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Clinical Cancer Research Vol. 8, 3401-3406, November 2002
© 2002 American Association for Cancer Research

Clinical Trials

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

David R. Colnot, Gert J. Ossenkoppele, Jan C. Roos, Jasper J. Quak, Remco de Bree, Pontus K. Börjesson, Peter C. Huijgens, Gordon B. Snow and Guus A. M. S. van Dongen2

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
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Radiolabeled MAbs3 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 thrombocytopenia 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, 4, 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 cardiopulmonary dose-limiting toxicity was observed (6) .

Both transplantation of bone marrow and filtered blood stem cells require equipment and laboratory facilities for separation and cryopreservation, whereas both techniques are laborious and expensive. In comparison, G-CSF-stimulated unprocessed whole blood might be an alternative source of blood stem cells. Reinfusion of G-CSF-stimulated whole blood is a straightforward 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 found in the CD34+ population in whole blood transplants after 72 h of storage (12) . In multicyclic chemotherapy regimens of short duration, this procedure allowed dose intensification in patients with small cell lung cancer (7 , 13) . Moreover, myeloablative chemotherapy with whole blood rescue for patients with high-risk lymphoma and multiple myeloma was proven to be feasible (8 , 14 , 15) . To our knowledge, this whole blood procedure has never been applied in RIT studies.

Because the time interval between RIT and the development of myelotoxicity is 4–6 weeks, reinfusion of G-CSF-stimulated whole blood is a realistic option to reduce myelotoxicity of RIT because it allows the reinfused blood stem cells to home and proliferate in the bone marrow before myelotoxicity becomes manifest. A prerequisite for this approach is that most of the radioactivity has disappeared from blood and bone marrow at the time of reinfusion. In an earlier Phase I study, rhenium-186-labeled cMAb U36 was evaluated in patients with refractory HNSCC (16) . The MTA (at which a grade 4 hematological or grade 3 nonhematological toxicity developed in not more than one of six patients) was found to be 1.0 GBq/m2, with a maximum tolerated bone marrow dose of 0.9 ± 0.2 Gy. Dose-limiting grade 4 myelotoxicity occurred in two of three patients treated with 1.5 GBq/m2. The effective half-life of 186Relabeled cMAb U36 in blood was 37 h, meaning that after 72 h, 25% of the injected radioactivity was still present in the blood. This effective half-life is related to both the biological half-life of the MAb and the physical half-life of the radionuclide, according to the equation 1/T1/2 effective = 1/T1/2 biological + 1/T1/2 physical. In the current study, we evaluated whether reinfusion of G-CSF-stimulated unprocessed whole blood after 72 h allows dose escalation of 186Relabeled cMAb U36 RIT.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Nine patients (five men and four women; age range, 48–71 years) were included in this study. Their characteristics are listed in Table 1Citation . All patients had clinical evidence of relapsed HNSCC, either locoregionally or at distant sites, for which no curative options were available. A histologically confirmed HNSCC in the past was required for inclusion. Other eligibility criteria were described in an earlier report on a Phase I dose-escalation study without blood stem cell support (16) . The study was approved by the Institutional Review Board of the Vrije Universiteit Medical Center (Amsterdam, the Netherlands). All patients gave written informed consent after thorough explanation of the study.


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  		Table 1 Patient characteristics

 
The antigen recognized by MAb U36 (Centocor B.V., Leiden, the Netherlands) is the keratinocyte-specific CD44 splice variant epican. The epitope is located in the v6 domain of CD44 (17) . CD44v6 is expressed by squamous cell carcinomas of the head and neck, lung, skin, esophagus, and cervix and also by adenocarcinomas of the breast, colon, lung, and stomach (18 , 19) . Antibody production, radiolabeling, and quality controls have been described in detail (16) . The radiochemical purity of 186Relabeled cMAb U36 ranged from 95% to 97% as assessed by TLC of the final product. The immunoreactive fraction of 186Relabeled cMAb U36 ranged from 89.0% to 93.8%.

