Initial experience with locoregional radioimmunotherapy using 131I-labelled monoclonal antibodies against tenascin (BC-4) for treatment of glioma (WHO III and IV)

G. Pöpperl; C. Götz; F.-J. Gildehaus; T. A. Yousry; H. J. Reulen; K. Hahn; K. Tatsch

doi:10.1055/s-0038-1623887

Nuklearmedizin - NuclearMedicine, Table of Contents

Nuklearmedizin 2002; 41(03): 120-128
DOI: 10.1055/s-0038-1623887

Original Article

Schattauer GmbH

Initial experience with locoregional radioimmunotherapy using ¹³¹I-labelled monoclonal antibodies against tenascin (BC-4) for treatment of glioma (WHO III and IV)

Initiale Erfahrungen mit der adjuvanten lokoregionalen Radioimmuntherapie mit ¹³¹I-markierten monoklonalen Tenascin-Antikörpern (BC-4) bei Patienten mit Gliom (WHO III und IV)

Authors

G. Pöpperl

¹Klinik und Poliklinik für Nuklearmedizin
C. Götz

²Klinik und Poliklinik für Neurochirurgie
F.-J. Gildehaus

¹Klinik und Poliklinik für Nuklearmedizin
T. A. Yousry

³Institut für Neuroradiologie der LMU München, Klinikum Großhadern, München, Deutschland
H. J. Reulen

²Klinik und Poliklinik für Neurochirurgie
K. Hahn

¹Klinik und Poliklinik für Nuklearmedizin
K. Tatsch

¹Klinik und Poliklinik für Nuklearmedizin

Abstract

Summary

Aim: None of the established treatments (surgery, radiotherapy, chemotherapy) for malignant glioma has improved its very poor prognosis. Adjuvant locoregional radioimmunotherapy (RIT) represents a new therapeutic approach. We present our initial experience with this therapeutic tool with respect to adverse effects, biokinetics and clinical follow-up. Methods: Following surgery and radiotherapy, 12 patients with glioma (4, WHO stage III; 8, WHO stage IV) underwent 1-5 RIT-cycles (average dose 1100 MBq ¹³¹labelled monoclonal BC-4 antibodies) at six week intervals. Follow-up included serial FDG-PET and MRI investigations. Evaluation of biokinetics included whole body scans, together with analysis of blood, urine and fluid from the tumor cavity. Results: Following RIT, four patients experienced temporary seizures, which, in one case, were associated with temporary aphasia. Eight patients developed HAMA (human anti-mouse antibodies) during follow-up. Mean biologic half-life of the radiopharmaceutical in the resection cavity was 3.9 d (range: 1.0-10.2 d) and remained stable intraindividually during further RIT-cycles. The antibody/radionuclide conjugate remained stable in the tumor cavity for at least 5 d. Median survival presently stands at 18.5 months compared to 9.7 months in a historical patient group (n = 89) undergoing conventional therapeutic strategies. Five patients show no signs of recurrence. In three patients with post-surgical evidence of residual tumor, one patient showed partial remission, one stable disease, and one progressive disease during RIT. Four patients without evidence of residual tumor mass at the beginning of RIT developed recurrence during therapy. Conclusions: Initial experience demonstrates that locoregional RIT is a well tolerated treatment modality that may represent a promising new approach in the management of patients with malignant glioma. Advantages of local application include passage of the blood-brain barrier, high concentration of activity within the resection cavity and low systemic toxicity.

Zusammenfassung

Ziel: Bei der Standardtherapie von Gliomen (Resektion, Radiatio, Chemotherapie) ist die Prognose sehr schlecht. Ein neuer Therapieansatz besteht in der additiven lokalen Radioimmuntherapie (RIT) mit ¹³¹I-markierten Tenascin- Antikörpern (BC-4). Diese Studie berichtet über unsere initialen Erfahrungen hinsichtlich Nebenwirkungen, Biokinetik und klinischem Verlauf. Methoden: Zwölf Patienten (4 Gliome WHO III, 8 Gliome WHO IV) erhielten nach Operation und perkutaner Radiatio 1-5 RIT-Zyklen im Abstand von 6 Wochen mit durchschnittlich 1100 MBq ¹³¹I-markierten Antikörpern über ein Ommaya-Reservoir. Der Verlauf wurde durch FDG-PET- und MRT-Untersuchungen dokumentiert. Die Biokinetik wurde an Ganzkörperaufnahmen, Blut- und Urinproben sowie Proben aus der Tumorhöhle nach RIT beurteilt. Ergebnisse: Unter RIT traten bei vier Patienten passagere Anfälle, bei einem in Kombination mit transienter Sprachstörung auf. Acht Patienten bildeten im Verlauf HAMAs (humane Antikörper gegen Mausantigen) aus. Die biologische HWZ der Aktivität in der Tumorhöhle lag im Mittel bei 3,9 d (1,0-10,2 d) und blieb intraindividuell bei Folgetherapien konstant. Das Radioimmunkonjugat in der Tumorhöhle blieb mindestens 5 d stabil. Die mittlere Überlebenszeit liegt zurzeit bei 18,5 Monaten und ist damit deutlich höher als bei einer historischen Patientengruppe mit Standardtherapie (9,7 Monate; n = 89). Fünf Patienten zeigen bisher keinen Hinweis auf ein Rezidiv. Bei drei Patienten mit einem Tumorrest nach Operation zeigte sich unter RIT in einem Fall partielle Remission, ein stabiler und ein progredienter Krankheitsverlauf. Vier Patienten ohne Tumorrest zu Therapiebeginn entwickelten unter Therapie ein Rezidiv. Schlussfolgerungen: Erste Erfahrungen mit der lokalen RIT zeigen, dass diese komplikationsarme Therapieform additiv zur Standardtherapie ein Erfolg versprechender Ansatz bei malignem Gliom ist. Vorteile liegen in der Umgehung der Bluthirnschranke, der hohen lokalen Aktivitätskonzentration und der niedrigen systemischen Toxizität.

