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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 Study¹

Departments of Otolaryngology/Head and Neck Surgery [D. R. C., J. J. Q., R. d. B., P. K. B., G. B. S., G. A. M. S. v. D.], Hematology [G. J. O., P. C. H.], and Nuclear Medicine [J. C. R.], Vrije Universiteit Medical Center, 1081 Hv Amsterdam, the Netherlands

Purpose: 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.

Experimental Design: 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 µg/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°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 10⁶ CD34⁺ cells/kg (range, 0.15–0.83 x 10⁶ CD34⁺cells/kg) and a mean committed colony-forming units granulocyte macrophage count of 5.62 x 10⁴/kg (range, 0.62–13.37 x 10⁴/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 ¹⁸⁶Re-labeled cMAb U36 can be achieved using reinfusion of G-CSF-stimulated unprocessed whole blood.

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