title: Reinfusion of unprocessed, granulocyte colony-stimulating factor-stimulated whole blood allows dose escalation of 186Relabeled chimeric monoclonal antibody U36 radioimmunotherapy in a phase I dose escalation study.
abstract: OBJECTIVE
  In an earlier Phase I radioimmunotherapy (RIT) study with rhenium-186-labeled chimeric monoclonal antibody (cMAb) U36 in patients with refractory head and neck squamous cell carcinoma, the maximum tolerated activity was established at 1.0 GBq/m2, at which bone marrow doses ranged from 0.7 to 1.1 Gy. In the present study, further dose escalation in RIT was evaluated using a facile method of reinfusion of granulocyte colony-stimulating factor (G-CSF)-stimulated unprocessed whole blood.
  
  
  METHODS
  Nine patients with recurrent or metastatic head and neck squamous cell carcinoma were treated at radiation dose levels of 1.0, 1.5, and 2.0 GBq/m2. Before RIT, G-CSF (10 microg/kg/day) was administered s.c. at home during 5 days. On day 6, just before administration of 186Relabeled cMAb U36, 1 liter of whole blood was harvested and kept unprocessed at 4 degrees C until reinfusion after 72 h. Blood samples were taken for analysis of pharmacokinetics and bone marrow dosimetry. Patients were evaluated for myelotoxicity and tumor response.
  
  
  RESULTS
  Blood harvesting, RIT, and reinfusion of whole blood were well tolerated by all patients. G-CSF stimulation resulted in a mean of 0.41 x 10(6) CD34+ cells/kg (range, 0.15-0.83 x 10(6) CD34+cells/kg) and a mean committed colony-forming units granulocyte macrophage count of 5.62 x 10(4)/kg (range, 0.62-13.37 x 10(4)/kg). The mean biological half-life of 186Relabeled cMAb U36 in blood was 72.6 +/- 16.0 h, and bone marrow doses ranged from 2.1 to 2.8 Gy at the highest dose level. Myelotoxicity exceeding grade 3 was not observed. Stable disease was observed in five of nine patients, ranging from 3 to 5 months, and was still ongoing in one of these patients.
  
  
  CONCLUSIONS
  This study indicates that a doubling of the maximum tolerated activity and bone marrow dose of 186Relabeled cMAb U36 can be achieved using reinfusion of G-CSF-stimulated unprocessed whole blood.
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, Vrije Universiteit Medical Center, 1081 Hv Amsterdam, The Netherlands.
authors.forename: David R
authors.initials: DR
authors.lastname: Colnot
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Jan C
authors.initials: JC
authors.lastname: Roos
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: Quak
authors.forename: Remco
authors.initials: R
authors.lastname: de Bree
authors.forename: Pontus K
authors.initials: PK
authors.lastname: Börjesson
authors.forename: Peter C
authors.initials: PC
authors.lastname: Huijgens
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Snow
authors.forename: Guus A M S
authors.initials: GA
authors.lastname: van Dongen
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal; D018952:Antigens, CD34 / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*; D011874:Radiometry; D012008:Recurrence; D012211:Rhenium / Q000627:therapeutic use*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D011868:Radioisotopes; D016179:Granulocyte Colony-Stimulating Factor; D012211:Rhenium