Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies

Abstract

Summary We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tumours after the direct injection of 1311-monoclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-limiting toxicity is myelosuppression due to the passage of the radioimmunoconjugate from the CSF to the blood compartment. This occurs at doses of 2220 MBq of 131 I-MAb and above, although this is not seen in all patients studied and appears to be related to the degree of prior therapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF compartment by dose escalation and haemopoietic rescue, we have explored the possibility of repeatedly administering the radioimmunoconjugate. Eight patients were recruited to the study, two of whom received two and six of whom received three injections of 1311-MAb. After repeated administration of '311-MAb pharmacokinetic data revealed that, with one exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decreased with each injection. This was due to the development of an anti-mouse Ig response in the blood. Clearance of 131I-MAb from the ventricular CSF appears to be independent of the presence of an anti-mouse Ig response in this compartment. The differential clearance of the radioimmunoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved. Up to 5920 MBq of '311-MAb was administered as the third injection of radioimmunoconjugate and combined doses of up to 12 500 MBq were given without either haematological or neurological toxicity. These data illustrate that dose escalation and thus an increase in the dose rate delivered to tumour cells within the CSF is possible if ways are found to reduce the residence time of the radioimmunoconjugate in the blood compartment. Suggestions as to how this can best be achieved are reviewed in detail.

MEDULLOBLASTOMA IN CHILDREN 0–3 YEARS OLD: Forty Years' Experience in Slovenia

“…Survival of children with "high risk" medulloblastoma is still very poor. Hopefully newly developed treatment modalities and Cht combinations will show improvement [9][10][11].…”

Systemic chemotherapy, intrathecal chemotherapy, and symptom management in the treatment of leptomeningeal metastasis

“…These include methotrexate, cytosine arabinoside (Ara-C, cytarabine, or the liposomal form, DepoCyt), and thiotepa [23,27,64••,65••,71,75,77]. A number of investigational agents are being explored, including mafosfamide (a derivative of cyclophosphamide), busulfan, topotecan, diaziquinone, 4-hydroperoxy-cyclophosphamide (another derivative of cyclophosphamide), interferon, monoclonal antibodies, gene therapy, and interleukin-2 (Tables 1 and 4) [78][79][80][81][82][83][84][85][86][87][88][89][90]. However, these agents are only available in experimental protocols and are therefore inaccessible to most patients with leptomeningeal metastasis.…”

“…Monoclonal antibody therapy directed at meningeal metastasis is a relatively new approach that has the theoretical advantage of selectively targeting malignant cells that express specific antigens while sparing normal tissues that do not share these epitopes [81][82][83][84][85][86][87]. Most studies have used 131 Iodine linked to an antibody of interest (so-called radioimmunoconjugates) in the particular tumor being studied.…”

“…Most studies have used 131 Iodine linked to an antibody of interest (so-called radioimmunoconjugates) in the particular tumor being studied. Toxicity (especially systemic myelosuppression) and the need to have an appropriate antibody limit this approach at present, though it remains under exploration [81][82][83][84][85][86][87].…”

Safety of intrathecal administration of cytosine arabinoside and methotrexate in dogs and cats

“…Several agents have been used intrathecally in human medicine (cytosine arabinoside, methotrexate, thiotepa, liposomal cytosine arabinoside, steroids, monoclonal antibodies), but cytosine arabinoside and methotrexate are the most studied and currently used molecules . The most frequently reported side effect for cytosine arabinoside is arachnoiditis; considerably less frequently seizures, transient paraplegia, peripheral neuropathy, myelopathy and encephalopathy are reported.…”