CHANCELLOR'S PROFESSOR UCLA Los Angeles, California, United States
Introduction: : Invariant natural killer T (iNKT) cells are a unique T cell subset that bridges innate and adaptive immunity by recognizing lipid antigens via CD1d. Despite their rarity, iNKT cells exhibit rapid cytokine release and potent antitumor effects. Chimeric antigen receptor (CAR)-engineered iNKT (CAR-iNKT) cells enhance these capabilities by integrating tumor-targeting CARs with natural iNKT recognition pathways, enabling them to target tumors even in immunosuppressive microenvironments. Preclinical and clinical studies, including trials in neuroblastoma, demonstrate their efficacy and safety, showing reduced cytokine release syndrome compared to CAR-T cells. However, challenges remain for solid tumors due to poor trafficking and persistence. To address this, the iNKT-targeted Microparticle Recruitment and Activation System (iMRAS) was developed, integrating mechanical and chemical cues to recruit and activate CAR-iNKT cells. We hypothesize that iMRAS enhances the recruitment, activation, expansion, and persistence of CAR-iNKT cells for the therapy of solid tumors. By locally presenting CD1d ligands, cytokines, and biomimetic mechanical cues, iMRAS functions as an in vivo “charging station” that recruits, activates, and expands CAR-iNKT cells, overcoming barriers in trafficking and activation to improve antitumor efficacy.
Materials and
Methods: : iMRAS microparticles were generated using a PDMS microfluidic device fabricated via photolithography. An aqueous core containing alginate, PLGA nanoparticles, and Ca–EDTA was flowed through the device and sheared by an acidified oil phase, triggering alginate crosslinking to form uniform beads. These microparticles were tested in a human tumor xenograft model using NSG mice to evaluate their therapeutic efficacy.
Results, Conclusions, and Discussions:: Fluorescence imaging confirmed that iMRAS microparticles mimic APCs by displaying uniform CD1d and IL-15Rα on their surface, supporting effective CAR-iNKT cell activation. (Figure.1b) Quantification of BLI signals and tumor volume demonstrated enhanced iNKT cells recruitment in the iMRAS-treated group. (Figure.1c) In vivo bioluminescent imaging (BLI) showed that mice treated with CAR-iNKT with iMRAS exhibited significantly lower tumor burden compared to CAR-iNKT alone or vehicle groups.(Figure.1e) Notably, survival analysis revealed prolonged survival in CAR-iNKT + iMRAS mice, with complete survival through the study period, compared to rapid mortality in control groups. (Figure.1f) Together, results validate iMRAS as a potent immune-activating platform that enhances CAR-iNKT cell persistence, activation, and systemic tumor clearance, highlighting its therapeutic potential for solid tumor immunotherapy. The iMRAS system, functionalized with CD1d–αGC and IL-15Tx complexes to mimic antigen-presenting cells, represents a versatile biomimetic platform for enhancing CAR-iNKT therapy. Its modular design allows incorporation of cytokines (e.g., IL-21), chemokines (e.g., CCL3, CXCL16), or immune checkpoint inhibitors (e.g., anti-PD-1) to further boost immune activation, memory formation, and trafficking. Constructed from biocompatible, FDA-approved materials, iMRAS is safe for diverse anatomical sites. This enables its use in various cancer models, including glioblastoma and hepatocellular carcinoma. When injected in situ, iMRAS can serve as a localized immune activator and drug delivery depot, expanding its potential as a powerful tool in solid tumor immunotherapy.
