Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4
Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4
复制标题
DOI：
10.1200/jco.2005.06.205
复制
发表时间：
2005-09-01
影响因子：
45.3
通讯作者：
Rosenberg, SA
中科院分区：
文献类型：
--
作者：
Attia, P;Phan, GQ;Rosenberg, SA
先前，我们报告了我们使用细胞毒性t淋巴细胞抗原-4（抗ctla -4）的全人源抗体结合肽疫苗治疗14例转移性黑色素瘤患者的经验。我们目前已经治疗了56例患者，以评估两种不同的抗ctla -4剂量方案，并探讨自身免疫与肿瘤消退之间的关系。患者和方法共有56例进行性IV期黑色素瘤患者被纳入研究。所有患者均具有Karnofsky性能状态>= 60%，无自身免疫史。29例患者每3周接受3mg /kg抗ctla -4治疗，27例患者初始剂量为3mg /kg，随后剂量减少至每3周1mg /kg。在这两个队列中，患者同时接种了来自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）。结果2例患者获得完全缓解（分别持续30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+月），总体客观缓解率为13%。肿瘤消退见于肺、肝、脑、淋巴结和皮下部位。在14例3/4级自身免疫毒性患者中，5例（36%）出现临床反应，而42例（5%）无自身免疫毒性患者中只有2例出现临床反应（P = 0.008）。两种剂量方案在反应率和毒性方面没有显著差异。结论抗ctla -4单克隆抗体加肽疫苗接种可引起转移性黑色素瘤患者持久的客观反应，并与自身免疫的诱导相关。
Purpose 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.Patients and Methods A total of 56 patients with progressive stage IV melanoma were enrolled onto the study. All had Karnofsky performance status >= 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).Results 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.Conclusion 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.