The goal of this translational project is to optimize targeted T-cells with chimeric antigen receptors (CARs) for use in mesothelioma. CARs are now beginning to show activity in a number of pilot clinical trials, however two issues have emerged that provide a barrier to rapid progress in the field: 1) available preclinical models have not accurately predicted the safety of CARs, and unexpected toxicities from cytokine release and tissue damage has been reported in recent trials;2) high costs and long lead times required for vector production have slowed the clinical application of T cells expressing CARs, and prevent a facile and iterative approach to optimize CAR design and determine the optimal target structures on tumor cells. Our preliminary data establishes that T lymphocytes can be efficiently modified by mRNA electroporation without integration associated safety concerns, and that repeated infusions of
Malignant mesothelioma is increasing in prevalence and is currently considered incurable. This project is testing methods to modify lymphocytes so that they can kill tumors efficiently, safely, and specifically. The approach includes providing lymphocytes for a clinical trial, analyzing the trial and conducting new animal experiments to widen the number of targets attacked.
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