To mobilize blood stem cells, G-CSF (Filgrastim, Neupogen; Amgen, Thousand Oaks, CA) at a dosage of 10 µg/kg for 5 days was administered s.c. at home. On day 6, just before RIT, two phlebotomies of 500 ml each were performed via an antecubital vein within 2–3 h. Patients were carefully monitored for blood pressure and heart rate during the procedure, and infusion of 500 ml of 0.65% saline was performed after each phlebotomy. Blood was collected in two 2,3-ethyl, hexyl-phtalate plasticized transfer bags (Nederlands Productie Laboratorium voor Bloedtransfusieapparatuur en Infusievloeistoffen BV, Emmer-Compascuum, the Netherlands) containing 70 ml of CPD as anticoagulant. After collection, the bags were sealed and stored unprocessed and unshaken at 4°C in a temperature-controlled refrigerator. Reinfusion of the unprocessed whole blood was performed after 72 h. The number of cells expressing the CD34 antigen and the committed CFU-GM in stored whole blood were assessed from a sample taken just before reinfusion (10) .

Just after collection of G-CSF-stimulated whole blood, 50 mg of 186Relabeled cMAb U36 were administered i.v. in 5 min. Blood samples were collected from the opposite antecubital vein and counted in a multiwell gamma counter (1470 Wizard; Wallac, Turku, Finland) for pharmacokinetic analyses and patient-specific bone marrow dosimetry according to Shen et al. (20) . This method takes the contribution of other organs and the whole body into account. The dose levels were 1.0, 1.5, and 2.0 GBq/m2 body surface area, and three patients were treated at each dose level. Vital functions (blood pressure, pulse rate, breathing rate, and temperature) were assessed before administration and 20, 40, 60, 120, and 240 min after administration. Patients were admitted for 21 h in a special treatment room at the department of nuclear medicine. Thereafter, they stayed in a single room at the otolaryngology/head and neck surgery ward until reinfusion. Scintigraphic imaging studies were performed with a large field-of-view gamma camera (Dual Head Genesys Imaging System; ADAC Laboratories, Milpitas, CA). Whole-body and lateral, anterior, and posterior planar images and single-photon emission computed tomography of the head and neck region were obtained in all patients. Patients were discharged after the reinfusion was completed.

Hematological parameters were obtained at least weekly until recovery of myelotoxicity was observed. The severity of toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (21) . Data on bone marrow dosimetry and development of myelotoxicity were compared with those from patients treated in an earlier study of 186Relabeled cMAb U36 without the use of whole blood reinfusion (16) . Physical examination and computed tomography or magnetic resonance imaging were performed every 4 weeks for evaluation of response. Stable disease was defined as a 50% reduction or a <=25% increase in the sum of the perpendicular diameter products and no new lesions, which had to persist for at least 3 months. Progression was defined as an unequivocal increase in size (>25%) of any lesion or the appearance of a new lesion.

All mean values reported represent ranges, arithmetic means, and corresponding SD.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
G-CSF treatment for blood stem cell mobilization did not cause side effects in any of the patients. The mean WBC count after G-CSF stimulation was 45.1 x 109/liter (range, 26.6–71.6 x 109/liter; Table 1Citation ). Whole blood harvesting did not lead to significant hypotension in patients, and administration of 186Relabeled cMAb U36, as well as reinfusion of whole blood, was well tolerated by all patients, without occurrence of acute side effects. Scintigraphy showed selective targeting of tumor lesions in all patients, and no accumulation at nontumor sites, except for the presence of radioactivity in feces and urine (Fig. 1)Citation . The mean number of CD34+ cells harvested after G-CSF stimulation was 0.41 x 106 cells/kg body weight (range, 0.15–0.83 x 106 cells/kg body weight), and a mean CFU-GM count of 5.62 x 104/kg was found (range, 0.62–13.37 x 104/kg; Table 1Citation ). Pharmacokinetic analysis revealed a mean biological half-life of 72.6 ± 16.0 h for 186Relabeled cMAb U36 in blood. Bone marrow doses ranged from 0.8 to 2.8 Gy, with a mean bone marrow dose of 0.64 ± 0.13 Gy/GBq (Table 2)Citation .



