Implantable Sponges for Potent and Persistent CAR T Cell Therapy Against Solid Tumors
Year: 2026
Type: other
Abstract: Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized the treatment of hematological cancers, with durable complete remissions in some patients. However, CAR T cell therapy is limited by excessive ex vivo production which increases costs, limits patients’ access, and produces cells with poor long-term persistence and in vivo expansion. These limitations are especially critical in solid tumors, where hypoxia and the immunosuppressive tumor microenvironment alter CAR T cell metabolism and promote CAR T cell exhaustion. Herein, we propose to use implantable macroporous scaffolds (DryDux) to enhance in vivo CAR T cell persistence and improve CAR T cell therapeutic efficacy against pancreatic tumors. DryDux scaffolds are seeded with T cells and immediately implanted, transducing >80% of T cells through a newly described mechanism: viral particles and cells flow through the pores during liquid absorption into the scaffold, causing high rates of cell/virus collision and binding. DryDux scaffolds incorporate sustained-release interleukin to nurture and expand the generated CAR T cells in vivo, slowly releasing high numbers of highly functional CAR T cells. The sustained CAR T cell release reduces systemic side effects and led to complete tumor eradication in mouse models of intraperitoneal ovarian cancer, metastatic lung cancer, and orthotopic pancreatic cancer at doses where conventional CAR T cells failed. While mice treated with conventional CAR T cells had undetectable CAR T cell levels after day 30, DryDux-treated mice remained tumor-free for more than 120 days and CAR T cells were detectable throughout these >120 day studies, maintaining memory phenotypes. In addition to the dramatic improvements in efficacy against solid tumors in orthotopic animal models, DryDux scaffolds streamline CAR T cell manufacturing. DryDux scaffolds promote cell expansion inside the patient, reducing the time, labor, and cost of producing CAR T cells from 14 days to 3 days, and potentially reducing per-patient manufacturing costs. DryDux has the potential to transform CAR T cell therapy by producing highly functional and persistent CAR T cells without elaborate manufacturing, enhancing patient access to this revolutionary, but costly, therapy. In this proposal, we seek to further develop DryDux scaffolds for CAR T cell manufacturing using the validated, tumor-specific B7-H3 antigen as our model target. We will first optimize cytokine formulations and characterize release kinetics (Aim 1), then evaluate scaffold placement and CAR T cell persistence in orthotopic tumor models (Aim 2), and finally assess safety and biocompatibility in immunocompetent mice (Aim 3). These studies will establish DryDux as a translatable platform that generates highly persistent CAR T cells in vivo within days rather than weeks. DryDux addresses both the manufacturing bottleneck and cellular exhaustion that currently limit CAR T therapy against solid tumors, potentially expanding treatment to the 90% of cancer patients whose tumors remain refractory to current approaches.
Source: California Digital Library
DOI: 10.48321/d18edac7e5
Author: Yevgeny Brudno
Institution: University of North Carolina at Chapel Hill
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W7166876959