAR-T cells targeting the GC cell antigen HER2 was developed.…”

Gastric Cancer: Molecular Mechanisms, Novel Targets, and Immunotherapies: From Bench to Clinical Therapeutics

“…CAR-T cells targeting HER2 have shown promising results in treating solid tumors [93]. The CAR design includes an extracellular antigen-binding region, a transmembrane region for signal transduction, and an intracellular signal transduction region.…”