title: 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).
authors.affiliation: Albert Einstein College of Medicine, Montefiore Medical Center-Moses Division, Bronx, NY 10467, USA. sbarta@montefiore.org
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Barta
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Zou
authors.forename: John
authors.initials: J
authors.lastname: Schindler
authors.forename: Niraj
authors.initials: N
authors.lastname: Shenoy
authors.forename: Tushar D
authors.initials: TD
authors.lastname: Bhagat
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D018941:Antigens, CD19 / Q000737:chemistry / Q000276:immunology; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D051379:Mice; D016688:Mice, Inbred NOD; D009367:Neoplasm Staging; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012276:Ricin / Q000737:chemistry / Q000627:therapeutic use; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000737:chemistry / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D004338:Drug Combinations; D000922:Immunotoxins; D051918:Sialic Acid Binding Ig-like Lectin 2; C577568:combotox; D003561:Cytarabine; D012276:Ricin