Department of Surgery, Medicine and Immunology, Rush University Medical Center, Chicago, IL, USA.
Ann Surg Oncol. 2010 Mar;17(3):718-30. doi: 10.1245/s10434-009-0809-6.
An oncolytic herpes simplex virus engineered to replicate selectively in tumor cells and to express granulocyte-macrophage colony-stimulating factor (GMCSF) was tested as a direct intralesional vaccination in melanoma patients. The work reported herein was performed to better characterize the effect of vaccination on local and distant antitumor immunity.
Metastatic melanoma patients with accessible lesions were enrolled in a multicenter 50-patient phase II clinical trial of an oncolytic herpesvirus encoding GM-CSF (Oncovex(GM-CSF)). An initial priming dose of 10(6) pfu vaccine was given by intratumoral injection, followed by 10(8) pfu every 2 weeks to 24 total doses. Peripheral blood and tumor tissue were collected for analysis of effector T cells, CD4(+)FoxP3(+) regulatory T cells (Treg), CD8(+)FoxP3(+) suppressor T cells (Ts), and myeloid-derived suppressive cells (MDSC).
Phenotypic analysis of T cells derived from tumor samples suggested distinct differences from peripheral blood T cells. There was an increase in melanomaassociated antigen recognized by T cells (MART-1)-specific T cells in tumors undergoing regression after vaccination compared with T cells derived from melanoma patients not treated with vaccine. There was also a significant decrease in Treg and Ts cells in injected lesions compared with noninjected lesions in the same and different melanoma patients. Similarly MDSC were increased in melanoma lesions but underwent a significant decrease only in vaccinated lesions.
Melanoma patients present with elevated levels of Tregs, Ts, and MDSC within established tumors. Direct injection of Oncovex(GM-CSF) induces local and systemic antigen-specific T cell responses and decreases Treg, Ts, and MDSC in patients exhibiting therapeutic responses.
一种经工程改造后可在肿瘤细胞中选择性复制并表达粒细胞-巨噬细胞集落刺激因子（GMCSF）的溶瘤单纯疱疹病毒被用作黑色素瘤患者的直接瘤内疫苗进行测试。本文报告的工作旨在更好地描述疫苗接种对局部和远处抗肿瘤免疫的影响。
有可触及病变的转移性黑色素瘤患者被纳入一项多中心 50 例患者的溶瘤单纯疱疹病毒编码 GM-CSF（Oncovex（GM-CSF））的 II 期临床试验。通过瘤内注射给予初始 10（6）pfu 疫苗剂量，然后每 2 周给予 10（8）pfu，共 24 剂。采集外周血和肿瘤组织，分析效应 T 细胞、CD4（+）FoxP3（+）调节性 T 细胞（Treg）、CD8（+）FoxP3（+）抑制性 T 细胞（Ts）和髓源性抑制细胞（MDSC）。
从肿瘤样本中分离出的 T 细胞的表型分析表明，与外周血 T 细胞相比存在明显差异。与未接种疫苗的黑色素瘤患者相比，接种疫苗后肿瘤消退的患者的肿瘤中识别黑色素瘤相关抗原的 T 细胞（MART-1）特异性 T 细胞增加。与同一和不同黑色素瘤患者的非注射病灶相比，注射病灶中的 Treg 和 Ts 细胞也显著减少。同样，MDSC 在黑色素瘤病灶中增加，但仅在接种疫苗的病灶中才显著减少。
在已建立的肿瘤中，黑色素瘤患者存在升高的 Treg、Ts 和 MDSC 水平。直接注射 Oncovex（GM-CSF）可诱导局部和全身抗原特异性 T 细胞反应，并降低治疗反应患者的 Treg、Ts 和 MDSC。
