T-Cell Therapy With Fludarabine Active in Synovial Sarcoma

NY-ESO-1 SPEAR T-cell therapy showed promising results and was reasonably safe in patients with synovial sarcoma, according to a new study. The use of multiple cohorts with variations on the treatment showed that the addition of fludarabine may be important to achieving those positive results.

Outcomes are generally poor with synovial sarcoma, “highlighting the need for more novel and effective therapies,” said Sandra P. D’Angelo, MD, of Memorial Sloan Kettering Cancer Center in New York. She presented results of a study of specific peptide enhanced affinity receptor (SPEAR) T cells that recognize an NY-ESO-1 derived peptide at the Connective Tissue Oncology Society (CTOS) 2017 Annual Meeting, held November 8–11 in Wailea, Hawaii.

The treatment involves the harvesting of lymphocytes by leukapheresis; the cells are then isolated, activated, transduced in order to express NY-ESO-1c259T, and expanded before being infused following lymphodepletion. The study included 46 patients across four cohorts with different lymphodepletion regimens. Patients in cohort 1 had high NY-ESO-1 expression, and received fludarabine and cyclophosphamide; cohort 2 had low expression and received the same regimen. Cohort 3 had high expression of NY-ESO-1 and received only cyclophosphamide, while cohort 4 had high expression and received fludarabine plus a lower dose of cyclophosphamide.

A total of 37 of the 46 patients received cell infusion. The median age across the cohorts was 33 years, and most patients had received at least two prior lines of chemotherapy. The median number of transduced cells was 2.7 × 10⁹.

The response rate (confirmed complete response plus partial responses) was 50% in cohort 1, with one complete response and five partial responses, as well as six patients with stable disease. The rate was poorer in the low-expression cohort 2, at 22%. Only one response was seen in cohort 3, where fludarabine was not used, for a response rate of 20%. Cohort 4 had three partial responses, for a rate of 27%.

The median response duration was 30.9 weeks in cohort 1, compared with only 8.4 weeks in cohort 2. In cohort 3 it was 32 weeks, and in cohort 4 it was 14 weeks. The median progression-free survival was 15 weeks in cohort 1, 13 weeks in cohort 2, 12 weeks in cohort 3, and 23 weeks in cohort 4.

“All patients experienced adverse events, and all were treatment-related,” D’Angelo said. Among the grade 3 or higher adverse events seen in more than 10% of patients were leucopenia, lymphopenia, neutropenia, anemia, and thrombocytopenia. Cytokine release syndrome was reported in 16 patients, and 4 were grade 3 or higher. All events resolved with supportive care.

“Fludarabine appears to be required for optimal efficacy,” D’Angelo said, adding that one challenge moving ahead is to find the most appropriate chemotherapy regimen to go along with infused T cells. “There are ongoing efforts to understand mechanisms of resistance, as well as sensitivity,” she concluded.