Author Of 1 Presentation
P0084 - Gene expression profiling and TCR diversity of ATA188, an off-the-shelf, allogeneic EBV-targeted T-cell immunotherapy for progressive MS (ID 1770)
Abstract
Background
There is increasing evidence that infection with the Epstein-Barr virus (EBV) plays a role in the development and pathogenesis of multiple sclerosis (MS) [Abrahamyan S et al. JNNP 2020; Pakpoor J, et al. Mult Scler 2012]. We have developed a novel allogeneic T cell therapy targeting EBV-encoded antigens, ATA188. Preliminary data from a phase 1 study (NCT03283826) suggests ATA188 is well tolerated and has shown initial efficacy in patients with progressive forms of MS [Pender MP et al. EAN 2020; LB130].
Objectives
The goal of this study was to characterize ATA188 allogeneic EBV-targeted T cells to delineate activated gene sets, molecular signatures and underlying functional pathways associated with effector cell function and therapeutic potential.
Methods
ATA188 T cells were profiled with a curated 326-gene panel using the NanoString nCounter® platform. Total RNA from control and antigen-activated EBV-specific CD8+ T cells were sorted following EBV stimulation, sequenced, and analyzed. Individual genes differentially expressed were identified and further subjected to enrichment analyses. Furthermore, deep TCRβ chain sequencing (TCR-seq) was conducted to define TCR clonal diversity and identity in ATA188 cells.
Results
Despite being derived from unrelated healthy donors, the ATA188 T cells showed considerable concordance in expression profiles (Spearman>0.80; p<E-10) within the control and activated states. Significantly differentially expressed genes (fold change>1.5, p<0.01) were identified, representing a distinct activation signature for ATA188 cells. The activated states were associated with upregulation of IL-2, IFNG, XCL1, CCL4, CSF2, TNFRSF9, and downregulation of KLF2. These patterns were consistent with activation of cytokine-receptor, JAK-STAT, T-cell receptor, and chemokine signaling pathways. Finally, TCR-seq analysis showed that ATA188 cells contain varying EBV-specific TCR clonotypes associated with specific restriction through one or more HLA alleles.
Conclusions
Transcriptional and TCR repertoire profiling of ATA188 revealed T-cell-intrinsic signatures and clonotypes associated with defined EBV-specific TCR repertoire, EBV-specific T-cell activation, and functional signaling pathways. These data are consistent with the proposed mechanism of action of ATA188 targeting EBV infected B cells by recognizing EBV antigens presented by defined TCRs.