Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.
Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.
复制标题
DOI：
10.1371/journal.pmed.1002139
复制
发表时间：
2016-10
期刊：
影响因子：
15.8
通讯作者：
Waldron-Lynch F
中科院分区：
文献类型：
--
作者：
Todd JA;Evangelou M;Cutler AJ;Pekalski ML;Walker NM;Stevens HE;Porter L;Smyth DJ;Rainbow DB;Ferreira RC;Esposito L;Hunter KM;Loudon K;Irons K;Yang JH;Bell CJ;Schuilenburg H;Heywood J;Challis B;Neupane S;Clarke P;Coleman G;Dawson S;Goymer D;Anselmiova K;Kennet J;Brown J;Caddy SL;Lu J;Greatorex J;Goodfellow I;Wallace C;Tree TI;Evans M;Mander AP;Bond S;Wicker LS;Waldron-Lynch F
白细胞介素-2（IL-2）在CD 4+调节性T细胞（T细胞）的扩增和功能中具有重要作用。Teff通过限制感染后的免疫反应来减少组织损伤，并调节自身反应性CD 4+效应T细胞（Tefs）以预防自身免疫性疾病，如1型糖尿病（T1 D）。对T1 D的遗传易感性导致IL-2通路的改变，这一发现支持T1 D作为细胞治疗靶点。阿地白介素（Proleukin;重组人IL-2），其在癌症免疫疗法中以高剂量施用以激活免疫系统，现在正被重新定位以通过靶向TcR以较低剂量治疗炎性和自身免疫性疾病。为了确定阿地白介素对TlD的剂量反应并找到在生理上增加TlD治疗的剂量，通过分析1型糖尿病中IL-2剂量对调节性T细胞的适应性研究（DILT 1D）中皮下阿地白介素单剂量的药代动力学和药效学，采用统计学和系统性方法，该研究是一项单中心、非随机、开放标签、适应性剂量探索试验，40名最近诊断为T1 D的成人参与者。主要终点是治疗后7天内测量的每名参与者的T细胞计数（定义为CD 3 + CD 4 + CD 25 highCD 127 low）较基线频率的最大百分比增加。初始学习阶段有5对参与者，每对接受5个预先分配的单次剂量（0.04 × 106 - 1.5 × 106 IU/m2）中的一个，以模拟剂量-反应曲线。然后将每个参与者的结果纳入中期统计模型，以确定最有可能诱导Treg频率增加10%和20%的两种剂量。对可评价人群（n = 39）的初步分析发现，阿地白介素诱导THBV10%和20%升高的最佳剂量为0.101 × 106 IU/m2（标准误[SE] = 0.078，95% CI = −0.052，0.254）和0.497 × 106 IU/m2（SE = 0.092，95% CI = 0.316，0.678）。在次要结局分析中，使用高度灵敏的IL-2测定法，即使在最低剂量（0.040 × 106和0.045 × 106 IU/m2）下，90 min时观察到的药物血浆浓度也超过体外测定的假设Treg特异性治疗窗（0.015-0.24 IU/ml）。在90 min和第1天观察到循环中Treg频率的快速降低，其具有剂量依赖性（平均降低11.6%，SE = 2.3%，范围10.0%-48.2%，n = 37），在第2天反弹，并在7天内增加至高于基线的频率。TEFs、自然杀伤细胞和嗜酸性粒细胞也有反应，其频率在血液中迅速且呈剂量依赖性下降，然后恢复或超过治疗前水平。此外，IL-2受体的两个信号转导亚基之一β链（CD 122）对TcB有剂量依赖性下调（平均降低= 58.0%，SE = 2.8%，范围9.8%-85.5%，n = 33），在治疗后90 min和第1天和第2天，其对阿地白介素的敏感性降低。由于血容量要求以及伦理和实践方面的考虑，本研究仅限于成人，仅分析外周血。DILT 1D试验结果，最值得注意的是由单次超低剂量的阿地白介素诱导的早期改变的运输和脱敏，在2-3天内消退，为下一次试验的设计提供了信息，以确定旨在建立20%-50%的稳态Treg频率增加的重复给药方案，最终目标是预防T1 D。ClinicalTrials.gov Frank Waldron-Lynch及其同事研究了1型糖尿病患者在单剂量重组白细胞介素-2后的免疫细胞生物标志物反应。胰岛素替代是唯一获批用于治疗1型糖尿病（T1 D）的疗法，可治疗症状，但不能治疗疾病的根本原因，即免疫介导的胰腺产生胰岛素的β细胞的破坏。阿地白介素，重组白细胞介素-2（IL-2），被选为候选免疫疗法，以防止或延迟自身免疫，因为以前的遗传和表型分析表明，IL-2途径在T1 D的发展中发挥重要作用。IL-2对于维持防止自身免疫的调节性T细胞（Tcells）的功能至关重要。因此，我们预防T1 D方法的第一步是确定在生理范围内增加Treg数量的单剂量阿地白介素，旨在模拟IL-2途径的风险降低等位基因提供的针对T1 D的保护。我们在40名T1 D受试者中成功采用了最先进的剂量探索、开放标签、适应性临床试验设计，以确定将Treg频率提高10%和20%所需的阿地白介素剂量。阿地白介素诱导的Treg频率增加之前，血液中的阿地白介素在90分钟时达到峰值，导致循环中的T细胞亚群和其他细胞亚群的短暂剂量依赖性降低。在用阿地白介素剂量治疗后，TdR对IL-2的敏感性降低，在治疗后第3天恢复到基线。DILT 1D试验表明，可以进行适应性剂量探索试验，以基于免疫细胞生物标志物估计两种药物剂量作为主要结局。部分脱敏的Teptide可能有助于解释为什么一些参与者在以前的试验与每日给药方案没有响应阿地白介素，这表明在未来的试验中，药物不应该每天给药。
Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = −0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015–0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%–48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%–85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2–3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%–50%, with the eventual goal of preventing T1D. ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735 Frank Waldron-Lynch and colleagues investigate immune cell biomarker responses in patients with type 1 diabetes following a single dose of recombinant interleukin-2. Insulin replacement, the only approved therapy for the treatment of type 1 diabetes (T1D), treats the symptoms but not the underlying cause of the disease, namely, immune-mediated destruction of the insulin-producing β cells of the pancreas. Aldesleukin, recombinant interleukin-2 (IL-2), was selected as a candidate immunotherapy to prevent or delay autoimmunity because previous genetic and phenotypic analyses indicate a major role for the IL-2 pathway in the development of T1D. IL-2 is critical for maintaining the function of the regulatory T cells (Tregs) that prevent autoimmunity. Therefore, the first step in our approach to T1D prevention was to determine the single doses of aldesleukin that increase Treg numbers within the physiological range, aiming to mimic the protection against T1D afforded by the risk-reducing alleles of the IL-2 pathway. We successfully employed a state-of-the-art dose-finding, open label, adaptive clinical trial design in 40 participants with T1D to determine the doses of aldesleukin needed to raise Treg frequencies by 10% and 20%. Increased Treg frequencies induced by aldesleukin were preceded by a peak of aldesleukin in the blood at 90 minutes that caused a transient dose-dependent decrease of Tregs and other cell subsets in the circulation. Following treatment with a dose of aldesleukin, Tregs had a decreased sensitivity to IL-2 that returned to baseline on day 3 after treatment. The DILT1D trial showed that it is possible to conduct an adaptive dose-finding trial to estimate two drug doses based on an immune cell biomarker as a primary outcome. Partial desensitisation of Tregs might help explain why some participants in previous trials with daily dosing regimens did not respond to aldesleukin, suggesting that in future trials the drug should not be administered on a daily basis.