Reinfusion of Unprocessed, Granulocyte Colony-stimulating Factor- stimulated Whole Blood Allows Dose Escalation of 186 Relabeled Chimeric Monoclonal Antibody U36 Radioimmunotherapy in a Phase I Dose Escalation Study 1 David R. Colnot, Gert J. Ossenkoppele, Jan C. Roos, Jasper J. Quak, Remco de Bree, Pontus K. Bo ¨rjesson, Peter C. Huijgens, Gordon B. Snow, and Guus A. M. S. van Dongen 2 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 ABSTRACT 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 ac- tivity was established at 1.0 GBq/m 2 , 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 fac- tor (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/m 2 . Before RIT, G-CSF (10 g/kg/day) was administered s.c. at home during 5 days. On day 6, just before administration of 186 Relabeled cMAb U36, 1 liter of whole blood was har- vested and kept unprocessed at 4°C until reinfusion after 72 h. Blood samples were taken for analysis of pharmaco- kinetics and bone marrow dosimetry. Patients were evalu- ated 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  10 6 CD34  cells/kg (range, 0.15– 0.83  10 6 CD34  cells/kg) and a mean committed colony-forming units granulocyte macrophage count of 5.62  10 4 /kg (range, 0.62–13.37  10 4 /kg). The mean bio- logical half-life of 186 Relabeled 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 186 Re- labeled cMAb U36 can be achieved using reinfusion of G- CSF-stimulated unprocessed whole blood. INTRODUCTION Radiolabeled MAbs 3 can be used for selective delivery of radiation to tumor sites. For selective treatment of HNSCC, RIT might be an interesting approach as an adjuvant therapy because there is still a high failure rate, either locally or at distant sites, after locoregional treatment of HNSCC with surgery and/or radiotherapy. In patients with hematological malignancies, RIT has shown efficacy, resulting in improved remission and response rates (1, 2). In most of the RIT trials conducted thus far, radiogenic damage to the bone marrow has been the dose-limiting toxicity, resulting in thrombo- cytopenia and granulocytopenia occurring with a nadir of 4 – 6 weeks after RIT. Autologous transplantation of bone marrow or separated growth factor-mobilized blood stem cells can reduce myelotoxicity and allowed dose escalation of RIT (3–5). Stem cell transplantation in patients with relapsed B-cell lymphomas treated with high-dose RIT allowed bone marrow-absorbed doses as high as 6.4 Gy before cardio- pulmonary dose-limiting toxicity was observed (6). Both transplantation of bone marrow and filtered blood stem cells require equipment and laboratory facilities for sepa- ration and cryopreservation, whereas both techniques are labo- rious and expensive. In comparison, G-CSF-stimulated unproc- essed whole blood might be an alternative source of blood stem cells. Reinfusion of G-CSF-stimulated whole blood is a straight- forward and safe procedure, and it can be performed in a routine clinical setting at low cost (7, 8). The G-CSF-stimulated whole blood can be stored for at least 72 h at 4°C without significant loss of viability of the blood stem cells (9, 10). Whereas up to 90% of the CD34 + population shows early apoptotic changes after cryopreservation (11), only 5–10% apoptotic changes were Received 12/4/01; revised 8/5/02; accepted 8/6/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by Dutch Cancer Society Grant VU 96-1313 and Centocor Inc. (Malvern, PA). 2 To whom requests for reprints should be addressed, at Department of Otolaryngology/Head and Neck Surgery, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands. Phone: 31-20-4443690; Fax: 31-20-4443688; E-mail: gams.vandongen@ vumc.nl. 3 The abbreviations used are: MAb, monoclonal antibody; G-CSF, gran- ulocyte colony-stimulating factor; RIT, radioimmunotherapy; cMAb, chimeric MAb; HNSCC, head and neck squamous cell carcinoma; MTA, maximum tolerated activity; CFU-GM, colony-forming unit(s) granulocyte macrophage. 3401 Vol. 8, 3401–3406, November 2002 Clinical Cancer Research Research. on September 29, 2021. © 2002 American Association for Cancer clincancerres.aacrjournals.org Downloaded from