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Monoclonal Antibody Therapy with Edrecolomab in Breast Cancer Patients: Monitoring of Elimination of Disseminated Cytokeratin- Positive Tumor Cells in Bone Marrow1

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Monoclonal Antibody Therapy with Edrecolomab in Breast Cancer Patients: Monitoring of Elimination of Disseminated Cytokeratin- Positive Tumor Cells in Bone Marrow1 Vol. 5, 3999–4004, December 1999 Clinical Cancer Research 3999 Monoclonal Antibody Therapy with Edrecolomab in Breast Cancer Patients: Monitoring of Elimination of Disseminated Cytokeratin- positive Tumor Cells in Bone Marrow1 Stephan Braun,2 Florian Hepp, mor cells in bone marrow and typed EpCAM expression. Christina R. M. Kentenich, Wolfgang Janni, This allowed us to monitor the cytotoxic elimination of such cells after Edrecolomab application. Selection of EpCAM2/ Klaus Pantel, Gert Riethmu¨ller, Fritz Willgeroth, 1 CK tumor clones showed that further antibodies directed and Harald L. Sommer against tumor-associated antigens are warranted to improve I. Frauenklinik, Klinikum Innenstadt [S. B., F. H., C. R. M. K., W. J., the efficacy of monospecific approaches. F. W., H. L. S.], and Institute of Immunology [G. R.], Ludwig- Maximilians-Universita¨t, D-80337 Munich, and Frauenklinik, Universita¨tsklinikum Eppendorf, D-20251 Hamburg [K. P.], Germany INTRODUCTION A reliable indication of the efficacy of adjuvant therapy requires trials with large numbers of patients observed for ABSTRACT several years (1), especially in breast cancer, because residual Despite current advances in antibody-based immuno- tumor cells may exert their influence on survival at 10 years or therapy of breast and colorectal cancer, we have recently later (2). Because adjuvant treatment usually is delivered to shown that the actual target cells (e.g., tumor cells dissem- patients with clinically occult micrometastatic disease after the inated to bone marrow) may express a heterogeneous pat- successful resection of the primary tumor, the efficacy of ther- tern of the potential target antigens. Tumor antigen heter- apy can be only assessed retrospectively from the rate of disease- ogeneity may therefore represent an important limitation of free survival. Consequently, progress in this form of therapy is the efficacy of monospecific antibody therapy. To measure extremely slow and cumbersome, and therapy is difficult to the efficacy of such a monospecific approach, we analyzed tailor to the special needs of an individual patient. The impor- the elimination of tumor cells coexpressing the epithelial cell tance of a surrogate marker assay that would permit the imme- adhesion molecule (EpCAM) under therapy with murine diate assessment of therapy-induced cytotoxic effects on resid- monoclonal antibody 17-1A (Edrecolomab) directed against ual cancer cells is therefore obvious. EpCAM. In bone marrow aspirates from 10 breast cancer The immunocytochemical detection of hematogenously patients with metastatic (n 5 8) and locoregional recurrence disseminated tumor cells may represent such a surrogate marker (n 5 2), tumor cells were identified with the antibody A45- assay because numerous studies have demonstrated the prog- B/B3 directed against the epithelial differentiation marker nostic impact of such early tumor cell dissemination in breast cytokeratin (CK) and simultaneously typed for EpCAM cancer patients [e.g., reviewed in Ref. (3)]. In recent studies, we expression using the antibody 17-1A. Patients were treated and others have demonstrated the validity of the immunoassay with a single dose of 500 mg of Edrecolomab and monitored with antibodies directed against CK3 as specific marker antigen by bone marrow analyses before and at days 5–7 after of extrinsic epithelial cells in the background of mesenchymal antibody treatment. In all 10 patients, we assessed a marked bone marrow cells (4–8). In this study, we have therefore 1 reduction in the mean numbers of both CK cells (73 versus applied the monoclonal antibody A45-B/B3 directed against the 1 1 15; P 5 0.003, t test) and EpCAM /CK cells (17 versus 1; heterodimers CK8/18 and CK8/19 as well as a common epitope 6 P 5 0.003, t test) per 10 bone marrow cells. Complete of several CK polypeptides (4, 9). 1 elimination of EpCAM cells was possible in four patients. Cytotoxic chemotherapy regimens currently applied for We conclude that Edrecolomab can be used in breast cancer advanced breast cancer might fail to eliminate dormant, non- 1 1 patients to target isolated EpCAM /CK cancer cells. Using proliferating tumor cells (10), which may explain metastatic CK-based immunoassays, we reliably detected residual tu- relapse after chemotherapy, and even after high-dose chemo- therapy (11, 12). In this view, cytotoxic antibodies represent a promising therapeutic option for the specific treatment of min- imal residual disease (13). Nevertheless, epithelial cancer cells Received 3/9/99; revised 7/12/99; accepted 9/2/99. are known for their genetic instability, which generates a high The costs of publication of this article were defrayed in part by the degree of heterogeneity of the different tumor cell clones found payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to in an individual tumor. Using double-labeling techniques, we indicate this fact. previously have shown that this tumor antigen heterogeneity can 1 This work was supported by grants from the Foundation “Freunde der Maistrasse,” Munich, the Curt-Bohnewand-Foundation, Munich, and the Friedrich-Baur-Foundation, Munich. 