WT1-pulsed dendritic cell vaccination for neovascular age-related macular degeneration: a phase I pilot feasibility study

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of vision loss. Although anti-VEGF therapy is effective, frequent injections carry risks and may not fully address the underlying disease process. Wilms' tumor gene 1 (WT1), an upstream regulator of VEGF, is expressed in choroidal neovascular membranes and may represent a biologically relevant adjunctive target in nAMD. This pilot study evaluated the safety, tolerability, and immunogenicity of WT1-targeted dendritic cell (WT1-DC) vaccines and their effects on retinal morphology and visual function in nAMD patients, with secondary endpoints including clinical outcomes and in vitro WT1-specific T-cell responses. METHODS: Two patients initially received three monthly intravitreal injections of aflibercept (2 mg each), followed by 15 subcutaneous vaccinations with WT1-DCs. The vaccine contained both WT1-specific helper and killer peptides restricted to HLA-A*24:02. In addition, a helper peptide restricted to MHC class II and class I (HLA-A*02:01/02:06) was used. RESULTS: WT1-DC vaccination was well tolerated, and adverse events were limited. One patient maintained a stable retinal morphology and visual acuity without additional anti-VEGF therapy, whereas the other experienced recurrent subretinal fluid accumulation requiring intermittent rescue injections and a gradual decline in best-corrected visual acuity. Peripheral blood mononuclear cells from both patients exhibited functional CD4 + and CD8 + T-cell responses during vaccination and produced IFN-γ and TNF-α upon WT1 peptide stimulation in vitro. CONCLUSIONS: WT1-DC vaccination was feasible and well tolerated in these two patients who were clinically managed within the nAMD spectrum. Exploratory laboratory findings suggested WT1 peptide-responsive T-cell activity in vitro, but clinically meaningful in vivo immunogenicity was not established. Given the extremely small sample size, the confounding effect of prior anti-VEGF loading therapy, and diagnostic uncertainty regarding CNV etiology in one patient, no conclusions regarding therapeutic efficacy can be drawn. These observations support further investigations of WT1-DC vaccination in larger controlled studies. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTc030210068), registered May 7, 2021.