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  		Fig. 1. Whole-body scan (patient 8) acquired at 72 h after administration of 186Relabeled cMAb U36. At the site of recurrence in the left oropharynx, accumulation of 186Relabeled cMAb U36 is clearly visible. Except for blood pool activity, a more or less homogeneous distribution of 186Relabeled cMAb U36 is seen for the remainder of the whole body.

 

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  		Table 2 Dose levels, BM dosimetry, myelotoxicity, and response after 186Relabeled cMAb U36 RIT with reinfusion of G-CSF-stimulated unprocessed whole blood

 
The nadir of platelets was observed 4–5 weeks after administration of 186Relabeled cMAb U36, and the nadir of WBCs and granulocytes was observed after 5–6 weeks. In none of the patients was a platelet count of <20 x 109/liter observed. For three patients, platelets were <50 x 109/liter for 5–21 days (Table 2)Citation . The granulocyte nadir was <1.0 x 109/liter in four patients, lasting for 2, 4, 7, and 11 days, respectively. Three patients required transfusion of packed RBCs for low hemoglobin levels, which was regarded as grade 3 toxicity. In one of these patients (patient 1), the transfusion was performed because of low hemoglobin level shortly after reinfusion of the unprocessed whole blood, which was therefore most likely the result of hemolysis rather than radiation induced. Patient 4 was given three packed RBCs as well as a single transfusion of platelets because of a sudden low hemoglobin level (4.5 mmol/liter) at 4 weeks after RIT, which was attributed to gastrointestinal bleeding caused by concomitant use of corticosteroids and nonsteroidal anti-inflammatory drugs. At the time of the transfusion, there was grade 3 thrombocytopenia, which showed recovery within 5 days. The other patient (patient 6) was given two transfusions of three packed RBCs for hemoglobin levels of 5.2 and 5.5 mmol/liter at 3.5 and 4 weeks after RIT, respectively. He suffered from cachexia and frequent bleeding as a result of tumor progression.

Overall, myelotoxicity exceeding grade 3 was not observed (Table 2)Citation , and nonhematological toxicity consisted of a grade 2 mucositis in one patient (patient 5). Less severe myelotoxicity was observed as compared with patients treated at the highest dose levels in the previous Phase I study without the use of reinfusion of G-CSF-stimulated whole blood (Table 3Citation ; Ref. 16 ). None of the patients who received up to 2.0 GBq/m2 developed more than grade 3 myelotoxicity. The MTA in the previous study was established at 1.0 GBq/m2, with grade 4 myelotoxicity in two of three patients receiving 1.5 GBq/m2. Introduction of this procedure allowed increase of the maximum tolerated bone marrow doses from 0.9 ± 0.2 Gy to 2.5 ± 0.4 Gy and an increase of the MTA from 1.0 GBq/m2 to at least 2.0 GBq/m2 (Table 3)Citation .


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  		Table 3 Comparison of mean BM dose and maximum hematological toxicity grade after RIT with 186Relabeled cMAb U36 in patients treated without reinfusion of G-CSF-stimulated whole blood and patients treated with reinfusion of G-CSF-stimulated whole blooda

 
Stable disease was observed in five patients for a period of 3–5 months and is still ongoing in one patient (patient 9). No partial or complete responses were seen.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, reinfusion of G-CSF-stimulated unprocessed whole blood was used for dose intensification of RIT with 186Relabeled cMAb U36. As in chemotherapy, myelotoxicity, in general, is dose-limiting in RIT studies. Whereas after chemotherapy myelotoxicity becomes manifest within a few days, the nadir of platelets and granulocytes after RIT occurs at 4–6 weeks. This might allow blood stem cells, if reinfused at a time point at which an acceptable low radiation level is present in blood, to home and proliferate in the bone marrow before myelotoxicity becomes manifest, thereby reducing the severity of myelotoxicity.

