Fast Tumor-Infiltrating Lymphocytes (TILs) for Treatment of Metastatic Cancer with Malignant Pleural Effusion: Protocol for the Phase I Regional Immuno-oncology Trial (RIOT)-4

Malignant pleural effusions (MPE) are a manifestation of advanced malignancy associated with poor prognosis, limited survival, and significant symptom burden. Current management is largely palliative and focused on fluid control rather than disease-modifying regional therapy. Malignant pleural effusions frequently contain abundant pleural infiltrating T (PIT) cells, representing an accessible and clinically feasible starting material for rapid autologous adoptive cellular therapy (ACT). RIOT-4 is a single-center, Phase I translational feasibility and safety clinical trial evaluating intrapleural administration of a locally manufactured PIT-derived ACT product generated using a closed GMP-compliant CliniMACS Prodigy® platform. The primary objective is to evaluate the safety and feasibility of intrapleural administration of a locally manufactured Fast TIL product in combination with low-dose intrapleural interleukin-2 (IL-2). Secondary objectives include ACT product characterization, immune profiling of pleural fluid and peripheral blood, T cell receptor (TCR) repertoire dynamics, cytokine/secretome analysis, spatial immune mapping, and preliminary clinical response assessment. This trial leverages institutional GMP cellular therapy infrastructure to generate a rapid, autologous Fast TIL product from pleural effusion as a novel compartmental immunotherapy strategy for patients with malignant pleural disease.