The addition of fludarabine to cyclophosphamide for lymphodepleting chemotherapy enhances the persistence of infused NY-ESO-1 TCR anticancer therapy TBI-1301.

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.