Chimeric antigen receptor modified hematopoietic stem cells (CAR-HSCs) arm all immune forces for anti-tumor in mice

Chimeric antigen receptor T cell (CAR-T) is the main salvage therapy for relapsed or refractory large B-cell lymphoma (r/r LBCL). However, over 50% of patients relapse after CAR-T therapy. In this work, we transduced the CAR gene into hematopoietic stem cells (HSCs) using a lentiviral vector. Chimeric antigen receptor-modified HSC (CAR-HSCs) were transplanted into mice after lethal irradiation. CAR gene transduction did not compromise the ability of HSCs to expand, self-renew, or reconstitute. CAR was expressed on T cells, natural killer cells, B cells, monocytes, and neutrophils in the peripheral blood. CAR-HSCs transplantation significantly reduced CD19⁺ tumor burden and prolonged the survival of mice with preclinical tumor without severe toxicity. CAR-HSCs also differentiated into different CAR-expressing immune cells that reshaped the tumor microenvironment by increasing the proportion of antitumor cells (like CD8⁺ T cells) and the antitumor response, and by decreasing immunosuppressive cells, such as tumor-associated macrophage subtype 2. This study demonstrated a preclinical proof-of-principle for CAR-HSCs therapy in r/r LBCL, suggesting an opportunity for its clinical translation.