Emerging targeted and cellular therapies in the treatment of advanced and metastatic synovial sarcoma

Abstract

Synovial sarcoma is a soft tissue sarcoma accounting for approximately 1,000 cases per year in the United States. Currently, standard treatment of advanced and metastatic synovial sarcoma is anthracycline-based chemotherapy. While advanced synovial sarcoma is more responsive to chemotherapy compared to other soft tissue sarcomas, survival rates are poor, with a median survival time of less than 18 months. Enhanced understanding of tumor antigen expression and molecular mechanisms behind synovial sarcoma provide potential targets for treatment. Adoptive Cell Transfer using engineered T-cell receptors is in clinical trials for treatment of synovial sarcoma, specifically targeting New York esophageal squamous cell carcinoma-1 (NY-ESO-1), preferentially expressed antigen in melanoma (PRAME), and melanoma antigen-A4 (MAGE-A4). In this review, we explore the opportunities and challenges of these treatments. We also describe artificial adjuvant vector cells (aAVCs) and BRD9 inhibitors, two additional potential targets for treatment of advanced synovial sarcoma. This review demonstrates the progress that has been made in treatment of synovial sarcoma and highlights the future study and qualification needed to implement these technologies as standard of care.

Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma

“…The median duration of response was 52 weeks. The median PFS was 58.3 vs. 11.0 weeks in SyS responders vs. SyS non-responders, respectively [33,45,75,76]. The study is still recruiting SyS patients and further results are awaited.…”

“…FHD-609 is an intravenous BRD9 degrader that bridges BRD9 with the E3 ubiquitin ligase substrate cereblon (CRBN) E3 that leads to proteasomal degradation. These therapies are under initial evaluation in phase I clinical trials, which are now recruiting patients with advanced SyS who failed prior anti-cancer therapies [44,45].…”

“…NY-ESO-1 is a highly immunogenic CTA aberrantly expressed in 60-80% of SyS [45,65,66], independently from the morphological or the translocation type [67]. In 2014, a pilot clinical trial (NCT00670748) on HLA-A*02-positive SyS patients with >50% expression of NY-ESO-1 demonstrated objective clinical responses in 11 metastatic SyS patients heavily pretreated out of 18 (61%) receiving retrovirally transduced NY-ESO-1 TCR-T-cells plus systemic IL2 [66].…”

“…In 2014, a pilot clinical trial (NCT00670748) on HLA-A*02-positive SyS patients with >50% expression of NY-ESO-1 demonstrated objective clinical responses in 11 metastatic SyS patients heavily pretreated out of 18 (61%) receiving retrovirally transduced NY-ESO-1 TCR-T-cells plus systemic IL2 [66]. More recently, a phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT01343043), including 45 metastatic SyS patients treated with transgenic T-cells targeting NY-ESO-1 in the contest of HLA-A*02 alleles, demonstrated an ORR of 20-50% among four cohorts allocated between levels of NY-ESO-1 expression and lymphodepletion regimens [45,56,[68][69][70]. The treatment had a controllable safety profile and a post-hoc analysis provided further outputs.…”

“…ASP0739 are human artificial adjuvant vector cells loaded with the CD1d ligand alpha-galactosylceramide and are modified to express NY-ESO-1, which potentially induced the cytotoxic T-cell mediated response against tumor cells expressing NY-ESO-1. A phase I/II trial has been designed to evaluate safety and anti-tumor efficacy of this aAVC product targeting NY-ESO-1 in combination with pembrolizumab (anti-PD-1) for the treatment of SyS, MRCLS, ovarian carcinoma, non-small cell lung cancer, and esophageal squamous cell carcinoma (NCT04939701) [45].…”