Keywords

Glioblastoma - astrocytoma - radioimmunotherapy - BC-4 antibodies

Schlüsselwörter

Glioblastom - Astrozytom - Radioimmuntherapie - Tenascin-Antikörper - BC-4-Antikörper

Full Text

References

Literatur
1 Akabani G, Reist CJ, Cokgor I. et al. Dosimetry of ¹³¹I-labeled 81C6 monoclonal antibody administered into surgically created resection cavities in patients with malignant brain tumors. J Nucl Med 1999; 40: 631-8.
2 Akabani G, Cokgor I, Coleman RE. et al. Dosimetry and dose-response relationships in newly diagnosed patients with malignant gliomas treated with iodine- 131-labeled anti-tenascin monoclonal antibody 81C6 therapy. Int J Radiat Oncol Biol Phys 2000; 46: 947-58.
3 Arista A, Sturiale C, Riva P. et al. Intralesional administration of I-131 labelled monoclonal antibodies in the treatment of malignant gliomas. Acta Neurochir (Wien) 1995; 135: 159-62.
4 Bansal K, Engelhard HH. Gene therapy for brain tumors. Curr Oncol Rep 2000; 2: 463-72.
5 Behr TM, Wormann B, Gramatzki M. et al. Lowversus high-dose radioimmunotherapy with humanized anti-CD22 or chimeric anti-CD20 antibodies in a broad spectrum of B cell-associated. Clin Cancer Res 1999; 5: 3304s-14s.
6 Bigner DD, Brown MT, Friedman AH. et al. Iodine- 131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results. J Clin Oncol 1998; 16: 2202-12.
7 Black PM. Brain tumors. Part 1. N Engl J Med 1991; 324: 1471-6.
8 Black PM. Brain tumors. Part 2. N Engl J Med 1991; 324: 1555-64.
9 Black PM. Management of malignant glioma: role of surgery in relation to multimodality therapy. J Neurovirol 1998; 4: 227-36.
10 Black PM. Surgery for cerebral gliomas: past, present, and future. Clin Neurosurg 2000; 47: 21-45.
11 Brem H, Lawson HC. The development of new brain tumor therapy utilizing the local and sustained delivery of chemotherapeutic agents from biodegradable polymers. Cancer 1999; 86: 197-9.
12 Burnet NG, Taylor RE. Malignant cerebral glioma. Modern radiotherapy techniques are needed to spare normal brain tissue. BMJ 1997; 14: 900-1.
13 Cokgor I, Akabani G, Kuan CT. et al. Phase I trial results of iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas. J Clin Oncol 2000; 18: 3862-72.
14 Davico Bonino L, De Monte LB, Spagnoli GC. et al. Bispecific monoclonal antibody anti-CD3 x anti-tenascin: an immunotherapeutic agent for human glioma. Int J Cancer 1995; 61: 509-15.
15 Deavaux BC, O’Fallon J, Kelly PJ. Resection, biopsy and survival in malignant glial neoplasms. J Neurosurg 1993; 78: 767-75.
16 Evan G. Cancer – a matter of life and cell death. Int J Cancer 1997; 71: 709-11.
17 Galanis E, Buckner JC. Chemotherapy of brain tumors. Curr Opin Neurol 2000; 13: 619-25.
18 Gregor A, Cull A. Radiotherapy for malignant glioma. BMJ 1996; 313: 1500-1.
19 Hopkins K, Chandler C, Bullimore J. et al. A pilot study of the treatment of patients with recurrent malignant gliomas with intratumoral yttrium-90 radioimmunoconjugates. Radiother Oncol 1995; 34: 121-31.
20 Hopkins K, Chandler C, Eatough J. et al. Direct injection of ⁹⁰Y-MoAbs into glioma tumor resection cavities leads to limited diffusion of the radioimmunoconjugates into normal brain parenchyma: a model to estimate absorbed radiation dose. Int J Radiat Oncol Biol Phys 1998; 40: 835-44.
21 Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Stat Assoc 1958; 53: 457-81.
22 Kim CH, Bak KH, Kim YS. et al. Expression of tenascin- C in astrocytic tumors: its relevance to proliferation and angiogenesis. Surg Neurol 2000; 54: 235-40.
