National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.
Front Immunol. 2020 Nov 9;11:595035. doi: 10.3389/fimmu.2020.595035. eCollection 2020.
Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793).
Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described.
All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations.
Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy.
clinicaltrials.org, identifier NCT03042793.
针对程序性死亡 1（PD-1）及其配体 PD-L1 的单克隆抗体免疫检查点阻断在癌症免疫治疗的兴起中发挥了重要作用。我们已经在健康供体和癌症患者中鉴定出了针对 PD-L1 的天然存在的自身反应性 T 细胞。用 PD-L1 肽（IO103）刺激这些细胞，激活它们表现出炎症和抗调节功能，包括对表达 PD-L1 的靶细胞的细胞毒性。这促使我们启动了使用 IO103 进行疫苗接种的首次人体研究，该研究在 clinicaltrials.org 上注册（NCT03042793）。
我们招募了 10 名多发性骨髓瘤患者，他们在接受自体干细胞支持的高剂量化疗后 6 个月内接受了治疗。在 1 年内，使用 IO103 与佐剂 Montanide ISA 51 进行皮下疫苗接种，最多可达 15 次。通过不良事件的常见毒性标准（CTCAE）评估安全性。使用 IFNγ 酶联免疫斑点和血液和皮肤浸润淋巴细胞中的细胞内细胞因子染色评估疫苗的免疫原性，从迟发型超敏反应部位获得。描述了临床过程。
所有 PD-L1 疫苗的不良反应均低于 CTCAE 3 级，大多数为 1-2 级注射部位反应。总不良事件发生率与人群预期相符。所有患者在迟发型超敏反应试验后在外周血单核细胞和皮肤浸润淋巴细胞中均表现出肽特异性免疫反应。临床过程与人群预期相符。10 名患者中有 3 名反应改善，与疫苗接种同时发生。
针对 PD-L1 的疫苗接种与低毒性和高免疫原性相关。这项研究促使我们启动了后期试验以评估疫苗的疗效。
clinicaltrials.org，标识符 NCT03042793。
