Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia

Abstract

The outcome for patients with refractory or relapsed acute lymphoblastic leukemia (ALL) treated with conventional therapy is poor. Immunoconjugates present a novel approach and have recently been shown to have efficacy in this setting. Combotox is a mixture of two ricin-conjugated monoclonal antibodies (RFB4 and HD37) directed against CD19 and CD22, respectively, and has shown activity in pediatric and adult ALL. We created a murine xenograft model of advanced ALL using the NALM/6 cell line to explore whether the combination of Combotox with the cytotoxic agent cytarabine (Ara-C) results in better outcomes. In our model the combination of both low- and high-dose Combotox and Ara-C resulted in significantly longer median survival. Sequential administration of Ara-C and Combotox, however, was shown to be superior to concurrent administration. These findings have led to a phase I clinical trial exploring this combination in adults with relapsed or refractory B-lineage ALL (ClinicalTrials.gov identifier NCT01408160).

Keywords::

• Leukemia
• acute lymphoblastic
• immunoconjugate
• cytarabine
• ricin
• animal model
• mouse
• NOD

Acknowledgements

The work was supported in part by the Paul Calabresi Career Development Award for Clinical Oncology (K12CA132783 - 03 grant). The authors thank Ellen S. Vitetta, PhD and Victor Ghetie, PhD at the Cancer Immunobiology Center of the University of Texas Southwestern Medical Center for their scientific support and expert advice.

Potential conflict of interest:

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