DOSE-ESCALATION WITH REPEATED INTRATHECAL INJECTIONS OF I-131-LABELEDMABS FOR THE TREATMENT OF CENTRAL-NERVOUS-SYSTEM MALIGNANCIES

We have previously demonstrated a 33% response rate in patients with p rimitive neurectodermal tumours after the direct injection of I-131-mo noclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-li miting toxicity is myelosuppression due to the passage of the radioimm unoconjugate from the CSF to the blood compartment. This occurs at dos es of 2220 MBq of I-131-MAb and above, although this is not seen in al l patients studied and appears to be related to the degree of prior th erapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF comp artment by dose escalation and haemopoietic rescue, we have explored t he possibility of repeatedly administering the radioimmunoconjugate. E ight patients were recruited to the study, two of whom received two an d six of whom received three injections of I-131-MAb. After repeated a dministration of I-131-MAb pharmacokinetic data revealed that, with on e exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decrease d with each injection. This was due to the development of an anti-mous e Ig response in the blood. Clearance of I-131-MAb from the ventricula r CSF appears to be independent of the presence of an anti-mouse Ig re sponse in this compartment, The differential clearance of the radioimm unoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved, Up to 5 920 MBq of I-131-MAb was administered as the third injection of radioi mmunoconjugate and combined doses of up to 12 500 MBq were given witho ut either haematological or neurological toxicity. These data illustra te that dose escalation and thus an increase in the dose rate delivere d to tumour cells within the CSF is possible if ways are found to redu ce the residence time of the radioimmunoconjugate in the blood compart ment. Suggestions as to how this can best be achieved are reviewed in detail.