Treatment strategies for advanced synovial sarcoma: from chemotherapy to TCR-engineered T-cell therapy.

Abstract

Synovial sarcoma (SS) is the most common soft tissue sarcoma in children and adolescents. Despite the availability of new agents such as pazopanib and trabectedin, the prognosis after recurrence remains poor. Adoptive cell therapy is an emerging therapeutic strategy based on the modulation, manipulation, and selection of autologous T-cells in vitro to overcome immune system tolerance to tumor cells. Cancer-testis antigens are particularly attractive targets for immune therapy because male germ cells lack human leukocyte antigen class I molecules, limiting T-cell responses triggered by antigen presentation. T-cell receptor (TCR) engineered T-cell therapy targeting NY-ESO-1 and MAGE-A4 holds significant promise because of the high positive expression of these antigens in tumors. This approach facilitates the reprogramming of T lymphocytes by a transgenic TCR through gene transfer of TCR α and β chains specific to tumor antigens, offering potential therapeutic advances for patients with advanced SS. Clinical trials of TCR-engineered T-cell therapy targeting NY-ESO-1 and MAGE-A4 have been conducted, with an objective response rate reported to be 40-60% across several trials. This promising efficacy suggests that TCR-engineered T-cell therapy could become an attractive novel therapeutic option for advanced SS, which has limited treatment options in later stages. However, if TCR-engineered T-cell therapy is to be used in clinical practice, the standard approach following the failure of doxorubicin-based chemotherapy in patients with advanced SS must be defined. Future studies will be critical for establishing treatment strategies in this field.