Convection-Enhanced Delivery of Tumor-Infiltrating Lymphocytes Enhances Intratumoral Distribution and Therapeutic Efficacy in an Orthotopic Rat Glioma Model.

Background: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) is a potential strategy for glioma treatment, but effective intracranial delivery remains a major obstacle. Convection-enhanced delivery (CED) may improve local parenchymal coverage by bypassing the blood-brain barrier and using pressure-driven interstitial transport. Methods: We evaluated whether CED could improve the early intracerebral distribution and antitumor activity of ex vivo-expanded TILs in an orthotopic rat C6 glioma model. Expanded TILs were characterized as a CD3-enriched lymphocyte product with inducible effector function against C6 glioma cells in vitro. TILs were administered as either Control-TILs by Hamilton syringe-based conventional intratumoral injection or CED-TILs by catheter-based CED infusion using matched cell dose, volume, infusion rate, target coordinates, and dwell time. Intracerebral CD3+ T-cell coverage, tumor progression, and overall survival were assessed. Short-term safety was evaluated in a separate cohort of naïve rats receiving CED-PBS or CED-TILs. Results: CED-TILs produced broader early intraparenchymal CD3+ T-cell coverage than Control-TILs, particularly at distal sampling sites from the infusion tract. Under this single-dose regimen, CED-TILs were associated with reduced tumor progression, decreased Ki67 expression, increased apoptosis-associated signaling, and prolonged survival. In the short-term naïve safety cohort, CED-TILs did not produce overt neurologic, histologic, hematologic, or systemic toxicity within the observation window. Conclusions: These findings support CED-TILs as an early proof-of-concept locoregional delivery strategy that improves early spatial CD3+ T-cell coverage and is associated with antitumor activity in a rat glioma model.