At the current stage of development, reinfusion of G-CSF-stimulated whole blood should be performed not more than 72 h after harvesting to guarantee the viability of the blood stem cells (9 , 10) . The effective half-life of 186Relabeled cMAb U36 is 37 h (16) , which means that at the time of reinfusion, radiation damage to circulating blood stem cells can still occur.

This preliminary Phase I study showed improved potential of RIT with 186Relabeled cMAb U36 in comparison with a previous study in which no reinfusion of G-CSF-stimulated unprocessed whole blood was performed. In the current study, patients tolerated higher total injected doses, and higher doses delivered to the bone marrow were tolerated. Stable disease was more frequently observed in the present study. In total, five of nine patients showed stable disease, and all three patients treated at the highest dose level showed stable disease. In the previous study, only 1 of 13 patients showed stable disease. The only responder had been treated at the highest dose level. The observation of stabilization of disease in patients treated in the current study offers opportunities for further development of RIT in an adjuvant setting because antibody uptake in small-volume tumors is found to be higher than uptake in large tumors (22 , 23) .

An aspect for further improvement is the storage time of whole blood, which is currently limited to 72 h. To increase the clinical applicability, as for RIT with radiolabeled MAbs with a relatively long effective half-life in blood, this storage time should be extended. Encouraging results with new storage mediums have shown preservation of clonogenic capacity of blood stem cells in whole blood for at least 7 days (24) , which could allow reinfusion at a later, more suitable time point after RIT, at which remaining radiation levels in blood have been further decreased. For leucopheresis or bone marrow transplantation, this problem of storage time does not play a role. However, both procedures require filtration techniques, cryopreservation, and expensive laboratory facilities. Reinfusion of G-CSF-stimulated unprocessed whole blood can be performed in almost every institution, and at considerably lower costs.

In conclusion, this study showed that a doubling of the MTA of 186Relabeled cMAb U36 could be achieved using reinfusion of G-CSF-stimulated unprocessed whole blood. Our results indicated that bone marrow doses up to 2.8 Gy could be reached without development of dose-limiting myelotoxicity or nonhematological toxicity. In five of nine patients with recurrent disease for whom no curative options were available, stabilization of disease was observed.


   FOOTNOTES
 
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). Back

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{at}vumc.nl Back

3 The abbreviations used are: MAb, monoclonal antibody; G-CSF, granulocyte 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. Back

Received 12/ 4/01; revised 8/ 5/02; accepted 8/ 6/02.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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P. K.E. Borjesson, Y. W.S. Jauw, R. Boellaard, R. de Bree, E. F.I. Comans, J. C. Roos, J. A. Castelijns, M. J.W.D. Vosjan, J. A. Kummer, C. R. Leemans, et al.
Performance of immuno-positron emission tomography with zirconium-89-labeled chimeric monoclonal antibody u36 in the detection of lymph node metastases in head and neck cancer patients.
Clin. Cancer Res., April 1, 2006; 12(7): 2133 - 2140.
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P. K. E. Borjesson, E. J. Postema, J. C. Roos, D. R. Colnot, H. A. M. Marres, M. H. van Schie, G. Stehle, R. de Bree, G. B. Snow, W. J. G. Oyen, et al.
Phase I Therapy Study with 186Re-labeled Humanized Monoclonal Antibody BIWA 4 (Bivatuzumab) in Patients with Head and Neck Squamous Cell Carcinoma
Clin. Cancer Res., September 1, 2003; 9(10): 3961S - 3972.
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