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
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
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DOI：
10.1007/bf01052668
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发表时间：
1995-01-01
影响因子：
3.9
通讯作者：
ZALUTSKY, MR
中科院分区：
文献类型：
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作者：
BIGNER, DD;BROWN, M;ZALUTSKY, MR
单克隆抗体（MAb）技术的出现使埃利希的“魔术子弹”假设成为一个可以实现的目标。尽管在20世纪60年代证明了多价抗体对人神经胶质瘤的特异性定位，但缺乏特异性、高亲和力的抗体群体和足够密度的确定的靶抗原排除了治疗应用。直到鉴定出可操作的特异性肿瘤相关抗原（存在于肿瘤组织中，但不存在于正常中枢神经系统组织中）;产生针对此类抗原的同质、高亲和力单克隆抗体;以及使用隔室给药（鞘内或囊内），才认识到原发性和转移性中枢神经系统肿瘤的被动免疫治疗的前景。我们在此报告了抗腱生蛋白单克隆抗体81 C6和单克隆抗体Me 1 -14的F（ab 2）（2）片段（识别神经胶质瘤和黑色素瘤的蛋白多糖硫酸软骨素相关蛋白）隔室给药的I期研究的初步数据，对原发性中枢神经系统肿瘤或转移到中枢神经系统的肿瘤患者进行I-131-标记的抗腱生蛋白MAb 81 C6对复发性神经胶质瘤的自发囊肿或手术产生的囊性切除空腔产生了显著的反应。在5例接受治疗的复发性囊性胶质瘤患者中，4例临床或影像学部分缓解。类似地，在手术产生切除腔的患者中，在囊内给予I-131标记的81 C6后，在治疗部位获得了部分缓解，并获得了长期稳定的疾病状态。在两个患者人群中均未观察到血液学或神经系统毒性的证据，但1例患者的既存癫痫发作疾病一过性加重除外。剂量学计算表明，高的囊内滞留4至6周，很少或没有全身传播，估计总剂量范围从12700 - 70290拉德。鞘内给药标记单克隆抗体肿瘤性脑膜炎患者的临床反应更难以评估。在用I-131标记的81 C6或I-131标记的Me 1 -14 F（ab）（2）治疗的患者中，已经实现了脑脊液和放射学反应，I期剂量递增试验的初步结果在疾病稳定和部分及完全缓解的病例比例方面令人鼓舞得到了重要的是，神经毒性几乎不存在，血液学毒性罕见，对治疗反应迅速。因此，在室间环境中，嵌合单克隆抗体分子或二聚体或单体单片段链（放射性标记或药物或毒素缀合）的前景是巨大的。单克隆抗体介导的靶向治疗中枢神经系统肿瘤的可能性是很多的，有前途的。未来的工作将与新定义的抗原的精致的肿瘤特异性，如变异的表皮生长因子受体III分子。新的标记技术将允许卤素如I-131和At-211用于内化或膜定位抗原。内化的MAb将能够用作免疫毒素或用化疗剂标记。
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 Me1-14, 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 administered I-131-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 of I-131 labeled 81C6. No evidence of hematologic 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 either I-131-labeled 81C6 or I-131-labeled Me1-14 F(ab)(2), cerebrospinal fluid and radiographic 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 hematologic 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 as I-131 and At-211 to be used for internalized or membrane-localized antigens. Internalized MAbs will be able to be used as immunotoxins or labeled with chemotherapeutic agents.