First-in-Human Regulatory T Cell-Derived Exosomes Plus Ranibizumab for Refractory nAMD

Persistent fluid despite intravitreal anti-vascular endothelial growth factor (VEGF) treatment remains common in neovascular age-related macular degeneration (nAMD). Regulatory T cell-derived exosomes (TregExo) have preclinical immunomodulatory activity. To evaluate the safety and maximum tolerated dose (MTD) of intravitreal autologous TregExo plus ranibizumab in refractory nAMD. Design, Setting, and Participants: Single-centre, prospective, open-label phase 1a trial using a 3+3 dose-escalation design at Hebei General Hospital. Four participants with persistent intraretinal or subretinal fluid despite at least 3 consecutive monthly intravitreal anti-VEGF injections were treated. One intravitreal injection of autologous TregExo (planned doses, 0.05, 0.5, or 1.5 mg) coformulated with ranibizumab, 0.5 mg. The primary outcome was safety and MTD determination. Dose-limiting toxicity (DLT) was prespecified as severe sterile intraocular inflammation, sustained intraocular pressure greater than 30 mm Hg, loss of more than 15 ETDRS points, or another serious ocular adverse event within 30 days. Exploratory visual and anatomic outcomes were assessed through day 90. Four participants were treated: 3 at 0.05 mg and 1 at 0.5 mg. No DLT or intraocular inflammation occurred in the 0.05-mg cohort, and intraocular pressure remained stable. Two low-dose participants improved from ETDRS scores of 3 and 9 at baseline to 35 at day 90; Patient 1 had a macular thickness reduction from 318.2 to 253.9 µm. The 0.5-mg participant developed sterile intraocular inflammation with vision loss and a large intraretinal cyst, which resolved after local corticosteroid therapy. Dose escalation was stopped, and 0.05 mg was the protocol-defined MTD. Intravitreal autologous TregExo plus ranibizumab had an identifiable dose ceiling: 0.05 mg was tolerated, whereas 0.5 mg was associated with DLT. Further controlled evaluation of lower-dose TregExo-based adjunctive therapy in refractory nAMD is warranted. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2500095798.