Advanced Rigidity-based Material for Enhanced Immunotherapy

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DESCRIPTION (provided by applicant): The adaptive immune system is a powerful platform for development of targeted, robust, and persistent treatment of a range of diseases. A central step in many forms of adoptive T cell immunotherapy is the ex vivo expansion of a starting population of T cells. This project focuses on development of a new cell culture platform that will enhance the process of T cell expansion, leveraging the recent discovery that T cells are sensitive to the mechanical rigidity of the material presenting activating antibodies to CD3 and CD28, which provide antigenic and costimulatory signals, respectively. Specifically, T cell proliferation and retention of CD62L increased with decreasing stiffness of the support material. The goal of this proposed work is to transform the planar polydimethylsiloxane (PDMS) elastomer platform used in those initial studies into a system more compatible with contemporary T cell expansion; this is currently carried out using a polymer bead format to induce T cell activation. Specifically, we propose to develop, under the PAR-13-137 BRG program, a fiber-based format for PDMS that will offer enhances surface area for T cell stimulation in a compact volume that is also easy to incorporate into existing bioreactor systems. These studies are organized into three complementary Specific Aims: SA1) develop PDMS fibers into a cell culture format through the use of electrospinning, SA2) develop a chemical system for covalent immobilization of activating biomolecules onto the PDMS fibers, which would address anticipated regulatory and handling challenges, and SA3) determine the fiber morphologies and compositions that provide the best control over the number and phenotypic profile of cells generated using this platform. Successful completion of these studies will provide key information required for subsequent animal studies testing the safety and efficacy of T cells expanded using this platform.