Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes
Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes
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DOI：
10.1002/ijc.27939
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发表时间：
2013-06-01
影响因子：
6.4
通讯作者：
Bregni, Marco
中科院分区：
文献类型：
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作者：
Russo, Vincenzo;Pilla, Lorenzo;Bregni, Marco
癌症疫苗最近已被证明可以诱导一些临床益处。临床活性和抗疫苗T细胞应答之间的关系有些争议。事实上，在许多试验中，已经证明疫苗特异性T细胞的诱导超过了观察到的临床反应。在这里，我们评估了23例MAGE-A3+黑色素瘤患者的免疫学和临床反应，这些患者接受了基因工程改造的自体淋巴细胞治疗，以表达肿瘤抗原MAGE-A3和单纯疱疹病毒（HSV-TK）的病毒基因产物胸苷激酶。HSV-TK被用作不良事件情况下的安全系统，并作为示踪抗原监测治疗患者的免疫能力。分别在90%和27%的患者中观察到疫苗接种后抗TK和抗MAGE-A3 T细胞的增加。在19名患有可测量疾病的患者中，我们观察到疾病控制率为26.3%，有1例客观临床反应，4例持久稳定的疾病。在接种疫苗时无疾病证据（NED）的5名患者中，有3名在73+、70+和50+个月后仍为NED。值得注意的是，我们报告说，只有经历MAGE-A3特异性免疫应答的患者才显示出临床益处。此外，我们报告说，响应者和非响应者患者激活和扩大T细胞对示踪抗原TK以类似的方式，这表明，局部而不是全身免疫抑制可能参与限制临床相关的抗肿瘤免疫反应。
Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3+ melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses.