PHASE-I STUDIES OF TREATMENT OF MALIGNANT GLIOMAS AND NEOPLASTIC MENINGITIS WITH I-131 RADIOLABELED MONOCLONAL-ANTIBODIES ANTI-TENASCIN 81C6 AND ANTI-CHONDROITIN PROTEOGLYCAN SULFATE ME1-14 F(AB')(2) - A PRELIMINARY-REPORT

The advent of monoclonal antibody (MAb) technology has made Ehrlich's postulate of the 'magic bullet' an attainable goal. Although specific localization of polyvalent antibodies to human gliomas was demonstrate d in the 1960s, the lack of specific, high affinity antibody populatio ns and of defined target antigens of sufficient density precluded ther apeutic applications. Not until the identification of operationally sp ecific tumor-associated antigens (present in tumor tissue but not norm al central nervous system tissue); production of homogeneous, high aff inity MAbs to such antigens; and the use of compartmental administrati on (intrathecal or intracystic), has the promise of passive immunother apy of primary and metastatic central nervous system neoplasms been re cognized. We report here preliminary data from Phase I studies of the compartmental administration of the anti-tenascin MAb 81C6 and F(ab2)( 2) fragments of MAb Me1-14, which recognizes the proteoglycan chondroi tin sulfate-associated protein of gliomas and melanomas, to patients w ith primary central nervous system tumors or tumors metastatic to the central nervous system. Phase I dose escalation studies of intracystic ally administered I-131-labeled anti-tenascin MAb 81C6 to either spont aneous cysts of recurrent gliomas or surgically created cystic resecti on cavities have resulted in striking responses. Of five patients with recurrent cystic gliomas treated, four had partial responses, clinica lly or radiographically. Similarly, in patients with surgically create d resection cavities, a partial response at the treatment site and ext ended stable disease status has been obtained following intracystic ad ministration of I-131 labeled 81C6. No evidence of hematologic or neur ologic toxicity has been observed in either patient population, with t he exception of transient exacerbation of a pre-existing seizure disor der in a single patient. Dosimetry calculations indicated high intracy stic retention for four to six weeks with little or no systemic dissem ination; estimated total doses intracystically ranged from 12,700-70,2 90 rad. Intrathecal administration of labeled MAbs to patients with ne oplastic meningitis is more difficult to assess in terms of clinical r esponsiveness. Of patients so treated with either I-131-labeled 81C6 o r I-131-labeled Me1-14 F(ab)(2), cerebrospinal fluid and radiographic responses have been achieved, and survival prolongation through mainte nance of stable disease has been observed in several cases. Initial re sults from Phase I dose escalation trials are encouraging in terms of the proportion of cases of disease stabilization and partial and compl ete responses obtained. Importantly, neurotoxicity has been virtually nonexistent, and hematologic toxicity rare and rapidly responsive to t reatment. In the intracompartmental setting, then, the promise of chim erized MAb molecules or of dimeric or monomeric single-fragment chains , either radiolabeled or drug- or toxin-conjugated, is great. The poss ibilities of MAb-mediated, targeted therapy for tumors of the central nervous system are many and promising. Future work will be with newly defined antigens of exquisite tumor specificity, such as the variant e pidermal growth factor receptor III molecule. New labeling technology will allow halogens such as I-131 and At-211 to be used for internaliz ed or membrane-localized antigens. Internalized MAbs will be able to b e used as immunotoxins or labeled with chemotherapeutic agents.