Previous studies established that regression of human tumors positive for HER2 in immunodeficient mice is induced by antibody-drug conjugates (ADCs) targeting human HER2 (hHER2+). Xia et al. established two hHER+ tumor models in immunocompetent mice and demonstrated the antitumor effects of HER2-targeted ADCs. Additionally, ADCs reduced the number and tumorigenicity of hHER2+ cancer stem cells, prolonged survival, and induced immune memory. Synergistic efficacy was observed with combination ADCs and anti-PD-L1. ADCs had proinflammatory effects on gene activation – an effect augmented by anti-PD-L1.
Contributed by Margot O’Toole
ABSTRACT: We previously tested HER2-targeted antibody-drug conjugates (ADCs) in immunocompromised (SCID) mice, precluding evaluation of host immunity, impact on cancer stem cells (CSCs), and potential benefit when combined with PD-L1 blockade. In this study, we tested HER2-targeted ADC in two immunocompetent mouse tumor models. HER2-targeted ADC specifically inhibited the growth of HER2-expressing tumors, prolonged animal survival, and reduced HER2+ and PD-L1+ cells. ADC + anti-PD-L1 antibody augmented therapeutic efficacy, modulated immune gene signatures, increased the number and function of CD3+ and CD19+ tumor-infiltrating lymphocytes (TILs), induced tumor antigen-specific immunological memory, stimulated B cell activation, differentiation, and IgG1 production both systemically and in the tumor microenvironment. In addition, ADC therapy modulated T cell subsets and their activation in TILs. Furthermore, HER2-targeted ADC reduced the number and tumorigenicity of ALDHhi CSCs. This study demonstrates that HER2-targeted ADC effectively targets ALDHhi CSCs and this effect is augmented by co-administration of anti-PD-L1 antibody.