Abstract 4291: Synecta™ T1 cell-derived nanoparticles enable accelerated, potent T cell expansion for scalable adoptive immunotherapy manufacturing

Abstract Background: While Adoptive immunotherapies are expanding clinically, their translation is limited by the lack of scalable, standardized manufacturing. Critical attributes, including T-cell activation and expansion, directly impact yield and product quality. Synecta is a cell-derived nanoparticle (CDNP) platform designed to drive rapid T-cell expansion while streamlining manufacturing. Synecta T1 incorporates membrane-bound stimulatory signals (OKT3-scFv, CD86, 4-1BBL) and cytokines (IL-7, IL-15Rα/IL-15), enabling potent activation and accelerated expansion Methods: T cells from healthy donor (HD) and patient (PT) samples were isolated, activated, transduced, and expanded using Synecta T1 or a comparator activation system. T-cell functionality was assessed using cytotoxicity assays and repeated antigen-exposure models. Mechanistic studies included CTV proliferation, evaluation of proliferation markers, and inhibitory assays targeting immune-synapse formation. High-resolution live-cell imaging using super-resolution confocal and lattice light-sheet microscopy was used to visualize synapse architecture. Metabolic profiling was performed using Seahorse assays. Results: Synecta T1-expanded HD and PT T cells exhibited rapid activation (>80% CD69/CD25 by Day 2) and accelerated expansion (2.2-fold HD, 1.4-fold PT samples by Day 3) while maintaining functional fitness under repeated antigen exposure. Rapid T cell expansion, directed by Synecta T1, correlates with early proliferation, as indicated by Cell Trace Violet dilution and the upregulation of proliferation markers.CDNPs express ICAM-1, a crucial adhesion molecule that stabilizes the interaction between Antigen-Presenting Cells (APCs) and T cells via LFA-1. Inhibition of ICAM-1/LFA-1 interaction with small molecules impaired the effective engagement between Synecta and T cells, suggesting that CDNPs' enhanced performance could stem from their ability to mimic the immune synapse. In fact, high-resolution live-cell imaging of CDNP-T cell interactions using F-actin and tubulin probes revealed the assembly and maturation of immune synapses, highlighted by the development of the peripheral supramolecular activation cluster (pSMAC) and the polarized translocation of the Microtubule-Organizing Center (MTOC) toward the CDNP interface. Furthermore, Seahorse analysis revealed that Synecta T1-expanded T cells rely less on glycolysis and more on oxidative phosphorylation, indicating metabolically efficient T cell products with a memory phenotype. Conclusions: Synecta is a first-of-its-kind ancillary material for adoptive cell therapies, enabling simpler, cost-effective manufacturing processes. This CDNP technology facilitates faster and simpler cell therapy manufacturing, consistently delivering cells with the desired attributes and yields. Citation Format: Deeksha Muthumani, Chiquita Hanindya, Gil Joseph, Victor Carpio, Bakir Valentić, Roddy O' Connor, Olga Barreiro, Ulrich H. Von Andrian, Peter Keller. Synecta™ T1 cell-derived nanoparticles enable accelerated, potent T cell expansion for scalable adoptive immunotherapy manufacturing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4291.