Intratumoral immunotoxin treatment of human malignant brain tumors in immunodeficient animals.
Treatment of malignant brain tumors remains a clinical challenge. New treatment modalities are under investigation and among these are intratumoral infusion of immunotoxins that bind to specific cell surface molecules on the malignant cells. We have compared the efficacy of the 425.3-PE immunotoxin (which targets the epidermal growth factor [EGF] receptor) with the well-known immunotoxin Tfn-CRM107 (which targets the transferrin receptor), for the treatment of subcutaneous and intracranial human gliomas in nude animals. Bolus intratumoral administration of 1 microg Tfn-CRM107 or 425.3-PE into sc U87Mg tumors in nude mice reduced the tumor volume to 29 and 79%, respectively, of that in the control group 18 days after start of treatment. Higher doses of Tfn-CRM107 were toxic to the animals, whereas 425.3-PE was tolerated, with a dose-response relationship of up to 8 microg, a dose that reduced the tumor volume to 2% of control. In nude rats, treatment of intracerebral U87Mg tumors with Tfn-CRM107 proved ineffective and doses above 10 ng/animal were toxic to tumor-bearing rats. In contrast, intratumoral administration of 4 microg 425.3-PE increased symptom-free survival from 23 days to 40 days, with 2/9 surviving more than 90 days. We have recently shown that immunodeficient rats inoculated intracerebrally with precultured glioblastoma biopsy specimens develop highly infiltrative brain tumors. Direct interstitial infusion of immunotoxins into such tumors reduced the number of animals with detectable tumors at autopsy after 3 months, from 8/9 in the control animals to 4/6 and 2/6 in animals treated with Tfn-CRM107 and 425.3-PE, respectively. In conclusion, the anti-EGF receptor immunotoxin 425.3-PE exhibited promising efficacy, comparable to or better than that of Tfn-CRM107, an immunotoxin that in early clinical trials has been found to give responses in patients with brain tumors.
Engebraaten
Olav
O
Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway. olav.engebraten@labmed.uio.no
Hjortland
Geir Olav
GO
Juell
Siri
S
Hirschberg
Henry
H
Fodstad
Oystein
O
D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001427:Bacterial Toxins / Q000627:therapeutic use*; D001706:Biopsy; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D066246:ErbB Receptors / Q000276:immunology; D005098:Exotoxins / Q000276:immunology*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018796:Immunoconjugates; D000922:Immunotoxins / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis; D051381:Rats; D011923:Rats, Nude; D015996:Survival Rate; D014168:Transferrin / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D066246:ErbB Receptors; D005098:Exotoxins; D018796:Immunoconjugates; D000922:Immunotoxins; D009363:Neoplasm Proteins; D014168:Transferrin; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C404391:Tf-CRM107