361 Early differentiation and memory transcription programs drive long-term persistence of NY-ESO-1 specific TCR-T cells in adoptive cell therapy
Bibliographic record
Abstract
<h3>Background</h3> Adoptive transfer of T cell receptor gene-engineered T (TCR-T) cells can induce durable anti-cancer responses. TBI-1301 is a novel gene therapy produced by engineering autologous lymphocytes to express an NY-ESO-1-specific TCR using a retrovirus vector encoding siRNA to silence endogenous TCR. In this study, we characterize long-lived persisting transferred TBI-1301 TCR-T cells following adoptive transfer at the single-cell level. <h3>Methods</h3> Patients eligible for the approved study (UHN REB 15-9534) included those with informed consent, HLA-A*02:01 or A*02:06 haplotype, and NY-ESO-1 expression by IHC. PBMCs were harvested and processed to generate engineered TBI-1301 TCR-T cells. Patients received an infusion of 5x10<sup>9</sup> cells on day 0 after lymphodepletion with cyclophosphamide (CY) alone (750 mg/m<sup>2</sup> on day -7 and -6) or in combination with fludarabine (FLU) (30 mg/m<sup>2</sup> on day -7 and -6). Endpoints included safety, efficacy, and biological correlates for persistence of TCR-T cells post-infusion. The TBI-1301 infusion product and persisting TBI-1301 TCR-T cells were assessed by multi-parameter flow cytometry, single-cell RNA and TCR sequencing analysis. <h3>Results</h3> Clinical activity of TBI-1301 has previously been described. In the CY only cohort, 5/9 experienced grade 1–2 CRS, and, for the CY/FLU cohort, 3/5 patients experienced grade 2 CRS. The RECIST response rate in synovial sarcoma patients, whose tumors express high levels of NY-ESO-1, was 28.6%. In patients receiving CY alone, persistence beyond 100 days was detected in 3 patients at low levels (0.03–0.05% of CD8 T cells). In contrast, higher levels of persistence (5.6–7.7% of CD8 T cells) were observed in 2 patients receiving CY/FLU. Long-lived TBI-1301 cells exhibited a naïve/memory phenotype expressing CD45RA and CCR7. Single cell RNA sequencing analysis enabled the tracking of the infused TBI-1301 T cells from day 0 to day 125, including clonotypic cells sharing the same TCR sequences. UMAP visualization revealed that persisting TCR-T are distinct from infused cells, with higher expression of TCF7, LEF1, and CCR7 in both peripheral CD8+ and CD4+ TCR-T cells. In CD8+ T cells on day 125, differentiation trajectories of endogenous and TCR-T cells were recapitulated using potential of heat diffusion for affinity-based transition embedding (PHATE) and Slingshot pseudotime. Single-cell gene signature scoring revealed that TCR-T cells were enriched with a Tstem gene signature, whereas endogenous T cells exhibited a Tpex gene signature. <h3>Conclusions</h3> These data demonstrate sustained persistence of infused TBI-1301 T cells. Understanding the cell states of persisting TCR-T cells provides valuable insights for developing combination approaches to enhance the efficacy of new therapeutics. <h3>Trial Registration</h3> ClinicalTrials. gov NCT02869217. <h3>Ethics Approval</h3> Subjects underwent informed consent to a University Health Network Research Ethics Board protocol, UHN REB # 15-9534.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".