CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation.
Blood. 2008 Oct 30. [Epub ahead of print]
Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, Lowy I, Solomon SR, Morris LE, Holland HK, Mason JR, Alyea EP, Soiffer RJ, Ball ED.
Division of Blood and Marrow Transplantation, University of California, San Diego, La Jolla, CA, United States.
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 clinicaltrials.gov under NCI protocol ID P6082 |
