Background: NY-ESO-1c259T-cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 (SPEAR T-cells) are being studied in an ongoing multi-cohort clinical trial in synovial sarcoma (NCT01343043). We compared safety, efficacy and cell persistence between two cohorts using different doses of lymphodepleting chemotherapy. Methods: There are four cohorts separated by differing antigen expression levels and lymphodepletion regimens, and this assessment compares cohorts 1 (closed) and 4 (ongoing). In both, ≥50% patient tumor cells expressed NY-ESO-1 at 2+/3+ levels by immunohistochemistry. Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion in cohort 1 consists of fludarabine 30 mg/m2/d × 4 d and cyclophosphamide 1800 mg/m2/d × 2d, and in cohort 4 consists of fludarabine 30 mg/m2/d × 3d and cyclophosphamide 600 mg/m2/d × 3d. Target dose is 1–6 × 109 transduced cells. Disease is assessed at weeks 4, 8 and 12 and every 3 months until disease progression. Results: 12 patients were treated in cohort 1 and 14 patients in cohort 4 (as of 23Nov17). Median transduced cell dose was 3.6 × 109 cells in cohort 1 and 2.6 × 109 cells in cohort 4. Treatment-related adverse events (AEs) were observed in 100% of patients in cohort 1 and 86% in cohort 4; related serious adverse events (SAEs) were reported in 50% of cohort 1 and 14% of cohort 4. There were no fatal AEs. Overall response rate (ORR) in cohort 4 is 29% vs 50% in cohort 1, and duration of response is in cohort 4 is 16 weeks vs 31 weeks in cohort 1. The best overall response of stable is 50% in cohort 1 and 64% in cohort 4. Median peak expansion of transduced T-cells in peripheral blood in responders is lower in cohort 4 (40,137 copies/μg DNA) vs cohort 1 (106,174 copies/μg DNA). Median absolute lymphocyte counts following lymphodepletion were 1×107/L (range 0-3) in cohort 1 and 9×107/L (0-40) in cohort 4. Conclusions: The greater ORR and higher peak expansion in cohort 1 may be attributable to the dose intensity of the lymphodepleting regimen. Although related SAEs were reported in a higher proportion in cohort 1 than 4, the safety and tolerability are acceptable in both, and cell doses were similar. The data and overall benefit:risk considerations support utilizing higher doses of preconditioning chemotherapy in future trials.

Citation Format: Sandra P. D'Angelo, Dejka Araujo, Brian Van Tine, George Demetri, Mihaela Dutra, John Glod, Warren Chow, Stephen Grupp, Alibiruni Abdul Razak, William Tap, Breelyn Wilky, Erin Van Winkle, Elliott Norry, Samik Basu, Karen Chagin, Malini Iyengar, Trupti Trivedi, Rafael Amado, Crystal Mackall. Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A007.