Background Skin cancers are common post-transplant malignancies in stem cell transplant (SCT) and solid organ transplant (SOT) recipients. The use of immune checkpoint inhibitors has improved outcomes in the general patient population but is associated with a high risk of allograft rejection in transplant recipients. RP1 is an oncolytic immunotherapy that expresses a fusogenic glycoprotein (GALV-GP-R−) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The purpose of this study is to assess the safety and efficacy of single-agent RP1 in SCT/SOT recipients with skin cancer.

Methods The trial will enroll up to 65 transplant recipients with histologically confirmed recurrent and/or locally advanced cutaneous squamous cell carcinoma (CSCC) and up to 10 patients with non-CSCC skin cancer in two parts. Part A will enroll kidney and liver transplant recipients until safety is established, and Part B will also enroll other transplant types. Patients must have stable allograft function, and ECOG performance status ≤1. Patients with visceral metastases are excluded. Patients receive an initial RP1 dose at 1 x 10⁶ plaque-forming units (PFU)/mL followed by 1 x 10⁷ PFU/mL after 2 weeks and continuing every 2 weeks until prespecified study endpoints are met. Tumor biopsies are collected for biomarker analyses and HSV-1 serostatus is monitored.

Results Part A of the trial enrolled 13 kidney transplant patients (median age: 68 [range 57–81] years). The most common (>20%) treatment-emergent adverse events (TEAEs) were fatigue (46%); pyrexia (38%); chills (31%); and injection site pain, nausea, urinary tract infection, and vomiting (23% each). No immune-mediated adverse events (irAEs) or evidence of allograft rejection were observed. One patient died of COVID-19-related pneumonia, 1 from progressive disease, and 1 from cerebrovascular accident. The preliminary objective response rate (ORR) for the 11 evaluable patients was 27% (3/11; all confirmed complete response [CR]). One patient (9%) had stable disease. Immunohistochemistry from tumor biopsies indicated influx of CD8+ T cells and upregulation of PD-L1 expression upon RP1 post-treatment. Additional biomarker data from gene expression analysis will be presented.

Conclusions This is the first trial assessing single-agent RP1 activity in SCT/SOT patients. RP1 monotherapy showed compelling antitumor activity (ORR 27%; all CR) in evaluable patients from Part A of the study. No irAEs and/or evidence of allograft rejection were observed. RP1 monotherapy was well tolerated, and the safety profile was similar to non-immunocompromised patients with advanced skin cancers (IGNYTE study). Enrollment has now been expanded to include patients with non-kidney/liver transplants.

Trial Registration Clinicaltrials.gov; NCT04349436

Ethics Approval The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and was approved by the Institutional Review Board/Ethics Committee at each participating site. Written informed consent was obtained from all patients prior to the conduct of any study-related procedures.