Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma
Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma
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DOI：
10.1172/jci24624
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发表时间：
2005-07-01
影响因子：
15.9
通讯作者：
Marincola, FM
中科院分区：
文献类型：
--
作者：
Kaufman, HL;DeRaffele, G;Marincola, FM
转移性黑色素瘤的免疫治疗仍然是一个重大的临床挑战。黑色素瘤微环境可能导致局部T细胞耐受，部分通过下调共刺激分子，如B7.1（CD 80）。据我们所知，我们报告了第一次临床试验的结果，使用表达B7.1的重组牛痘病毒（rV-B7.1）进行每月一次的病灶内注射。接种可接近的黑素瘤病变。在12名患者中进行了标准的2剂量递增I期临床试验。该方法耐受性良好，仅报告低热、肌痛和疲劳，2例患者发生白癜风。在1例患者中观察到客观部分应答，在2例患者中观察到疾病稳定，其中1例在接种后59个月无疾病存活。所有患者均表现出疫苗接种后抗牛痘病毒抗体和T细胞应答的增加。在HLA-A*0201患者中测试全身免疫性，所述患者在局部rV-B7.1疫苗接种后通过ELISPOT测定证明gp 100和T细胞I（MART-1）（也称为Melan-A）识别的黑素瘤抗原特异性T细胞的频率增加。通过定量实时RT-PCR评估局部免疫，这表明肿瘤消退与CD 8和IFN-γ表达增加相关。表达137.1的牛痘病毒的局部递送耐受性良好，并且代表了用于改变黑素瘤患者中的局部肿瘤微环境的创新策略。
Immunotherapy for the treatment of metastatic melanoma remains a major clinical challenge. The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80). We report the results from the first clinical trial, to our knowledge, using a recombinant vaccinia virus expressing B7.1 (rV-B7.1) for monthly intralesional. vaccination of accessible melanoma lesions. A standard 2-dose-escalation phase I clinical trial was conducted with 12 patients. The approach was wen tolerated with only low-grade fever, myalgias, and fatigue reported and 2 patients experiencing vitiligo. An objective partial response was observed in 1 patient and disease stabilization in 2 patients, 1 of whom is alive without disease 59 months following vaccination. All patients demonstrated an increase in postvaccination antibody and T cell responses against vaccinia virus. Systemic immunity was tested in HLA-A*0201 patients who demonstrated an increased frequency of gp100 and T cells specific to melanoma antigen recognized by T cells I (MART-1), also known as Melan-A, by ELISPOT assay following local rV-B7.1 vaccination. Local immunity was evaluated by quantitative real-time RT-PCR, which suggested that tumor regression was associated with increased expression of CD8 and IFN-gamma. The local delivery of vaccinia virus expressing 137.1 was well tolerated and represents an innovative strategy for altering the local tumor microenvironment in patients with melanoma.