Nitschke Nikolaj Juul, Bjoern Jon, Iversen Trine Zeeberg, Andersen Mads Hald, Svane Inge Marie
Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
Stem Cell Investig. 2017 Sep 21;4:77. doi: 10.21037/sci.2017.08.06. eCollection 2017.
Indoleamine 2,3-dioxygenase (IDO) and survivin have been identified as potential targets for cancer vaccination. In this phase II study a vaccine using the peptides Sur1M2 and IDO5 was combined with the chemotherapy temozolomide (TMZ) for treatment of metastatic melanoma patients. The aim was to simultaneously target several immune inhibiting mechanisms and the highly malignant cells expressing survivin.
HLA-A2 positive patients with advanced malignant melanoma were treated biweekly with 150 mg/m TMZ daily for 7 days followed by subcutaneous vaccination with 250 µg of each peptide in 500 µL Montanide solution at day 8. Granulocyte-macrophage colony-stimulating factor was used as an adjuvant and topical imiquimod was applied prior to vaccination. Treatment was continued until disease progression. Clinical response was evaluated by PET-CT and immunological outcome was assessed by ELISPOT and flow cytometry.
In total, 17 patients were treated with a clinical benefit rate of 18% including one patient with partial tumor regression. Immune analyses revealed a vaccine specific response in 8 (67%) of 12 patients tested, a significant decrease in the frequency of CD4+ T-cells during treatment, a tendency towards decreasing frequencies of naïve CD4+ and CD8+ T-cells, and increasing frequencies of memory CD4+ and CD8+ T-cells.
These results demonstrate that vaccine-induced immunity towards survivin and IDO-derived peptides can be achieved in combination with TMZ in patients mainly suffering from grade M1c melanoma including patients with brain metastases. A significant clinical activity could not be proven in this small study and a larger setup is needed to properly assess clinical efficacy.
吲哚胺2,3-双加氧酶（IDO）和生存素已被确定为癌症疫苗接种的潜在靶点。在这项II期研究中，一种使用Sur1M2和IDO5肽的疫苗与化疗药物替莫唑胺（TMZ）联合用于治疗转移性黑色素瘤患者。目的是同时针对多种免疫抑制机制以及表达生存素的高恶性细胞。
HLA-A2阳性的晚期恶性黑色素瘤患者每两周接受一次治疗，每天150mg/m² TMZ，持续7天，然后在第8天皮下接种250μg每种肽，溶于500μL Montanide溶液中。使用粒细胞-巨噬细胞集落刺激因子作为佐剂，在接种疫苗前应用局部咪喹莫特。治疗持续至疾病进展。通过PET-CT评估临床反应，通过ELISPOT和流式细胞术评估免疫结果。
总共治疗了17例患者，临床获益率为18%，包括1例部分肿瘤消退的患者。免疫分析显示，在12例接受检测的患者中有8例（67%）出现了疫苗特异性反应，治疗期间CD4+ T细胞频率显著下降，初始CD4+和CD8+ T细胞频率有下降趋势，记忆CD4+和CD8+ T细胞频率有上升趋势。
这些结果表明，在主要患有M1c级黑色素瘤（包括脑转移患者）的患者中，与TMZ联合使用时，可以实现针对生存素和IDO衍生肽的疫苗诱导免疫。在这项小型研究中未能证明有显著的临床活性，需要更大规模的研究来正确评估临床疗效。