23 Larson DA, Wara WM. Radiotherapy of primary malignant brain tumors. Semin Surg Oncol 1998; 14: 34-42.
24 Natali PG, Nicotra MR, Bigotti A. et al. Comparative analysis of the expression of the extracellular matrix protein tenascin in normal human fetal, adult and tumor tissues. Int J Cancer 1991; 47: 811-6.
25 Riva P, Arista A, Sturiale C. et al. Treatment of intracranial human glioblastoma by direct intratumoral administration of ¹³¹I-labelled anti-tenascin monoclonal antibody BC-2. Int J Cancer 1992; 51: 7-13.
26 Riva P, Tison V, Arista A. et al. Radioimmunotherapy of gastrointestinal cancer and glioblastomas. Int J Biol Markers 1993; 8: 192-7.
27 Riva P, Arista A, Sturiale C. et al. Glioblastoma therapy by direct intralesional administration of I-131 radioiodine labeled antitenascin antibodies. Cell Biophys 1994; 24-25: 37-43.
28 Riva P, Arista A, Tison V. et al. Intralesional radioimmunotherapy of malignant gliomas. An effective treatment in recurrent tumors. Cancer 1994; 73: 1076s-82s.
29 Riva P, Arista A, Franceschi G. et al. Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with ¹³¹I: comparison of the results obtained in recurrent and newly diagnosed tumors. Cancer Res 1995; 55: 5952s-6s.
30 Riva P, Franceschi G, Arista A. et al. Local application of radiolabeled monoclonal antibodies in the treatment of high grade malignant gliomas: a six-year clinical experience. Cancer 1997; 80: 2733s-42s.
31 Riva P, Franceschi G, Frattarelli M. et al. ¹³¹I radioconjugated antibodies for the locoregional radioimmunotherapy of high-grade malignant gliomaphase I and II study. Acta Oncol 1999; 38: 351-9.
32 Riva P, Franceschi G, Frattarelli M. et al. Locoregional radioimmunotherapy of high-grade malignant gliomas using specific monoclonal antibodies labeled with 90Y: a phase I study. Clin Cancer Res 1999; 5: 3275s-80s.
33 Riva P, Franceschi G, Riva N. et al. Role of nuclear medicine in the treatment of malignant gliomas: the locoregional radioimmunotherapy approach. Eur J Nucl Med 2000; 27: 601-9.
34 Sasaki M, Plate KH. Gene therapy of malignant glioma: recent advances in experimental and clinical studies. Ann Onco 1998; 9: 1155-66.
35 Siri A, Carnemolla B, Saginati M. et al. Human tenascin: primary structure, pre-mRNA splicing patterns and localization of the epitopes recognized by two monoclonal antibodies. Nucleic Acid Research 1991; 19: 525-31.
36 Stummer W, Novotny A, Stepp H. et al. Fluorescenceguided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 2000; 93: 1003-13.
37 Wagner W, Schuller P, Willich N. et al. Intraoperative radiotherapy (IORT) in malignant brain tumors. Strahlenther Onkol 1995; 171: 154-64.
38 Weadock KS, Sharkey RM, Varga DC. et al. Evaluation of a remote radioiodination system for radioimmunotherapy. J Nucl Med 1990; 31: 508-11.
39 Zalutsky MR, Moseley RP, Coakham HB. et al. Pharmacokinetics and tumor localization of ¹³¹I-labeled anti-tenascin monoclonal antibody 81C6 in patients with gliomas and other intracranial malignancies. Cancer Res 1989; 49: 2807-13.
40 Zalutsky MR, Bigner DD. Radioimmunotherapy with alpha-particle emitting radioimmunoconjugates. Acta Oncol 1996; 35: 373-9.
41 Zalutsky MR, Stabin MG, Larsen RH. et al. Tissue distribution and radiation dosimetry of astatine-211-labeled chimeric 81C6, an alphaparticle- emitting immunoconjugate. Nucl Med Biol 1997; 24: 255-61.
42 Zalutsky MR, Akabani G, Friedman HS. et al. Radioimmunotherapy of recurrent glioma patients using alpha-particle-emitting astatine-211 labeled chimeric anti-tenascin monoclonal antibody. J Nucl Med 2001; 42: 121P-2P.