Combined ex vivo treatment with immunotoxins and mafosfamid: a novel immunochemotherapeutic approach for elimination of neoplastic T cells from autologous marrow grafts.

Abstract

We evaluated a novel ex vivo "purging" protocol for selective elimination of neoplastic T cells from human marrow by using a sensitive clonogenic assay. Immunotoxins (IT) were synthesized by conjugating ricin (R) to four different monoclonal antibodies (MoAb) directed against distinct markers of T cell lineage. Treatment with anti-p67-R produced effective elimination of leukemic T cells from human marrow. The cyclophosphamide congener mafosfamid (ASTA Z 7577) markedly enhanced the target cell cytotoxicity of IT and extended the final level of clonogenic kill 2 to 3 logs. Our data show that anti-p67-R in combination with mafosfamid resulted in a maximum elimination of 6.2 logs of neoplastic T cells with minimal toxicity to normal bone marrow progenitors. The efficiency of this protocol was not reduced in the presence of excess normal bone marrow cells. Similar findings were obtained by using a cocktail of four different anti-T cell IT. This approach is unique in combining both immunologic (IT) and chemical (mafosfamid) strategies for more effective ex vivo bone marrow purging in autologous bone marrow transplantation for T cell acute lymphoblastic leukemia/lymphoblastic lymphoma.