Posoleucel for BK Polyomavirus in Kidney Transplant Recipients
Year: 2024
Type: article
Abstract: A randomized controlled trial (RCT) by Chandraker and colleagues published in JASN reported that posoleucel for BK polyomavirus (BKPyV)-DNAemia/nephropathy was not associated with a higher rate of treatment-related adverse events, including rejection, graft-versus-host disease, cytokine release syndrome, kidney graft failure, or death.1 Despite the small sample size, this phase 2 RCT was also promising with respect to the secondary objective, namely the reduction of BKPyV-DNAemia. However, decline of ≥1 log10 copies/mL only occurred in 60%–75% of patients at 24 weeks, having a median decline of only 1.4 log10 copies/ml. These results are in contrast to earlier observations2 achieving >2 log10 copies/mL decline or complete clearance of BKPyV-DNAemia, including for patients with ≥10,000 copies/mL. If so, what could contribute to the limited efficacy? Off-the-shelf products are derived from single donors having variable cell-mediated immunity levels for each of the viruses, including for BKPyV. Although there was partial HLA class 1 and 2 matching according to recipient or donor allograft, there was no HLA class 1 matching in 18%–55% of posoleucel recipients. To increase efficacy attributable to posoleucel or similar cell-mediated immunity–based therapies over the current standard of care (i.e., screening for new-onset BKPyV-DNAemia and reducing immunosuppression),2 we see the following options: • to focus on patients failing recommended standard of care, whereby low/undetectable BKPyV-specific cell-mediated immunity could further refine patient inclusion criteria benefitting from posoleucel. However, delaying standard of care for more than 8 weeks is likely to increase the rate of patients with irreversible kidney allograft damage and undesirable outcomes. Perhaps, one predefined consensus step of immunosuppressant reduction common to both arms would allow us to rapidly identify patients with insufficient BKPyV-DNAemia decline and BKPyV-specific cell-mediated immunity rise after 4 weeks and provide the largest functional posoleucel benefit without precipitating acute rejection. • to prioritize HLA class 1 matching and to preferentially include HLAs presenting immunodominant 9mer epitopes for cytotoxic CD8 T cells,3 to enhance virological and clinical efficacy. • to enhance ex vivo expansion of BKPyV-specific cell-mediated immunity. As part of our ongoing study (study approval Ethics Committee of Both Basel cantons 267/06),3 we have compared PBMC responses using conventional cultures and the G-rex-open system. The total number of T cells was increased using the G-rex-open, and the expansion could be shortened from 14 to 10 days (Figure 1). We also noted that there was a significant upregulation of programmed cell death protein-1 (PD-1) in G-rex-open despite detectable BKPyV-specific stimulation responses in vitro. PD-1 blockade by pembrolizumab increased the BKPyV-specific polyfunctional cell-mediated immunity (not shown). Because PD-ligand 1 is expressed by human renal tubular epithelial cells,4ex vivo expansion and PD-1 expression may need new approaches for optimized virus-specific T-cell therapies in patients receiving kidney transplant. Figure 1: Comparison of BKPyV-specific T-cell responses using different cell culture protocols. Healthy donor PBMCs were isolated as described previously (study approval Ethics Committee of Both Basel cantons 267/06),3 seeded in G-Rex vessels or conventional 24-well plates and stimulated with BKPyV-encoded 27mer peptide pool covering the large T-antigen for the indicated time. (A) Overall CD4 and CD8 T-cell number before and after expansion determined by flow cytometry. (B) PD-1 expression on BKPyV-specific CD8 and CD4 T cells before (day 0) or after expansion with BKPyV large T-antigen 27mer pool. (C) BKPyV-specific T-cell responses measured by IFNy production after rechallenge with BKPyV large T-antigen immunodominant 9mer pool (9mP) or 15mer pool (15mP). BKPyV, BK polyomavirus; PD-1, programmed cell death protein-1.We conclude that the study by Chandraker and colleagues is an important step toward future RCTs that identify patients failing to respond to standard of care and that optimize adoptive T-cell therapy by improving HLA class 1 matching and exhaustion marker induction without increasing acute rejection and thereby address this unmet need of patients receiving kidney transplant facing BKPyV-DNAemia/nephropathy.
Institutions: University of Basel, University Hospital of Basel
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Universität Basel
Award: G6222184925
OpenAlex ID: W4402675889