Coupling Adoptive Cell Therapy with Boron Neutron Capture Therapy: Using Functional Tumor-Infiltrating Lymphocytes for Tumor Delivery of Boron Carbide Nanoparticles.

Abstract

Nanomedicine offers promising strategies for targeted drug delivery, imaging, and molecular-level therapies. However, the clinical translation of nanomedicine has often been hindered by the complex interactions of nanoparticles (NPs) with biological systems. This study investigates a cell-based delivery platform designed to overcome some of these limitations, using clinical-grade tumor-infiltrating lymphocytes (TILs) as biological carriers of boron carbide (B₄C) NPs in boron neutron capture therapy (BNCT). Biological vectors, such as TILs, could enable selective tumor targeting, leading to highly localized ¹⁰B levels and minimizing off-target accumulation. We evaluated the uptake and retention of composite Fe₂O₃-B₄C NPs (FeBNPs) using both immortalized Jurkat T cells and primary human TILs. Both cell types efficiently internalized FeBNPs without cytotoxic effects, maintained their functionalities, and retained the boron-rich NPs for up to 72 h. Imaging confirmed intracellular localization, and neutron autoradiography demonstrated that TILs accumulated sufficient ¹⁰B for therapeutic efficacy, eliminating the need for isotopically enriched compounds like L-4-boronophenylalanine (BPA) or sodium borocaptate (BSH). Coculture experiments with Jurkat and HeLa cells confirmed that lymphocyte-delivered boron could mediate localized radiation damage via neutron capture. These findings support the concept of TILs as "Trojan Horses" for boron delivery, allowing for overcoming traditional barriers in NP-based therapies and taking advantage of their innate tumor-homing ability. This approach not only enhances BNCT selectivity and efficacy but also supports the integration of nanomedicine with adoptive cell therapy in a combined cancer treatment framework.