Foon K A, John W J, Chakraborty M, Sherratt A, Garrison J, Flett M, Bhattacharya-Chatterjee M
Lucille Parker Markey Cancer Center, Department of Internal Medicine, Division of Hematology/Oncology, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Clin Cancer Res. 1997 Aug;3(8):1267-76.
Carcinoembryonic antigen (CEA) is expressed in a wide variety of adenocarcinomas, and it is well recognized that cancer patients are immunologically "tolerant" to CEA. The purpose of this study was to determine whether we could break immune tolerance to CEA by vaccinating patients with a monoclonal anti-idiotype antibody that is the internal image of CEA and to determine what impact this might have on patient survival. Twenty-four patients with advanced CEA-positive colorectal cancer who failed standard therapies except for two were entered into this Phase Ib trial. One patient was considered not assessable, because on the day of entering into the study, she was diagnosed with acute myelogenous leukemia. Patients were treated with 1, 2, or 4 mg of aluminum hydroxide-precipitated 3H1 anti-idiotype antibody every other week for four injections and then monthly until tumor progression was observed. Immunological monitoring included humoral and cellular idiotypic and CEA responses, and all patients were evaluated for toxicity, response, and survival. Hyperimmune sera from 17 of 23 patients demonstrated an anti-anti-idiotypic Ab3 response, and 13 of these responses were demonstrated to be true anti-CEA responses (Ab1'). The antibody response was polyclonal, and 11 mediated antibody-dependent cellular cytotoxicity. Ten patients had idiotypic T-cell responses, and five had specific T-cell responses to CEA. None of the patients had objective clinical responses, but overall median survival for the 23 evaluable patients was 11.3 months, with 44% 1-year survival (95% confidence interval, 23-64%). Toxicity was limited to local swelling and minimal pain. Anti-idiotype monoclonal antibody 3H1 that mimics CEA was able to break immune tolerance in the majority of treated patients. Overall survival of 11.3 months was comparable to other phase II data with advanced colorectal cancer patients treated with a variety of chemotherapy agents, including irinotecan, with considerably less toxicity. Although it is not clear that the vaccine itself had an impact on survival, this should be determined in a Phase III randomized trial.
癌胚抗原（CEA）在多种腺癌中均有表达，而且癌症患者对CEA具有免疫“耐受性”这一点已得到广泛认可。本研究的目的是确定通过给患者接种作为CEA内影像的单克隆抗独特型抗体能否打破对CEA的免疫耐受，并确定这可能对患者生存产生何种影响。除两名患者外，24例标准治疗失败的晚期CEA阳性结直肠癌患者进入了这项Ib期试验。有一名患者被认为不可评估，因为在进入研究当天，她被诊断出患有急性髓细胞白血病。患者每隔一周接受1、2或4毫克氢氧化铝沉淀的3H1抗独特型抗体注射，共注射四次，然后每月注射一次，直至观察到肿瘤进展。免疫监测包括体液和细胞独特型及CEA反应，所有患者均接受毒性、反应和生存情况评估。23例患者中有17例的超免疫血清表现出抗抗独特型Ab3反应，其中13例反应被证实为真正的抗CEA反应（Ab1'）。抗体反应是多克隆的，11例介导抗体依赖性细胞毒性。10例患者有独特型T细胞反应，5例对CEA有特异性T细胞反应。所有患者均未出现客观临床反应，但23例可评估患者的总体中位生存期为11.3个月，1年生存率为44%（95%置信区间，23 - 64%）。毒性仅限于局部肿胀和轻微疼痛。模拟CEA的抗独特型单克隆抗体3H1能够打破大多数接受治疗患者的免疫耐受。11.3个月的总生存期与其他II期数据相当，那些数据是关于接受包括伊立替康在内的多种化疗药物治疗的晚期结直肠癌患者的，且毒性要小得多。虽然尚不清楚疫苗本身是否对生存有影响，但这应在III期随机试验中确定。
