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

Q4 · MEDICINE

Article

Author: Ulrich Steidl ; Niraj Shenoy ; Amit Verma ; Tushar D. Bhagat ; Yiyu Zou ; Stefan K. Barta ; John Schindler

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).

01 Jun 2008·Leukemia ResearchQ4 · MEDICINE

Improving treatment strategies for acute lymphoblastic leukemia by combining immunotherapy and chemotherapy

Q4 · MEDICINE

Communications

Author: Ivana Gojo

A review.The research of Stanciu-Herrera et al. (2008) entitled "Anti-CD19 and anti-CD22 monoclonal antibodies increase the effectiveness of chemotherapy in pre-B acute lymphoblastic leukemia cell lines" is reviewed with commentary and referencesThese authors report preclin. data on the efficacy of "naked" murine anti-CD19 (HD37) and anti-CD22 (RFB4) monoclonal antibodies (mAbs) alone or in combination with daunorubicin and vincristine in human precursor B-cell acute lymphoblastic leukemia (ALL) cell lines and a mouse xenograft model.In this model, treatment with vincristine and daunorubicin alone provided only a minor survival advantage.HD37 also had only a minor inhibiting effect on tumor growth, while RFB4 was ineffective.HD37, but less so RFB4, combined with daunorubicin and particularly vincristine, exhibited synergistic activity, with 40% of mice in the latter group becoming long-term survivors.Efficacy can be ascribed to the synergistic activity of the "naked" HD37 mAb and vincristine in inducing tumor apoptosis.

01 Apr 2008·Leukemia ResearchQ4 · MEDICINE

Anti-CD19 and anti-CD22 monoclonal antibodies increase the effectiveness of chemotherapy in Pre-B acute lymphoblastic leukemia cell lines

Q4 · MEDICINE

Article

Author: L. Herrera ; C. Morgan ; C. Stanciu-Herrera

The monoclonal antibodies (MAbs) HD37 and RFB4 bind to receptors on precursor B acute lymphoblastic leukemia (ALL) cells. These MAbs were tested alone and in combination with chemotherapy for their anti-leukemic activity. HD37 and not RFB4 increased the in vitro cytotoxicity of daunorubicin (DNR) and vincristine (VCR) in three Pre-B ALL cell lines. HD37 alone induced apoptosis in 30% of the cells versus 2% for RFB4. The treatment of SCID/ALL mice with either chemotherapy agent minimally prolonged their mean survival time (MST) versus controls but HD37 or RFB4 plus VCR significantly extended the MST. Forty percent of the mice treated with HD37 plus VCR survived. In conclusion, chemotherapy was made more effective when combined with HD37, and less so with RFB4.

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