抗 PD-1 和抗 CTLA-4 对接受抗逆转录病毒治疗的 HIV 合并癌症患者 HIV 储存库的影响：艾滋病恶性肿瘤联盟 095 研究。
Impact of Anti-PD-1 and Anti-CTLA-4 on the Human Immunodeficiency Virus (HIV) Reservoir in People Living With HIV With Cancer on Antiretroviral Therapy: The AIDS Malignancy Consortium 095 Study.
机构信息
The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.
Department of Haematology and Oncology, Lennox Hill Hospital, New York, New York, USA.
出版信息
Clin Infect Dis. 2021 Oct 5;73(7):e1973-e1981. doi: 10.1093/cid/ciaa1530.
BACKGROUND
Antibodies to programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may perturb human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) by reversing HIV latency and/or boosting HIV-specific immunity, leading to clearance of infected cells. We tested this hypothesis in a clinical trial of anti-PD-1 alone or in combination with anti-CTLA-4 in people living with HIV (PLWH) and cancer.
METHODS
This was a substudy of the AIDS Malignancy Consortium 095 Study. ART-suppressed PLWH with advanced malignancies were assigned to nivolumab (anti-PD-1) with or without ipilimumab (anti-CTLA-4). In samples obtained preinfusion and 1 and 7 days after the first and fourth doses of immune checkpoint blockade (ICB), we quantified cell-associated unspliced (CA-US) HIV RNA and HIV DNA. Plasma HIV RNA was quantified during the first treatment cycle. Quantitative viral outgrowth assay (QVOA) to estimate the frequency of replication-competent HIV was performed before and after ICB for participants with samples available.
RESULTS
Of 40 participants, 33 received nivolumab and 7 nivolumab plus ipilimumab. Whereas CA-US HIV RNA did not change with nivolumab monotherapy, we detected a median 1.44-fold increase (interquartile range, 1.16-1.89) after the first dose of nivolumab and ipilimumab combination therapy (P = .031). There was no decrease in the frequency of cells containing replication-competent HIV, but in the 2 individuals on combination ICB for whom we had longitudinal QVOA, we detected decreases of 97% and 64% compared to baseline.
CONCLUSIONS
Anti-PD-1 alone showed no effect on HIV latency or the latent HIV reservoir, but the combination of anti-PD-1 and anti-CTL-4 induced a modest increase in CA-US HIV RNA and may potentially eliminate cells containing replication-competent HIV.
CLINICAL TRIALS REGISTRATION
NCT02408861.
背景
抗程序性细胞死亡蛋白 1（PD-1）和细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）的抗体可能通过逆转 HIV 潜伏和/或增强 HIV 特异性免疫，从而清除感染细胞，在抗逆转录病毒治疗（ART）期间干扰人类免疫缺陷病毒（HIV）的持续存在。我们在一项临床试验中检验了这一假说，该试验评估了抗 PD-1 单药治疗或联合抗 CTLA-4 治疗在 HIV 感染者（PLWH）合并癌症患者中的效果。
方法
这是 AIDS 恶性肿瘤联盟 095 研究的一项子研究。ART 抑制的合并晚期恶性肿瘤的 PLWH 被分配接受纳武单抗（抗 PD-1）联合或不联合伊匹单抗（抗 CTLA-4）治疗。在免疫检查点阻断（ICB）治疗前、第一次和第四次给药后 1 天和 7 天采集样本，我们定量分析了细胞相关未剪接（CA-US）HIV RNA 和 HIV DNA。在第一个治疗周期期间定量检测血浆 HIV RNA。对于有样本可用的参与者，在 ICB 治疗前后进行定量病毒扩增试验（QVOA）以评估复制能力完整的 HIV 的频率。
结果
在 40 名参与者中，33 名接受了纳武单抗治疗，7 名接受了纳武单抗联合伊匹单抗治疗。虽然纳武单抗单药治疗对 CA-US HIV RNA 没有影响，但我们在接受纳武单抗联合伊匹单抗联合治疗的第一剂后检测到中位数增加了 1.44 倍（四分位距，1.16-1.89；P =.031）。未检测到复制能力完整的 HIV 细胞频率下降，但在 2 名接受联合 ICB 治疗的个体中，与基线相比，我们检测到下降了 97%和 64%。
结论
抗 PD-1 单药治疗对 HIV 潜伏期或潜伏 HIV 储存库没有影响，但抗 PD-1 和抗 CTLA-4 联合治疗诱导 CA-US HIV RNA 适度增加，可能潜在地消除含有复制能力完整 HIV 的细胞。
临床试验注册
NCT02408861。
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