University of Wisconsin Carbone Cancer Center, Madison, 53792, USA.
Cancer Immunol Immunother. 2012 Jul;61(7):1137-47. doi: 10.1007/s00262-011-1193-1. Epub 2011 Dec 31.
CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1-28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.
CTLA-4 阻断在人类临床试验中显示出抗肿瘤疗效。抗肿瘤机制推测部分通过肿瘤特异性 T 细胞的扩增介导。雄激素剥夺是转移性前列腺癌患者治疗的基石，已被证明可引起前列腺组织凋亡和淋巴细胞炎症。我们假设雄激素剥夺后联合使用抗 CTLA-4 抗体治疗可以增强雄激素剥夺引起的肿瘤特异性免疫反应。我们在此报告一项评估靶向 CTLA-4 的人源化单克隆抗体 CP-675,206（ tremelimumab）与抗雄激素联合应用于雄激素剥夺的 I 期临床试验结果。符合条件的患者为首次手术后和/或放射治疗后 PSA 复发的前列腺癌患者，未接受过雄激素剥夺治疗，且无放射性转移疾病证据。患者接受两个周期的治疗，间隔 3 个月，在每个周期中，患者接受比卡鲁胺 150mg 每日一次（第 1-28 天），第 29 天接受 tremelimumab。试验的主要终点是安全性。次要终点包括 PSA 动力学测量和最大耐受剂量的确定。11 名患者入组并完成至少 1 年的随访。剂量限制毒性包括 3 级腹泻和皮疹。在治疗后不久的一段时间内，未观察到 PSA 倍增时间的有利变化；然而，三名患者在完成治疗后数月可检测到 PSA 倍增时间延长。PSA 血清中延迟、持久的有利变化表明，未来的研究可以在评估疾病进展时间的研究中探索这种联合治疗。
