Phase I studies of treatment of malignant gliomas and neoplastic meningitis with131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab?)2-a preliminary report

Abstract

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 demonstrated in the 1960s, the lack of specific, high affinity antibody populations and of defined target antigens of sufficient density precluded therapeutic applications. Not until the identification of operationally specific tumor-associated antigens (present in tumor tissue but not normal central nervous system tissue); production of homogeneous, high affinity MAbs to such antigens; and the use of compartmental administration (intrathecal or intracystic), has the promise of passive immunotherapy of primary and metastatic central nervous system neoplasms been recognized. 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 Mel-14, which recognizes the proteoglycan chondroitin sulfate-associated protein of gliomas and melanomas, to patients with primary central nervous system tumors or tumors metastatic to the central nervous system. Phase I dose escalation studies of intracystically administered¹³¹I-labeled anti-tenascin MAb 81C6 to either spontaneous cysts of recurrent gliomas or surgically created cystic resection cavities have resulted in striking responses. Of five patients with recurrent cystic gliomas treated, four had partial responses, clinically or radiographically. Similarly, in patients with surgically created resection cavities, a partial response at the treatment site and extended stable disease status has been obtained following intracystic administration of¹³¹I-labeled 81C6. No evidence of hematologie or neurologic toxicity has been observed in either patient population, with the exception of transient exacerbation of a pre-existing seizure disorder in a single patient. Dosimetry calculations indicated high intracystic retention for four to six weeks with little or no systemic dissemination; estimated total doses intracystically ranged from 12,700–70,290 rad. Intrathecal administration of labeled MAbs to patients with neoplastic meningitis is more difficult to assess in terms of clinical responsiveness. Of patients so treated with either¹³¹I-labeled 81C6 or¹³¹I-labeled Mel-14 F(ab)₂, cerebrospinal fluid and radiographie responses have been achieved, and survival prolongation through maintenance of stable disease has been observed in several cases. Initial results from Phase I dose escalation trials are encouraging in terms of the proportion of cases of disease stabilization and partial and complete responses obtained. Importantly, neurotoxicity has been virtually nonexistent, and hematologie toxicity rare and rapidly responsive to treatment. In the intracompartmental setting, then, the promise of chimerized MAb molecules or of dimeric or monomeric single-fragment chains, either radiolabeled or drug- or toxin-conjugated, is great. The possibilities 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 epidermal growth factor receptor III molecule. New labeling technology will allow halogens such as¹³¹I and²¹¹At to be used for internalized or membrane-localized antigens. Internalized MAbs will be able to be used as immunotoxins or labeled with chemotherapeutic agents.