The addition of fludarabine to cyclophosphamide for lymphodepleting chemotherapy enhances the persistence of infused NY-ESO-1 TCR anticancer therapy TBI-1301.
Bibliographic record
Abstract
2539 Background: Adoptive transfer of T cell receptor (TCR) gene-engineered 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 that encodes siRNA to silence endogenous TCR. In this study, we examined a repeat infusion of TBI-1301 and the addition of fludarabine to cyclophosphamide for pre-infusion lymphodepletion. Methods: Eligibility included informed consent, HLA-A*02:01 or A*02:06 haplotype, and NY-ESO-1 expression by IHC. Eligible patients underwent harvest of PBMC which were processed at the treating site to generate engineered TBI-1301 cells. The study design infused 5x109 cells on day 0 and day 14 to patients following lymphodepletion with cyclophosphamide (CY; 750 mg/m2 on day -7 and -6) plus fludarabine (FLU; 30 mg/m2 on day -7 and -6). Repeat infusions were performed in two cohorts: Cohort B - patients who had previously received NY-ESO-1 TCR-transduced cells and Cohort C - NY-ESO-1 TCR treatment naïve patients. Endpoints included safety, efficacy, and biological correlates for persistence of NY-ESO-1-specific T cells post infusion. Results: Ten patients were enrolled in cohorts B and C. Nine patients in total are evaluable for response and toxicity, and no DLTs have been observed. In cohort B, 5 patients (5 synovial sarcoma) were treated, and 5 have received the target dose. In cohort C, 5 patients (3 synovial sarcoma, 2 melanoma) were treated, and 4 have received the target dose. One patient received a single infusion due to bacteremia on week 2. One of 5 patients in cohort B was previously treated with TBI-1301 cells in cohort C. In each cohort, 4 patients experienced grade 1-2 cytokine release syndrome. Best overall response by RECIST v1.1 was 3 stable disease, and 2 progressive disease in cohort B; and 2 stable disease and 2 progressive disease in cohort C. When compared to the earlier cohort, biomarker analysis demonstrated substantially longer persistence of transferred TBI-1301 cells in infused patients who received fludarabine (up to 372+ and 460+ days), and the cells displayed a less differentiated phenotype. Conclusions: Repeat infusions of TBI-1301 following lymphodepletion appears to be safe and to possess anti-tumor activity. Addition of FLU to the lymphodepletion regimen may contribute to longer persistence of gene-engineered T cells. Clinical trial information: NCT02869217.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".