2 To whom requests for reprints should be addressed, at Ludwig- Maximilians-Universita¨t Mu¨nchen, Maistrasse 11, D-80337 Munich, 3 The abbreviations used are: CK, cytokeratin; EpCAM, epithelial cell Germany. Phone: 49-89-5160 4239; Fax: 49-89-5160 4339; E-mail: adhesion molecule; APAAP, alkaline phosphatase-antialkaline phospha- [email protected]. tase. Downloaded from clincancerres.aacrjournals.org on October 6, 2021. © 1999 American Association for Cancer Research. 4000 Monitoring of Edrecolomab Cytotoxicity in Breast Cancer Table 1 Patients’ characteristics and outcome under therapy with a single dose of 500 mg of Edrecolomab Prior to treatment After treatment Patient no. Site of recurrence CK1 EpCAM1 CK1 EpCAM1 Related toxicity 1 Bone, lung 97a 10/21 (47.6)b 2a 0/5 (0.0)b Diarrhea (grade I) 2 Bone, liver, lung 227 110/127 (86.6) 26 2/10 (10.0) Urticaria and mild bronchospasms (grade III); diarrhea (grade I) 3 Bone 67 37/37 (100) 11 1/6 (16.7) Diarrhea (grade I); emesis (grade II) 4 Lung 17 6/10 (60.0) 5 0/6 (0.0) Diarrhea (grade I) 5 Lung 115 65/120 (54.6) 20 2/19 (10.5) Diarrhea (grade I) 6 Locoregional 10 6/10 (60.0) 2 0/2 (0.0) None 7 Locoregional 5 4/5 (80.0) 0 0/0 (0.0) Diarrhea (grade I) 8 Bone 35 13/20 (65.0) 6 1/10 (10.0) Diarrhea (grade I) 9 Bone, liver 150 78/139 (56.1) 37 5/27 (18.5) None 10 Lung 10 6/9 (66.7) 3 1/5 (20.0) None a Single APAAP immunostaining: values given as number of CK1 cells per 2 3 106 mononuclear cells. b Immunogold-alkaline phosphatase double-labeling: values are given as number of EpCAM1/CK1 (double-positive) cells per total number of CK1 cells (%). be also detected on single tumor cells that are present in bone infusions were performed at the I. Frauenklinik, Klinikum In- marrow aspirates from cancer patients (10, 14). Because these nenstadt, Ludwig-Maximilians-Universita¨t (Munich, Germany). cells represent the actual targets of adjuvant therapy with cyto- Patients’ clinical characteristics are shown in Table 1. toxic antibodies, a heterogeneous antigen-profile of the dissem- Edrecolomab (500 mg; Glaxo-Wellcome) was given as a inated tumor cell clone might be a limitation of the efficacy of single dose intravenously. The antibody infusion was prepared such approaches. in sterile glass bottles containing 250 ml of 0.9% NaCl and In the present study, we investigated the effect of a mono- infused over a time period of 2 h with continuous monitoring of specific therapy on the elimination of tumor cells in bone vital signs. During the study period, patients received no further marrow aspirates from advanced breast cancer patients. For antitumoral therapy. Written informed consent was obtained antibody treatment, we chose the murine monoclonal antibody from all patients. The study has been approved by the local 17-1A (Edrecolomab) directed against EpCAM, which is widely board of the Ethics Committee. expressed on tumor cells of various origins, including breast Tissue Preparation. The volumes of all bone marrow cancer (14–16). In a previous study, Edrecolomab was shown to aspirates yielded a mean of 1.75 3 107 mononuclear cells. After prevent metastatic relapse in Dukes’ C colon cancer patients centrifugation through a Ficoll-Hypaque density gradient (den- (17, 18). To estimate the efficacy of this approach, we moni- sity, 1.077 g/mol; Pharmacia) at 900 3 g for 30 min, interface tored the elimination of single target cells by analysis of fol- cells were washed, and 106 cells were centrifuged onto each low-up bone marrow aspirates. Our data suggest that tumor cells glass slide at 150 3 g for 5 min (19). After overnight air-drying, in bone marrow can be detected reliably and typed for antigen slides were either stained immediately or stored at 280°C. expression, which allowed monitoring of the cytotoxic elimina- Immunocytochemical Bone Marrow Screening. To tion of such cells after Edrecolomab application. Because of the screen for the presence of breast cancer micrometastases, the consistency of the findings, we advocate the implementation of antibody A45-B/B3 (Micromet) directed to a common epitope immunocytochemical monitoring into the design of future im- of CK polypeptides, including the heterodimers CK8/18 and munotherapy trials for immediate efficacy estimation and rec- CK8/19, was used at 1.0–2.0 mg/ml (5, 19). The specific anti- ognition of the selection of therapy-resistant tumor cell clones. body reaction was developed with the sensitive APAAP tech- nique combined with the new fuchsin method to indicate anti- PATIENTS AND METHODS body binding (20), as described previously (5, 19).
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