Cytometric analysis of T cell phenotype using cytokine profiling for
improved manufacturing of an EBV-specific T cell therapy.
Abstract
Adoptive immunotherapy using Epstein-Barr Virus (EBV)-specific T cells
is a potentially curative treatment for patients with EBV-related
malignancies where other clinical options have proved ineffective. We
describe improved GMP-compliant culture and analysis processes for
conventional lymphoblastoid cell line (LCL)-driven EBV-specific T cell
manufacture, and describe an improved phenotyping approach for analyzing
T cell products. We optimized the current LCL-mediated clinical
manufacture of EBV-specific T cells to establish an improved process
using xenoprotein-free GMP-compliant reagents throughout, and compared
resulting products with our previous banked T cell clinical therapy. We
assessed effects of changes to LCL: T cell ratio in T cell expansion,
and developed a robust flow cytometric marker panel covering T cell
memory, activation, differentiation and intracellular cytokine release
to characterize T cells more effectively. These data were analyzed using
t-Stochastic Neighbour Embedding (t-SNE) algorithm. The optimized
GMP-compliant process resulted in reduced cell processing time and
improved retention and expansion of central memory T cells.
Multi-parameter flow cytometry determined the optimal protocol for LCL
stimulation and expansion of T cells and demonstrated that cytokine
profiling using IL-2, TNF-α and IFN-γ was able to determine the
differentiation status of T cells throughout culture and in the final
product. We show that fully GMP-compliant closed-process culture of
LCL-mediated EBV-specific T cells is feasible and profiling of T cells
through cytokine expression gives improved characterization of start
material, in-process culture conditions and final product. Visualization
of the complex multi-parameter flow cytometric data can be simplified
using t-SNE analysis.