Pembrolizumab is a monoclonal antibody against PD-1 approved for several cancers. In HIV-infected individuals on suppressive antiretroviral therapy (ART), HIV is enriched in CD4 T-cells that express PD-1. Within a Cancer Immunotherapy Trials Network (CITN) study, we prospectively evaluated markers of HIV persistence to test the hypothesis that pembrolizumab administration might increase HIV transcription and viral production consistent with latency reversal.
CITN-12 is a prospective multicenter phase I study of pembrolizumab 200mg IV every 3 weeks in participants with HIV on ART and advanced cancer. Participants were enrolled in cohorts with CD4 counts of: 100-199 (C1), 200-350 (C2) and >350 cells/uL (C3). Specimens were collected at baseline, 2 hours, 1 day, 7 days (cycle 1 only) and before cycles 2 and 3. Plasma HIV RNA was measured using a single copy (sc) qRT-PCR for HIV gag. Intracellular unspliced (us) HIV RNA (RNA) and viral DNA (vDNA) were measured in CD4 T-cells. Pairwise correlation between assays was assessed by Pearson’s correlation coefficient. Kinetics of HIV plasma RNA, intracellular usRNA, usDNA, and usRNA/vDNA were evaluated by negative binomial regression. P<0.01 was considered statistically significant, p<0.05 a significant trend.
29 participants (C1 N= 6, C2 N=12, C3 N=11) with a range of tumors were evaluated; median age 56 years (IQR 50-61); 28 men, 1 woman. Baseline sc HIV = 1.1 copies/mL (IQR 0.3-2.4). Median baseline CD4 272 cells/uL (IQR 210-568). After pembrolizumab, mean usRNA and usRNA/DNA ratio were significantly elevated at Day 7 compared to baseline (usRNA: 1.43 fold, 95% CI 1.12 – 1.82, P=0.004; usRNA/DNA 1.63 fold, 95%CI 1.17-2.27, P=0.004) but not at day 21 (P=0.15, P=0.87 respectively). vDNA was decreased at 24 hours (0.82, 95%CI 0.70-0.97, P=0.02) but not on Day 7 (P=0.2) (Figure). No significant changes in plasma scHIV RNA were observed over 2 cycles. scHIV RNA , usRNA, and vDNA were not correlated (p>0.05).
Pembrolizumab leads to a transient increase in HIV transcription in CD4+ T-cells in vivo in individuals on ART consistent with latency reversal. It did not lead to increased plasma HIV RNA after administration of 2 doses. Evaluation of the long-term effects of pembrolizumab on HIV persistence and HIV specific immunity are ongoing. Further evaluation of monoclonal antibodies against PD-1 as a strategy for HIV cure is warranted.