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.
Adoptive immunotherapy is emerging as a powerful approach to treatment of cancer and other diseases. The proposed project seeks to improve this cellular therapy by developing a bioreactor system that provide more cells and with better control over the types of cells that are produced. Incorporation of the envisioned system into current immunotherapy protocols could enhance the efficacy and availability of these treatments.
|Nataraj, Neha M; Dang, Alex P; Kam, Lance C et al. (2018) Ex vivo induction of regulatory T cells from conventional CD4+ T cells is sensitive to substrate rigidity. J Biomed Mater Res A 106:3001-3008|
|Jin, Weiyang; Black, Charles T; Kam, Lance C et al. (2017) Probing Synaptic Biomechanics Using Micropillar Arrays. Methods Mol Biol 1584:333-346|
|Lambert, Lester H; Goebrecht, Geraldine K E; De Leo, Sarah E et al. (2017) Improving T Cell Expansion with a Soft Touch. Nano Lett 17:821-826|