|
| Status |
Public on Apr 15, 2024 |
| Title |
Response to Treg therapy is linked to rate of ex vivo Treg expansion |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Background: CD4+CD25hiCD127lo/-FOXP3+ regulatory T cells (Tregs) play a key role in preventing autoimmunity. In type 1 diabetes, adoptive transfer of autologous polyclonal Tregs has been shown to be safe in adults in Phase I clinical trials. Methods: We explore factors contributing to efficacy in autologous polyclonal expanded Tregs (expTregs) Phase 2 clinical trial in 111 children and adolescents with new-onset type 1 diabetes (Sanford/Lisata Therapeutics Trex Phase 2 clinical trial) randomized 1:1:1 high and low treatment to placebo. Cytometry, bulk and single cell RNA-seq were perfomed on selected expTregs and PBMC samples from subjects. Results: A single dose of expTreg therapy (1-24x106cells/kg) was safe but did not prevent the decline in residual beta cell function over one year compared to placebo (p=0.39), regardless of age, baseline C-peptide, or dose of expTregs. ExpTregs were highly activated and suppressive, and a transient increase of activated memory Tregs was detectable one week after infusion in the high dose cohort, suggesting effective transfer of expTregs. However, in vitro fold expansion on expTregs varied across subjects even when accounting for age. Lower fold expansion and its’ associated gene signature was linked with better outcome, regardless of Treg dose. Conclusion: These results suggest that expTregs quantity alone does not alter outcome; instead, expTreg quality may be an important factor contributing to the efficacy of adoptive Treg therapy to prevent type 1 diabetes progression.
|
| |
|
| Overall design |
Children and adolescents with recent-onset T1D aged 8 to <18 years (mean 13.66 ±2.52 SD) were enrolled in this study. Tregs sorted from PBMC samples from 14 placebo and 19 Treg-treated patients were taken for bulk RNA-Sequencing at 6 time points (or fewer, depending on sample availability) before and after treatment. 17 of 19 of those treated with Tregs also had samples containing sorted expanded Tregs generated for infusion. C-peptide response and Treg fold-expansion were also measured for these patients.
|
| |
|
| Contributor(s) |
Bender C, Wiedeman A, Hu A, Ylescupidez A, Sietsema WK, Griffen K, Gitelman S, Long A |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Sep 14, 2023 |
| Last update date |
Apr 15, 2024 |
| Contact name |
Stephanie Osmond |
| E-mail(s) |
sosmond@benaroyaresearch.org
|
| Organization name |
Benaroya Research Institute
|
| Street address |
1201 9th Ave
|
| City |
Seattle, |
| State/province |
WA |
| ZIP/Postal code |
98101 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (105)
|
|
| This SubSeries is part of SuperSeries: |
| GSE243278 |
A phase II randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes |
|
| Relations |
| BioProject |
PRJNA1017505 |
Less...
More...