CAR T cells targeting CD123, expressed on tumor cells from most HL patients and on M2-polarized tumor-associated macrophages (TAMs), completely eradicated HL, and led to a durable remission and memory response in 100% of mice in a xenograft model of progressive HL. In vitro, CART123 cells recognized and killed HL tumor cells and immunosuppressive TAMs.
Some patients with otherwise treatment-resistant Hodgkin lymphoma (HL) could benefit from chimeric antigen receptor T cell (CART) therapy. However, HL lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in HL, CART should target both malignant cells and the TME. We demonstrated CD123 on both HL cells and TME, including tumor-associated macrophages (TAM). In vitro, HL cells convert macrophages towards immunosuppressive TAM that inhibit T cell proliferation. In contrast, anti-CD123 CART recognized and killed TAM thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicate HL, and establish long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu.
Author Info: (1) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (2) Center for Cellular Immunotherapies, Perelman School of Medicine, University o
Author Info: (1) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (2) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (3) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (4) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (5) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania. (6) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania. (7) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Perelman School of Medicine of the University of Pennsylvania. (8) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania. (9) Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine. (10) Abramson Cancer Center, University of Pennsylvania saar.gill@uphs.upenn.edu.
