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  • Title: Effective immunochemotherapy of human t(4;11) leukemia in mice with severe combined immunodeficiency (SCID) using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin plus cyclophosphamide.
    Author: Jansen B, Kersey JH, Jaszcz WB, Gunther R, Nguyen DP, Chelstrom LM, Tuel-Ahlgren L, Uckun FM.
    Journal: Leukemia; 1993 Feb; 7(2):290-7. PubMed ID: 7678881.
    Abstract:
    Human mixed lineage leukemia cell line RS4;11 with the t(4;11)(q21;q23) translocation causes disseminated and invariably fatal leukemia in mice with severe combined immunodeficiency. Whereas an immunotoxin constructed from the murine anti-CD19(B43) monoclonal antibody and the plant toxin pokeweed antiviral protein (B43-PAP) has a potent in vitro anti-leukemic effect against clonogenic RS4;11 cells, its activity is further potentiated by the active cyclophosphamide congener mafosfamid. These intriguing observations prompted us to evaluate the in vivo antileukemic efficacy of combined immunochemotherapy employing B43-PAP immunotoxin plus cyclophosphamide against human t(4;11) leukemia cells in an RS4;11 severe combined immunodeficiency (SCID) mouse model system. Intravenous injections of B43-PAP or cyclophosphamide improved survival of SCID mice challenged with RS4;11 leukemia, as reflected by markedly prolonged median survival times. After intravenous inoculation of 5 x 10(7) RS4;11 leukemia cells, the median survival times were 41 days for saline-treated control mice (n = 12), 44 days for control mice treated with unconjugated B43 monoclonal antibody and PAP (n = 12), 56 days for mice treated with the control immunotoxin G17.2 (anti-CD4)-PAP (n = 6), 79 days for B43-PAP-treated test mice (n = 12), and 80 days for cyclophosphamide-treated test mice (n = 16). Notably, combined immunochemotherapy using B43-PAP plus cyclophosphamide was significantly more effective than either B43-PAP or cyclophosphamide alone. The median survival time for a total of 22 SCID mice undergoing combined immunochemotherapy with B43-PAP followed by cyclophosphamide (n = 12) or cyclophosphamide followed B43-PAP (n = 10) was > 150 days. The Kaplan-Meier estimates and standard errors of the probability of event-free survival at 5 months after inoculation of 5 x 10(7) RS4;11 cells were 21 +/- 13% for B43-PAP-treated mice, 7 +/- 6% for cyclophosphamide-treated mice, 90 +/- 10% for mice treated with B43-PAP followed by cyclophosphamide (n = 12), and 90 +/- 10% for mice treated with cyclophosphamide followed by B43-PAP (n = 10). Our results lead us to recommend that initial consideration be given to combined immunochemotherapy protocols using B43-PAP immunotoxin plus cyclophosphamide for treatment of refractory or relapsed t(4;11) leukemias.
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