Intranodal Immunization With a Vaccinia Virus Encoding Multiple Antigenic Epitopes and Costimulatory Molecules in Metastatic Melanoma
Intranodal Immunization With a Vaccinia Virus Encoding Multiple Antigenic Epitopes and Costimulatory Molecules in Metastatic Melanoma
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DOI：
10.1038/mt.2009.275
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发表时间：
2010-03-01
影响因子：
12.4
通讯作者：
Zajac, Paul
中科院分区：
文献类型：
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作者：
Adamina, Michel;Rosenthal, Rachel;Zajac, Paul
编码肿瘤相关抗原（TAAs）和粘附或共刺激分子的重组牛痘病毒（rVV）可能代表用于癌症免疫治疗的重要免疫原性试剂。最近，有人认为结内（IN）抗原接种比皮内（ID）疫苗接种更具免疫原性。然而，迄今为止尚未尝试IN rVV给药。我们在1/2期试验中在III期和IV期黑色素瘤患者中使用了编码gp 100（280-288）、Melan-A/MART-1（27-35）和酪氨酸酶（1-9）HLA-A0201限制性表位以及CD 80和CD 86共刺激分子的rVV。在开始治疗的15名患者中，包括两个IN免疫周期，每个周期包括一次rVV施用和三次相应肽的回忆注射，伴随皮下粒细胞巨噬细胞集落刺激因子补充，五名患者由于疾病进展而退出。剩余的10例患者中，7例显示出诱导细胞毒性T淋巴细胞（CTL）的证据，这些细胞毒性T淋巴细胞（CTL）针对至少一种正在研究的表位，可通过特定前体和多聚体染色的有限稀释分析（LDA）检测到。不良反应轻微（美国国家癌症研究所（NCI）1-2级），主要表现为发热、皮疹和瘙痒。这些数据表明，IN施用编码黑素瘤相关表位和共刺激分子的rVV是安全的和免疫原性的。
Recombinant vaccinia virus (rVV) encoding tumor-associated antigens (TAAs) and adhesion or costimulatory molecules may represent important immunogenic reagents for cancer immunotherapy. Recently, intranodal (IN) antigen administration was suggested to be more immunogenic than intradermal (ID) vaccination. However, IN rVV administration has not been attempted so far. We used a rVV encoding gp100(280-288), Melan-A/MART-1(27-35) and tyrosinase(1-9) HLA-A0201 restricted epitopes and CD80 and CD86 costimulatory molecules in stage III and IV melanoma patients in a phase 1/2 trial. Of 15 patients initiating treatment, including two cycles of IN immunization, each comprising one rVV administration and three recall injections of the corresponding peptides, accompanied by subcutaneous granulocyte macrophage-colony stimulating factor supplementation, five withdrew due to progressing disease. Of 10 remaining patients seven showed evidence of induction of cytotoxic T lymphocytes (CTLs) directed against at least one epitope under investigation, as detectable by limiting dilution analysis (LDA) of specific precursors and multimer staining. Adverse reactions were mild (National Cancer Institute (NCI) grade 1-2) and mainly represented by fever, skin rashes, and pruritus. These data indicate that IN administration of rVV encoding melanoma-associated epitopes and costimulatory molecules is safe and immunogenic.