Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Pinn Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
J Immunother Cancer. 2019 Jun 27;7(1):163. doi: 10.1186/s40425-019-0625-x.
Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8 T cell responses, whereas addition of an incomplete Freund's adjuvant (IFA) would reduce magnitude and persistence of immune responses.
Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS).
Fifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6.
LPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA.
The clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.
癌症疫苗需要佐剂来诱导有效的免疫反应；然而，对于最佳佐剂还没有共识。我们假设 Toll 样受体（TLR）3 激动剂聚肌胞苷酸（polyICLC）或 TLR4 激动剂脂多糖（LPS）与 CD4 T 细胞激活结合，将支持强大而持久的 CD8 T 细胞反应，而添加不完全弗氏佐剂（IFA）将降低免疫反应的幅度和持久性。
接受过 IIB-IV 期黑色素瘤切除的参与者接受了由 12 种受 I 类 MHC 限制的黑色素瘤肽（12MP）组成的疫苗，加上破伤风辅助肽（Tet）。参与者被随机分为 2:1 分配到队列 1（LPS 剂量递增）或队列 2（polyICLC）。每个队列包括 3 个亚组（a-c），分别接受 12MP+Tet+TLR 激动剂而不添加 IFA（0），或在疫苗 1 中添加 IFA（V1），或在所有 6 种疫苗中添加 IFA（V6）。记录毒性（CTCAE v4）。使用 IFNγ ELIspot 测定法在体外或体外刺激一次后（IVS）测量 T 细胞反应。
共纳入 53 名符合条件的患者，其中 51 名接受了治疗。在队列 1 中，有 0/33 名患者和队列 2 中有 2/18 名患者观察到与治疗相关的剂量限制毒性（DLT）（11%）。在队列 1（42%）和队列 2（56%）中检测到 12MP 的 CD8 T 细胞反应，亚组 V0、V1 和 V6 的分别为 18%、50%和 72%。当与 TLR 激动剂联合使用时，添加 IFA 的 LPS 和 polyICLC 是安全有效的疫苗佐剂。与中心假设相反，当添加到 TLR 激动剂时，IFA 增强了对肽疫苗的 T 细胞反应。未来的研究将旨在了解 IFA 产生有利影响的机制。
Mel58 临床试验在 IRB（#15781）和 FDA 批准下进行，并于 2012 年 4 月 25 日在 Clinicaltrials.gov 上注册（NCT01585350）。患者提供了参与的书面知情同意。招募于 2012 年 6 月 24 日开始。
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