Mincheff M, Tchakarov S, Zoubak S, Loukinov D, Botev C, Altankova I, Georgiev G, Petrov S, Meryman H T
American Foundation for Biological Research, Rockville, MD 20852, USA.
Eur Urol. 2000 Aug;38(2):208-17. doi: 10.1159/000020281.
Animal studies have indicated that the use of syngeneic dendritic cells that have been transfected ex vivo with DNA for tumor-specific antigen results in tumor regression and decreased number of metastases. Additional studies have also suggested the possibility to modulate the dendritic cells in vivo either by 'naked' DNA immunization or by injecting replication-deficient viral vectors that carry the tumor-specific DNA. Using the prostate- specific membrane antigen (PSMA) as a target molecule, we have initiated a clinical trial for immunotherapy of prostate cancer. The primary objective of the study was to determine the safety of the PSMA vaccine after repeated intradermal injections.
We have included the extracellular human PSMA DNA as well as the human CD86 DNA into separate expression vectors (PSMA and CD86 plasmids), and into a combined PSMA/CD86 plasmid. In addition, the expression cassette from the PSMA plasmid was inserted into a replication deficient adenoviral expression vector. Twenty-six patients with prostate cancer were entered into a phase I/II toxicity-dose escalation study, which was initiated in spring 1998. Immunizations were performed intradermally at weekly intervals. Doses of DNA between 100 and 800 microg and of recombinant virus at 5x10(8) PFUs per application were used.
No immediate or long-term side effects following immunizations have been recorded. All patients who received initial inoculation with the viral vector followed by PSMA plasmid boosts showed signs of immunization as evidenced by the development of a delayed-type hypersensitivity reaction after the PSMA plasmid injection. In contrast, of the patients who received a PSMA plasmid and CD86 plasmid, only 50% showed signs of successful immunization. Of the patients who received PSMA plasmid and soluble GM-CSF, 67% were immunized. However, all patients who received the PSMA/CD86 plasmid and sGM-CSF became immunized. The patients who did not immunize during the first round were later successfully immunized after a boost with the viral vector. The heterogeneity of the medical status and the presence in many patients of concomitant hormone therapy does not permit unequivocal interpretation of the data with respect to the effectiveness of the therapy. However, several responders, as evidenced by a change in the local disease, distant metastases, and PSA levels, can be identified. A phase II clinical study to evaluate the effectiveness of the therapy is currently underway.
动物研究表明，使用经体外转染肿瘤特异性抗原DNA的同基因树突状细胞可导致肿瘤消退并减少转移灶数量。其他研究还提示了通过“裸”DNA免疫或注射携带肿瘤特异性DNA的复制缺陷型病毒载体在体内调节树突状细胞的可能性。以前列腺特异性膜抗原（PSMA）作为靶分子，我们开展了一项前列腺癌免疫治疗的临床试验。该研究的主要目的是确定重复皮内注射PSMA疫苗后的安全性。
我们将细胞外人类PSMA DNA以及人类CD86 DNA分别导入表达载体（PSMA和CD86质粒），并导入组合的PSMA/CD86质粒。此外，将PSMA质粒的表达盒插入复制缺陷型腺病毒表达载体。26例前列腺癌患者进入了一项I/II期毒性剂量递增研究，该研究于1998年春季启动。免疫接种每周皮内进行一次。每次使用的DNA剂量为100至800微克，重组病毒剂量为5×10⁸个空斑形成单位。
未记录到免疫接种后的即时或长期副作用。所有先接受病毒载体初始接种随后用PSMA质粒加强免疫的患者均表现出免疫迹象，PSMA质粒注射后出现迟发型超敏反应即证明了这一点。相比之下，接受PSMA质粒和CD86质粒的患者中，只有50%表现出成功免疫的迹象。接受PSMA质粒和可溶性GM-CSF的患者中，67%产生了免疫反应。然而，所有接受PSMA/CD86质粒和sGM-CSF的患者均产生了免疫反应。第一轮未产生免疫反应的患者在接受病毒载体加强免疫后后来成功产生了免疫反应。患者医疗状况的异质性以及许多患者同时接受激素治疗的情况使得关于治疗有效性的数据无法得到明确解读。然而，可以识别出一些有反应者，局部疾病、远处转移和前列腺特异抗原（PSA）水平的变化证明了这一点。目前正在进行一项II期临床研究以评估该治疗的有效性。
