Attia Peter, Phan Giao Q, Maker Ajay V, Robinson Michael R, Quezado Martha M, Yang James C, Sherry Richard M, Topalian Suzanne L, Kammula Udai S, Royal Richard E, Restifo Nicholas P, Haworth Leah R, Levy Catherine, Mavroukakis Sharon A, Nichol Geoff, Yellin Michael J, Rosenberg Steven A
Surgery Branch, National Cancer Institute, National Institutes of Health, CRC, Room 3W-3940, 10 Center Dr, Bethesda, MD 20892-1201, USA.
J Clin Oncol. 2005 Sep 1;23(25):6043-53. doi: 10.1200/JCO.2005.06.205. Epub 2005 Aug 8.
Previously, we reported our experience treating 14 patients with metastatic melanoma using a fully human antibody to cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) in conjunction with peptide vaccination. We have now treated 56 patients to evaluate two different dose schedules of anti-CTLA-4 and to explore the relationship between autoimmunity and tumor regression.
A total of 56 patients with progressive stage IV melanoma were enrolled onto the study. All had Karnofsky performance status > or = 60% with no prior history of autoimmunity. Twenty-nine patients received 3 mg/kg anti-CTLA-4 every 3 weeks, whereas 27 received 3 mg/kg as their initial dose with subsequent doses reduced to 1 mg/kg every 3 weeks. In both cohorts patients received concomitant vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V).
Two patients achieved a complete response (ongoing at 30 and 31 months, respectively) and five patients achieved a partial response (durations of 4, 6, 25+, 26+, and 34+ months, respectively), for an overall objective response rate of 13%. Tumor regression was seen in lung, liver, brain, lymph nodes, and subcutaneous sites. Of 14 patients with grade 3/4 autoimmune toxicity, five (36%) experienced a clinical response compared with only two responses in the 42 patients (5%) with no autoimmune toxicity (P = .008). There were no significant differences in response rate or toxicity between the two dose schedules.
Administration of anti-CTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses, which correlate with the induction of autoimmunity, in patients with metastatic melanoma.
此前，我们报告了使用一种完全人源化的细胞毒性T淋巴细胞相关抗原4抗体（抗CTLA - 4）联合肽疫苗治疗14例转移性黑色素瘤患者的经验。我们现在已治疗了56例患者，以评估抗CTLA - 4的两种不同剂量方案，并探讨自身免疫与肿瘤消退之间的关系。
共有56例IV期进展期黑色素瘤患者入组本研究。所有患者卡氏评分≥60%，且既往无自身免疫病史。29例患者每3周接受3mg/kg抗CTLA - 4治疗，而27例患者初始剂量为3mg/kg，随后剂量减至每3周1mg/kg。在两个队列中，患者均接受来自gp100黑色素瘤相关抗原的两种修饰的HLA - A*0201限制性肽（gp100:209 - 217[210M]和gp100:280 - 288[288V]）的联合疫苗接种。
2例患者获得完全缓解（分别持续30个月和31个月），5例患者获得部分缓解（持续时间分别为4、6、25 +、26 +和34 +个月），总体客观缓解率为13%。在肺、肝、脑、淋巴结和皮下部位均可见肿瘤消退。在14例发生3/4级自身免疫毒性的患者中，5例（36%）出现临床缓解，而在42例无自身免疫毒性的患者中仅有2例（5%）出现缓解（P = 0.008）。两种剂量方案在缓解率或毒性方面无显著差异。
对于转移性黑色素瘤患者，给予抗CTLA - 4单克隆抗体联合肽疫苗接种可引起持久的客观缓解，且与自身免疫的诱导相关。
