Modeling Human Leukemia Immunotherapy in Humanized Mice

• NSG mice grafted with thymus/oncogenic HSC develop human immune system and leukemia.
• Leukemia transfer to mice with autologous immunity suffices to model immunotherapy.
• Lymphopenia enhances RLI-mediated HVGR and anti-leukemia activity in mixed chimeras.This study establishes a humanized mouse model with human immunity and autologous leukemia. Using this model, the authors demonstrate that lymphopenia promotes the rejection of donor hematopoietic chimerism and the associated anti-leukemia response by recipient leukocyte infusion in mixed allogeneic chimeras.

The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse) model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL), which was transplantable to secondary recipients with an autologous human immune system. Using this model, we show that lymphopenia markedly improves the antitumor efficacy of recipient leukocyte infusion (RLI), a GVHD-free immunotherapy that induces antitumor responses in association with rejection of donor chimerism in mixed allogeneic chimeras. Our data demonstrate the potential of this leukemic hu-mouse model in modeling leukemia immunotherapy, and suggest that RLI may offer a safe treatment option for leukemia patients with severe lymphopenia.