Woman forced to have three embryos implanted is allowed fetal reduction to save her life
Authors: Sophie Arie
Journal: BMJ (2004)

<h3>Objective:</h3> To characterize activation gene signatures and T-Cell Receptor (TCR) repertoire of ATA188 allogeneic EBV-specific T cells. <h3>Background:</h3> Accumulating evidence indicates that Epstein-Barr virus (EBV) is implicated in the development of MS. We have developed a novel allogeneic T-cell therapy targeting EBV-encoded antigens, ATA188, that has shown safety and initial efficacy in Progressive MS patients (NCT03283826). Transcriptional and TCR-repertoire profiling of ATA188 T cells was employed to delineate activated gene sets, molecular signatures and underlying functional pathways associated with effector cell function and therapeutic potential. <h3>Design/Methods:</h3> 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. Additionally, deep TCRβ chain sequencing (TCR-seq) was conducted to define TCR clonal diversity and identity in ATA188 cells. <h3>Results:</h3> Despite being derived from unrelated healthy donors, the ATA188 T cells showed considerable concordance in expression profiles (Spearman&gt;0.80; p&lt;E-10) within the resting and activated states. In total, significantly differentially expressed genes (fold change&gt;1.5, p&lt;0.01) were identified, representing a distinct activation signature for ATA188 cells. The activated states in-part identified upregulation of IL-2, IFNG, XCL1<i>, CCL4, CSF2, TNFRSF9</i>, and downregulation of <i>KLF2</i>. These were consistent with activation (p&lt;E-05) 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. <h3>Conclusions:</h3> 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 combined analyses of T cells comprising ATA188 are consistent with its proposed mechanism of targeting EBV infected B cells by recognizing MS-relevant EBV antigens on these cells via defined TCRs. <b>Disclosure:</b> Dr. Foubert has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Atara Biotherapeutics. Dr. Foubert holds stock and/or stock options in Atara Biotherapeutics which sponsored research in which Dr. Foubert was involved as an investigator. Dr. Foubert has received research support from Atara Biotherapeutics. Dr. Srihari has received research support from Atara Biotherapeutics. Dr. Le Texier has received research support from Atara Biotherapeutics. Dr. Shen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Atara Biotherapeutics. Dr. Shen holds stock and/or stock options in Atara Biotherapeutics which sponsored research in which Dr. Shen was involved as an investigator. Dr. Shen has received research support from Atara Biotherapeutics. Dr. Forozan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Atara Biotherapeutics. Dr. Forozan holds stock and/or stock options in Atara Biotherapeutics which sponsored research in which Dr. Forozan was involved as an investigator. Dr. Forozan has received research support from Atara Biotherapeutics. Dr. Smith has received research support from Atara Biotherapeutics. Dr. Khanna has received royalty, license fees, or contractual rights payments from Atara Biotherapeutics. Dr. Khanna holds stock and/or stock options in Atara Biotherapeutics which sponsored research in which Dr. Khanna was involved as an investigator. Dr. Khanna has received research support from Atara Biotherapeutics. Dr. Aftab has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Atara Biotherapeutics. Dr. Aftab has received royalty, license fees, or contractual rights payments from Atara Biotherapeutics. Dr. Aftab holds stock and/or stock options in Atara Biotherapeutics which sponsored research in which Dr. Aftab was involved as an investigator.