Current Status of Engineered T-Cell Therapy for Synovial Sarcoma

Abstract

Synovial sarcoma is a rare soft tissue sarcoma characterized by a t(X;18) translocation, which results in a SYT-SSX gene fusion. In the metastatic setting, chemotherapy has limited, durable efficacy prompting the necessity for new therapeutic modalities. One emerging new strategy involves T-cell-directed therapy such as tumor-infiltrating lymphocytes or the development of T cells that are genetically engineered to express a T-cell receptor against a cancer testis antigen. Of these approaches, engineered T cells that recognize NY-ESO-1 are the furthest along in development. Completed and on-going clinical trials have shown promise and there are efforts to continue to optimize the current approach.

Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab

“…The burgeoning field of immuno-oncology has led to improvement in patient outcomes across a wide range of cancer types, with FDA approvals in melanoma, Merkel cell carcinoma, urologic malignancies, and non-small cell lung cancer, among others, in both the metastatic and adjuvant settings (5)(6)(7). The success of immune checkpoint inhibitors has led to considerable interest in evaluating immunotherapy for sarcomas (3,(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Systemic Treatment for Adults with Synovial Sarcoma

“…Patients were randomized 1:1 to three cycles of standard treatment consisting of ifosfamide 3 g/m 2 on days 1–3 and epirubicin 60 mg/m 2 on days 1–2 of every 21 days vs. histology-tailored chemotherapy, which was in SS high-dose ifosfamide 1 g/m 2 on days 1–14 of every 28 days [ 15 ••]. After a median follow-up of 12.3 months for the total study population ( n = 287), the projected DFS at 46 months was 62% (95% CI 48–77) in the standard chemotherapy group and 38% [ 21 ••, 22 , 23 – 26 , 27 •, 28 •, 29 , 30 – 37 , 38 •, 39 , 40 – 44 , 45 ••, 46 , 47 , 48 , 49 •, 50 , 51 , 52 •, 53 , 54 ] in the histotype-tailored chemotherapy group (stratified log-rank p = 0.004; hazard ratio 2.00, 95% CI 1.22–3.26; p = 0.006). Subgroup analysis indicated no preference for histology-tailored chemotherapy in the SS cohort (HR 1.85, 95% CI 0.69–5.22).…”

“…In the field of immunotherapy, the use of engineered T cells directed against the NY-ESO-1 cancer/testis antigen, which is expressed in 80% of SS patients, has been the most promising approach in SS in clinical testing so far [ 52 •]. Objective responses were reported in 4/6 heavily pre-treated, metastatic, NY-ESO-1-expressing SS patients treated with lymphodepleting preparative chemotherapy followed by autologous T cells transduced with an NY-ESO-1-reactive T cell receptor, including tumor regressions.…”

Non-gastrointestinal stromal tumours soft tissue sarcomas: an update

“…One cancer testis antigen, NY-ESO-1 is highly prevalent in synovial sarcoma, and there are studies using ACT with objective responses observed. It remains investigational until the present moment, however [63].…”