An animal model for human cellular immunotherapy: specific eradication of human acute lymphoblastic leukemia by cytotoxic T lymphocytes in NOD/scid mice

Abstract

Abstract Adoptive immunotherapy using in vitro–generated donor-derived cytotoxic T lymphocytes (CTLs) can be effective in the treatment of relapsed leukemia after allogeneic transplantation. To determine effector cell characteristics that result in optimal in vivo antileukemic efficacy, we developed an animal model for human CTL therapy. Nonobese diabetic/severe combined immunodeficiency (NOD/scid) mice were inoculated with either of 2 primary human acute lymphoblastic leukemia (ALL), denoted as SK and OF. Anti-SK and anti-OF CTLs were generated in vitro by repeated stimulation of donor peripheral blood mononuclear cells with either SK or OF cells. Both CTL lines displayed HLA-restricted reactivity against the original targets and non-major histocompatibility class (MHC)–restricted cross-reactivity in vitro. The CTLs were administered intravenously weekly for 3 consecutive weeks to mice engrafted with either SK or OF leukemia. In 3 of 8 SK-engrafted and anti-SK–treated mice, complete remissions were achieved in blood, spleen, and bone marrow. In the remaining 5 animals partial remissions were observed. In 4 of 4 OF-engrafted anti-OF–treated mice partial remissions were observed. The antileukemic effect of specific CTLs was exerted immediately after administration and correlated with the degree of HLA disparity of the donor-patient combination. In cross-combination–treated animals, no effect on leukemic progression was observed indicating that in vivo antileukemic reactivity is mediated by MHC-restricted effector cells. The CTLs, however, displayed an impaired in vivo proliferative capacity. Ex vivo analysis showed decreased reactivity as compared to the moment of infusion. We therefore conclude that the model can be used to explore the requirements for optimal in vivo efficacy of in vitro– generated CTLs.