St Stephen's AIDS Trust, Chelsea and Westminster Hospital, London, United Kingdom.
PLoS One. 2013 Sep 17;8(9):e73765. doi: 10.1371/journal.pone.0073765. eCollection 2013.
Preclinical studies of overlapping 15mer peptides, spanning SIV, SHIV or HIV, pulsed on autologous PBMC ex vivo have demonstrated high level, virus-specific T cell responses and viral suppression in non-human primates (NHP). Opal-HIV-Gag(c) consists of 120 synthetic 15mer peptides spanning Clade C, consensus Gag, manufactured to current good manufacturing practice; having been evaluated in a good laboratory practice toxicology study in Macaca mulatta. We evaluated the safety and preliminary immunogenicity of such peptides administered intravenously after short-duration ex vivo incubation, to HIV-positive adults on suppressive antiretroviral therapy.
A first-in-human, placebo-controlled, double-blind, dose escalation study was conducted. Twenty-three patients with virus suppressed by antiretroviral therapy were enrolled in four groups 12 mg (n = 6), 24 mg (n = 6), 48 mg (n = 2) or matching placebo (n = 8). Treatment was administered intravenously after bedside enrichment of 120 mL whole blood for white cells using a closed system (Sepax S-100 device), with ex vivo peptide admixture (or diluent alone) and 37°C incubation for one hour prior to reinfusion. Patients received 4 administrations at monthly intervals followed by a 12-week observation post-treatment. Opal-HIV-Gag(c) was reasonably tolerated at doses of 12 and 24 mg. There was an increased incidence of temporally associated pyrexia, chills, and transient/self-limiting lymphopenia in Opal-HIV-Gag(c) recipients compared to placebo. The study was terminated early, after two patients were recruited to the 48 mg cohort; a serious adverse event of hypotension, tachycardia secondary to diarrhoea occurred following a single product administration. An infectious cause for the event could not be identified, leaving the possibility of immunologically mediated product reaction.
A serious, potentially life-threatening event of hypotension led to early, precautionary termination of the study. In the absence of a clearly defined mechanism or ability to predict such occurrence, further development of Opal-HIV-Gag(c) will not be undertaken in the current form.
ClinicalTrials.gov NCT01123915; EudraCT: 2008-005142-23.
在体外对重叠的 15 mer 肽进行预临床研究，这些肽跨越 SIV、SHIV 或 HIV，并用自体 PBMC 脉冲刺激，已在非人类灵长类动物（NHP）中证明了高水平、病毒特异性的 T 细胞反应和病毒抑制。Opal-HIV-Gag(c) 由 120 个合成的 15 mer 肽组成，跨越 Clade C、共识 Gag，按照当前良好生产规范制造；已经在猕猴中进行了良好实验室规范毒理学研究的评估。我们评估了静脉内给予此类肽的安全性和初步免疫原性，这些肽在体外孵育短时间后，给予接受抑制性抗逆转录病毒治疗的 HIV 阳性成年人。
进行了首例人类、安慰剂对照、双盲、剂量递增研究。23 名病毒被抗逆转录病毒治疗抑制的患者被分为四组，12mg（n=6）、24mg（n=6）、48mg（n=2）或匹配的安慰剂（n=8）。在床边使用封闭系统（Sepax S-100 设备）从 120ml 全血中富集白细胞后，静脉内给予治疗，在重新输注前进行外源性肽混合物（或单独稀释剂）和 37°C 孵育 1 小时。患者每月接受 4 次治疗，然后在治疗后进行 12 周的观察。在 12 和 24mg 剂量下，Opal-HIV-Gag(c) 可合理耐受。与安慰剂相比，Opal-HIV-Gag(c) 接受者发热、发冷和短暂/自限性淋巴细胞减少的发生率增加，且与治疗相关。该研究在两名患者被招募到 48mg 队列后提前终止，单次产品给药后发生低血压、心动过速继发腹泻的严重不良事件。无法确定该事件的感染原因，留下免疫介导的产品反应的可能性。
低血压严重、潜在危及生命的事件导致研究提前预防性终止。在没有明确的机制或预测这种情况的能力的情况下，将不会以当前形式进一步开发 Opal-HIV-Gag(c)。
ClinicalTrials.gov NCT01123915；EudraCT：2008-005142-23。
