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.
Author Info: (1) University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA; Department of Hematology & Oncology, The Third Affiliated Hospital of Anhui Medical University, Hefei 2300
Author Info: (1) University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA; Department of Hematology & Oncology, The Third Affiliated Hospital of Anhui Medical University, Hefei 230032, China.(2) University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. (3) University of Michigan Rogel Cancer Center, Ann Arbor, MI, 48109, USA. (4) Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. (5) AstraZeneca, Gaithersburg, MD, USA. (6) Department of Hematology & Oncology, The Third Affiliated Hospital of Anhui Medical University, Hefei 230032, China. (7) University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA. Electronic address: mwicha@umich.edu. (8) University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA. Electronic address: qiaoli@umich.edu.
