Introduction and objective
There are few efficacious bladder-preserving therapies for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). Pembrolizumab, an immune checkpoint inhibitor (ICI) targeting programmed cell death 1 (PD1) receptor, is approved in this setting. Nadofaragene firadenovec is an intravesical adenoviral vector-based therapy that delivers IFNA2 to urothelial cells, and has shown durable response in a multicenter phase 3 trial for BCG-unresponsive NMIBC. We evaluated the status of PD1 and its ligand (PD-L1) in transurethral resection (TUR) specimens from patients treated with nadofaragene, and examined the role for combining nadofaragene with anti-PD1 therapy in BCG-unresponsive NMIBC.
Methods
TUR specimens were available for 85 patients treated on a single-arm phase 3 trial with nadofaragene once every three months for up to four doses. Response was assessed at 12 months or disease recurrence, whichever was earlier. TUR of tumor was done at enrollment, and a templated biopsy at 12 months or study withdrawal. PD1/PD-L1 status were assayed per routine immunohistochemical protocols. PD1 (positive, >0% cells) and PD-L1 (positive, ≥1% cells) quantification were performed for urothelial and infiltrating lymphocyte compartments. Orthotopic tumors in C57Bl/6 mice were treated with intravesical adenoviral-IFN versus control, and PD1/PD-L1 status was assessed.
Results
Urothelial PD1 and PD-L1 status assessed on study-entry (Sin) and study-exit (Sout) TUR specimens were not associated with treatment response (all, p ≥0.26). Sin lymphocyte PD1+ was seen in 52% responders (R) and 57% nonresponders (NR) (p=0.72). Sin lymphocyte PD-L1+ was seen in 77% R and 92% NR (p=0.15). 62% NR had Sout lymphocyte PD1+ compared with 26% R (p=0.002). Sout lymphocyte PD-L1+ was also higher in NR compared with R (78% versus 50%, p=0.024). Differences in Sout lymphocyte positivity status between R and NR were evident as early as three months after therapy for PD1 (p=0.040) and PD-L1 (p=0.029). Co-expression assays on orthotopic bladder tumors showed PD1 overexpression on T lymphocytes in control mice compared with those that responded to intravesical adenoviral-IFN.
Conclusions
Nadofaragene NR patients had relative PD1/PD-L1 overexpression in tumor-infiltrating lymphocytes, although this was not seen at baseline. In vivo models replicated these findings. Taken together, this suggests a role for ICI in BCG-unresponsive NMIBC who may have partial or short-term response to nadofaragene.
Source of funding
FKD Therapies. Clinical trial # NCT02773849