CURE OF MULTIDRUG-RESISTANT HUMAN B-CELL LYMPHOMA XENOGRAFTS BY COMBINATIONS OF ANTI-B4-BLOCKED RICIN AND CHEMOTHERAPEUTIC DRUGS

The CD-19-directed immunotoxin anti-B4-blocked ricin (anti-B4-bR) is c urrently in clinical trials for the treatment of B-cell malignancies, To explore the potential of using anti-B4-bR with chemotherapy protoco ls we tested the in vivo efficacy of the immunotoxin in combination wi th two multi-drug chemotherapeutic regimens in severe combined immunod eficient (SCID) mice bearing disseminated tumors of the multidrug-resi stant human B-cell lymphoma Namalwa/mdr-1, In cytotoxicity studies in vitro, combinations of the immunotoxin with cisplatin produced supra-a dditive killing effects on both Namalwa and Namalwa/mdr-1 cells, where as anti-B4-bR combined with 4-hydroperoxy-cyclophosphamide caused addi tive killing of both cell lines. In vivo cyclophosphamide, cisplatin, vincristine, doxorubicin, and etoposide as single agents, were effecti ve in prolonging the survival of SCID mice burdened with the Namalwa t umor, whereas only cyclophosphamide and cisplatin were effective on Na malwa/mdr-1 tumors. Treatment of Namalwa/mdr-1-bearing mice with anti- B4-bR alone or with the drug combination CHOE (consisting of cyclophos phamide, vincristine, doxorubicin, and etoposide) alone increased the lifespan of the tumor-burdened mice by 58% and 73%, respectively. Howe ver, treatment with five daily bolus intravenous injections of anti-B4 -bR followed by CHOE increased the lifespan by 173%, and 20% of the mi ce were cured, The drug combination CCE (cyclophosphamide, cisplatin, and etoposide) alone could increase the lifespan of the Namalwa/mdr-1 tumor-burdened mice by 129% compared with untreated controls, Combinat ion therapy with anti-B4-bR and CCE produced long-term cures in 50% of the tumor-burdened mice. These results suggest that anti-B4-bR in com bination with current multidrug regimens may constitute a highly effic acious modality for the treatment of drug-resistant B-cell malignancie s. (C) 1996 by The American Society of Hematology.