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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1581-1588.
Prepublished online as a Blood First Edition Paper on October 30, 2008; DOI 10.1182/blood-2008-07-168468.
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Submitted July 18, 2008
Accepted October 11, 2008
CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation
Asad Bashey*, Bridget Medina, Sue Corringham, Mildred Pasek, Ewa Carrier, Linda Vrooman, Israel Lowy, Scott R Solomon, Lawrence E Morris, H Kent Holland, James R Mason, Edwin P Alyea, Robert J Soiffer, and Edward D Ball
Division of Blood and Marrow Transplantation, University of California, San Diego, La Jolla, CA, United States
Blood and Marrow Transplant Group of Georgia at Northside Hospital, Atlanta, GA, United States
Medarex, Inc., Bloomsbury, NJ, United States
BMT, Scripps Clinic, La Jolla, CA, United States
Hematologic Malignancies, Dana Farber Cancer Institute, Boston, MA, United States
* Corresponding author; email: abashey{at}bmtga.com.
Relapse of malignancy following allogeneic hematopoietic cell transplantation (allo-HCT) remains a therapeutic challenge. Conventional therapies are not curative in this setting, and donor lymphocyte infusions have limited efficacy in non-CML malignancies. Blockade of the CTLA4 molecule can effectively augment anti-tumor immunity mediated by autologous effector T-cells. We have assessed the safety and preliminary efficacy of a neutralizing, human anti-CTLA4 monoclonal antibody, Ipilimumab, in stimulating the graft-versus-malignancy effect following allo-HCT. Twenty-nine patients with malignancies that were recurrent or progressive following allo-HCT, received ipilimumab as a single infusion at dose cohorts between 0.1 and 3.0 mg/kg. Dose-limiting toxicity was not encountered, and ipilimumab did not induce GVHD or graft rejection. Organ-specific immune adverse events (IAE) were seen in 4 patients (grade 3 arthritis, grade 2 hyperthyroidism, recurrent grade 4 pneumonitis). Three patients with lymphoid malignancy developed objective disease responses following ipilimumab (CR in two patients with Hodgkin's disease and PR in a patient with refractory mantle cell lymphoma). At the 3.0 mg/kg dose active serum concentrations of ipilimumab were maintained for more than 30 days following a single infusion. Ipilimumab, as administered in this clinical trial, does not induce or exacerbate clinical GVHD but may cause organ-specific IAE and regression of malignancy. This study is registered at http://clinicaltrials.gov under NCI protocol ID P6082.
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