CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation.
Relapse of malignancy after allogeneic hematopoietic cell transplantation (allo-HCT) remains a therapeutic challenge. Blockade of the CTLA4 molecule can effectively augment antitumor 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 (GVM) effect after allo-HCT. Twenty-nine patients with malignancies that were recurrent or progressive after 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 graft-versus-host disease (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: complete remission (CR) in 2 patients with Hodgkin disease and partial remission (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 after 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.
Bashey
Asad
A
Division of Blood and Marrow Transplantation, University of California, San Diego Moores Cancer Center, La Jolla, CA, USA. abashey@bmtga.com
Medina
Bridget
B
Corringham
Sue
S
Pasek
Mildred
M
Carrier
Ewa
E
Vrooman
Linda
L
Lowy
Israel
I
Solomon
Scott R
SR
Morris
Lawrence E
LE
Holland
H Kent
HK
Mason
James R
JR
Alyea
Edwin P
EP
Soiffer
Robert J
RJ
Ball
Edward D
ED
D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced; D060908:CTLA-4 Antigen; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology; D020544:Graft vs Leukemia Effect / Q000187:drug effects*; D006801:Humans; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D007938:Leukemia / Q000401:mortality / Q000628:therapy*; D008223:Lymphoma / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000517:prevention & control*; D011014:Pneumonia / Q000139:chemically induced; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab