QIMR Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute

Author Of 2 Presentations

Biomarkers and Bioinformatics Poster 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)

Speakers
Presentation Number
P0084
Presentation Topic
Biomarkers and Bioinformatics

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.

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Clinical Trials Poster Presentation

P0226 - Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive forms of multiple sclerosis (ID 1635)

Speakers
Presentation Number
P0226
Presentation Topic
Clinical Trials

Abstract

Background

Epstein-Barr virus (EBV) is a necessary risk factor for the development of multiple sclerosis (MS) [Abrahamyan S et al. JNNP 2020; Pakpoor J et al. Mult Scler 2012]. Early experience with autologous EBV-specific T-cell adoptive immunotherapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018].

Objectives

This Phase I study evaluated the safety and potential efficacy of off-the-shelf, allogeneic EBV-targeted T-cell therapy (ATA188) in adults with progressive forms of MS (NCT03283826).

Methods

In part 1, four cohorts received escalating doses of ATA188 to determine the recommended part 2 dose (RP2D). Patients (pts) were followed for 1-year and given the option to participate in a 4-year open label extension (OLE) at the RP2D (cohort 3 dose). In addition to safety, sustained disability improvement (SDI) was assessed, defined as improvement in Expanded Disability Status Scale (EDSS) or Timed 25-Foot Walk (T25FW) at ≥2 consecutive time points [Pender MP et al. EAN 2020; LB130]. Other measures evaluated include Fatigue Severity Scale (FSS), 12-item MS Walking Scale (MSWS-12), MS Impact Scale-29 (physical; MSIS-29), and whole brain volume (via magnetic resonance imaging [MRI]). As of August 2020, we expect 12-month (m) data for all 4 cohorts, which marks the end of the dose finding portion of this study, will be available for presentation.

Results

As of April 2020, 25 pts had received ≥1 dose of ATA188. No grade >3 events, dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion reactions were observed. Two treatment-emergent serious adverse events were reported: muscle spasticity (grade 2; not treatment related) and MS relapse (grade 3; possibly treatment related). Efficacy endpoints were assessed in cohorts 1–4 (n=24) at 6m and in cohorts 1–3 (n=17) at 12m. Six pts met SDI criteria at 6m and 5 pts met it at 12m, which was driven by EDSS in all but 2 pts at both 6 and 12m. At both timepoints, a higher proportion of pts showed SDI with increasing dose. In cohorts 1–3, all pts with SDI at 6m maintained it through 12m. Pts with SDI (vs those without) tended to have greater improvements in FSS, MSWS-12, and MSIS-29 (physical) scores, as well as less reduction in whole brain volume on MRI, from baseline to 12m. As of June 2020, OLE data from the 15m timepoint were available for 4 pts; 3 had SDI at 6m and 12m which was maintained at 15m.

Conclusions

Preliminary data indicate ATA188 is well tolerated. A higher proportion of pts showed sustained disability improvement (SDI) with increasing dose. Pts who achieved SDI at any timepoint maintained it at all future timepoints and tended to show improvements in fatigue, physical function, and MRI whole brain volume at 12m. Based on these data, part 2 of the study (randomized placebo-controlled portion) has been initiated using the cohort 3 dose.

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