Karanikas V, Thynne G, Mitchell P, Ong C S, Gunawardana D, Blum R, Pearson J, Lodding J, Pietersz G, Broadbent R, Tait B, McKenzie I F
Immunology and Vaccine Laboratory, The Austin Research Institute, Victoria, Australia.
J Immunother. 2001 Mar-Apr;24(2):172-83.
The mucin MUC1 is greatly increased in breast cancer and is a potential target for immunotherapy. In mice, MUCI conjugated to oxidized mannan (MUC1-mannan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this basis, three phase I trials were performed in patients with adenocarcinoma to evaluate the toxicity and the immunologic responses to mannan MUCI. Forty-one patients with metastatic or locally advanced carcinoma of the breast (trial 1), colon (trial 2), and various adenocarcinomas (trial 3) received increasing doses of M-FP (1 to 300 microg). The immunizations were given at weekly intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide (to increase cellular immunity) was given on weeks 1 and 4. M-FP was given intramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effects occurred, and delayed-type hypersensitivity responses were present only as a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with the intraperitoneal route yielding approximately 10-fold higher responses. Cellular responses (proliferation, cytotoxic T cells, or CD8 T cells secreting tumor necrosis factor-alpha alphand interferon-gamma in response to MUC1 stimulation in vitro) were found in 28% of the patients, which was similar to that seen without cyclophosphamide. In most patients, disease progressed, but in five it remained stable. In addition, there were no objective responses. M-FP is not toxic and induces immune responses that were amplified by the intraperitoneal route of immunization. Cyclophosphamide was of no benefit.
黏蛋白MUC1在乳腺癌中大量增加，是免疫治疗的潜在靶点。在小鼠中，与氧化甘露聚糖偶联的MUC1（MUC1-甘露聚糖融合蛋白[M-FP]）靶向甘露糖受体，可诱导高频率的细胞毒性T淋巴细胞和抗肿瘤反应。在此基础上，对腺癌患者进行了三项I期试验，以评估对甘露聚糖MUC1的毒性和免疫反应。41例转移性或局部晚期乳腺癌（试验1）、结肠癌（试验2）及各种腺癌（试验3）患者接受递增剂量的M-FP（1至300微克）。免疫接种每周进行一次（第1至3周），并在第7至9周重复。在第1周和第4周给予环磷酰胺（以增强细胞免疫）。试验1中M-FP通过肌肉注射给药，试验2中通过腹腔注射给药。未出现毒性作用，仅在显微镜下观察到迟发型超敏反应为淋巴细胞浸润。总体而言，约60%的患者产生了高滴度的MUC1免疫球蛋白G1抗体反应，腹腔注射途径产生的反应约高10倍。在28%的患者中发现了细胞反应（增殖、细胞毒性T细胞或体外对MUC1刺激分泌肿瘤坏死因子-α和干扰素-γ的CD8 T细胞），这与未使用环磷酰胺时的情况相似。大多数患者疾病进展，但有5例病情保持稳定。此外，未观察到客观缓解。M-FP无毒，可诱导免疫反应，腹腔免疫途径可增强这种反应。环磷酰胺无益处。
