Posoleucel in Kidney Transplant Recipients with BK Viremia: Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

Abstract

Key Points:

1. Posoleucel was generally safe, well tolerated, and associated with a greater reduction of BK viremia compared with placebo.

2. BK viremia reduction occurred coincident with an increase in the circulating frequency of BK virus–specific T cells in posoleucel recipients.

3. The presence and persistence of posoleucel was confirmed by T-cell receptor variable β sequencing.

Background: Kidney transplant recipients with BK virus infection are at risk of developing BK virus–associated nephropathy, allograft rejection, and subsequent graft loss. There are no approved treatments for BK virus infection. Posoleucel is an off-the-shelf, allogeneic, multivirus-specific T-cell investigational therapy targeting BK virus, as well as five other opportunistic viruses: adenovirus, cytomegalovirus, Epstein–Barr virus, human herpesvirus 6, and John Cunningham virus.

Methods: In this phase 2, double-blind study, kidney transplant recipients with BK viremia were randomized 1:1:1 to receive posoleucel weekly for 3 weeks and then every 14 days (bi-weekly dosing) or every 28 days (monthly dosing) or placebo for 12 weeks. Participants were followed for 12 weeks after completing treatment. The primary objective was safety; the secondary objective was plasma BK viral load reduction.

Results: Sixty-one participants were randomized and dosed. Baseline characteristics were similar across groups. No deaths, graft-versus-host disease, or cytokine release syndrome occurred. The proportion of patients who had adverse events (AEs) judged by the investigators to be treatment-related was slightly lower in recipients of posoleucel: 20% (4 of 20 patients) and 18% (4 of 22) in those infused on a bi-weekly and monthly schedule, respectively, and 26% (5 of 19) in placebo recipients. None of the grade 3–4 AEs or serious AEs in any group were deemed treatment-related. No deaths, graft-versus-host disease, or cytokine release syndrome occurred. Three participants had allograft rejection, but none were deemed treatment-related by investigators. In posoleucel recipients, BK viremia reduction was associated with an increase in the circulating frequency of BK virus–specific T cells, and the presence and persistence of posoleucel was confirmed by T-cell receptor sequencing.

Conclusions: Posoleucel was generally safe, well tolerated, and associated with a larger reduction of BK viremia compared with placebo. Limitations of this study include the relatively short duration of follow-up and lack of power to detect significant differences in clinical outcomes.

Clinical Trial registry name and registration number:: Study of Posoleucel (Formerly Known as ALVR105; Viralym-M) in Kidney Transplant Patients With BK Viremia, NCT04605484.

Graphical abstract

Figure 1

Participant disposition. f/u, follow-up; IS, immunosuppression; PSL, posoleucel.

Figure 2

The antiviral response to posoleucel at weeks 14 and 24. (A) BK viral load at screening for all participants by low (350 to >10,000 copies/ml) and high (≥10,000–10,000,000 copies/ml) viral load strata and treatment group (PBO versus posoleucel). Median and min to max values indicated, with all data points shown. Percentage of participants that achieved ≥1 log₁₀ (B) or ≥50% (C) BK viral load reduction by week 14 (PBO, N=5; group 1, N=8; group 2, N=8) and week 24 (PBO, N=4; group 1, N=8; group 2, N=8) in the high viral load stratum (≥10,000–10,000,000 copies/ml), stable IS subpopulation. (D) Median log₁₀ change in BK viral load from baseline by week 14 (PBO, N=5; group 1, N=8; group 2, N=8) and week 24 (PBO, N=4; group 1, N=8; group 2, N=8) in the high viral load stratum (≥10,000–10,000,000 copies/ml), stable IS subpopulation. Stable IS: <50% IS reduction within 30 (±2) days before randomization. BKV, BK virus; PBO, placebo; PSL, posoleucel.

Figure 3

Effect of posoleucel on functional BK virus–specific T-cell responses. Posoleucel enhances functional BK virus–specific T-cell responses. (A) VP1 and large T IFNγ ELISpot SFC per 5×10⁵ PBMCs shown before posoleucel or placebo dosing as peak ELISpot response at screening or baseline for all participants who completed the study (N=58) in low (N=33; 350 to >10,000 copies/ml) and high (N=25; ≥10,000–10,000,000 copies/ml) viral load strata. Detectable functional BK virus T-cell responses defined as ≥10 SFC. Data graphed as box plots with median indicated and all data points plotted. (B) VP1 and large T-IFN-γ ELISpot data shown as fold change of peak ELISpot response from week 2–24 versus predose (with a minimum of five BK virus–specific SFC set as a predose response threshold) in all participants who completed the study (N=58). Data graphed as box plots with median indicated and all data points plotted. PBO, n=18; group 1, n=20; group 2, n=20. (C) VP1 and large T IFN-γ ELISpot data shown as fold change of peak ELISpot response from week 2–24 versus predose (with a minimum of five BK virus–specific SFC set as a predose response threshold) in high viral load stratum stable IS subgroup participants who completed the study (n=20). Data graphed as box plots with median indicated and all data points plotted. PBO, n=4; group 1, n=8; group 2, n=8. (D) VP1 and large T IFN-γ ELISpot data shown as fold change of peak ELISpot response from week 2–6, week 2–14, and week 2–24 versus predose (with a minimum of five BK virus–specific SFC set as a predose response threshold) in high viral load stratum stable IS subgroup participants who completed the study (n=4 PBO, n=16 posoleucel). The mean fold change is shown plus and minus the SEM. (E) The percentage of participants with detectable posoleucel T-cell clones is plotted relative to study week. Week 1 represents TCRvβ immunosequencing data collected before posoleucel infusion. The number of participants with evaluable data in the study week time period shown is indicated. (F) TCRvβ sum frequencies of posoleucel T-cell clones during week 4–6, 12–16, and 22–24 are plotted by viral load strata (low stratum n=19; high stratum week 4–6 n=15, week 12–24 n=16). Truncated violin plots shown with median and quartiles indicated by solid and dashed lines, respectively. Stable IS: <50% IS reduction within 30 (±2) days before randomization. ELISpot, enzyme-linked immunosorbent spot; PBMC, peripheral blood mononuclear cell; PBO, placebo; SFC, spot-forming cells; TCRvβ, T-cell receptor variable β.