PRAME and HLA Class I expression patterns make synovial sarcoma a suitable target for PRAME specific T-cell receptor gene therapy (original) (raw)
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Engineered T Cells in Synovial Sarcoma: Persistence Pays Off!
Cancer Discovery
Synovial sarcoma (SS) is an aggressive malignancy that typically affects adolescents and young adults and is associated with poor prognosis. Although SS has failed to respond to immune checkpoint blockade, other strategies designed to generate an immune response, including adoptive cell therapies targeting the cancer testis antigen NY-ESO-1, have shown encouraging results. In this issue, D'Angelo and colleagues confi rm the safety and feasibility of adoptive T-cell therapy with autologous T cells engineered to express NY-ESO-1 c259 , an affi nity-enhanced T-cell receptor recognizing an HLA-A2-restricted NY-ESO-1-derived peptide, and demonstrate encouraging antitumor responses in 50% of treated patients, particularly in the setting of persistence of polyfunctional NY-ESO-1 c259-expressing T cells in circulation for at least 6 months. Cancer Discov; 8(8); 914-7.
Cancer control : journal of the Moffitt Cancer Center, 2011
Synovial sarcoma is a soft tissue malignancy with a predilection for adolescents and young adults. Despite recent improvements in the understanding of its character and etiology, few therapeutic advances have been made. The mortality rate is high among the young population it affects. The low incidence of most subtypes of sarcoma, such as synovial sarcoma, makes disease-specific trials difficult to organize. The biological differences between sarcoma subtypes make inclusion of multiple types in general trials unsatisfactory as well. A review of the literature regarding targetable pathways in synovial sarcoma was undertaken. A strategy has been devised to utilize available technologies in order to prioritize drug trial planning. Cell culture and xenograft research with synovial sarcoma cell lines have identified some critical pathways that may be targetable. Promising therapeutic strategies include newer cytotoxic chemotherapies, antiangiogenic agents, anti-IGF1R pathway agents, anti...
Immunohistochemical validation of TLE1, a novel marker, for synovial sarcomas
The Indian journal of medical research, 2012
Logistic and financial constraints limit application of several available immunohistochemical (IHC) markers and molecular analysis in every case of synovial sarcoma, diagnosed in our settings. Recently, TLE1 has been recognized as a robust IHC marker for diagnosing a synovial sarcoma. Here, we present IHC features of synovial sarcomas, including TLE1 expression in these cases and in some other tumours. Conventional sections from 42 synovial sarcomas (30 retrospective & 12 prospectively diagnosed) were subjected to TLE1 IHC staining, including 21 tumours confirmed with molecular testing. TLE1 immunostaining was graded from 0, 1+, 2+, 3+, with 2+ or 3+ grades interpreted as positive staining. Of the 42 tumours, 26 (61.9%) were of monophasic spindle cell type, 13 biphasic type (30.9%), two (4.7%) calcifying type and remaining one (2.3%) was a poorly differentiated synovial sarcoma. On immunohistochemistry (IHC), tumours were positive for epithelial membrane antigen (EMA) (26/34, 76.4%)...
Saudi journal of pathology and microbiology, 2020
Background: Synovial sarcoma is a translocation-associated mesenchymal neoplasm that represents around 10% of all soft tissue sarcomas. Diagnosing biphasic synovial sarcoma is generally straight forward, owing to distinctive histologic features. Transducer-like enhancer of split 1 (TLE1) is overexpressed in synovial sarcomas. Study aimed to evaluate sensitivity and specificity of TLE1 immunohistochemical expression in synovial sarcoma and its histological mimics. Methods: Conventional sections from 30 cases of synovial sarcoma, 24 cases of monophasic synovial sarcoma mimics and 6 cases of poorly differentiated sarcoma mimics were subjected to TLE1 IHC staining. TLE1 immunostaining was graded from 0, 1+, 2+, 3+, with 2+ or 3+ grades interpreted as positive staining. Results: Of the 60 tumours, majority are monophasic spindle cell type (56.6%), followed by biphasic (16.6%), monophasic epithelial (6.6%), poorly differentiated (13.3%) and calcifying type (6.6%). Upon expression of TLE1 in tumors, 20 cases showed Grade 3, 8 cases shown Grade 2, 2 cases shown Grade 1 TLE1 Expression in Synovial sarcoma. 2 cases shown Grade 3 and 2 cases shown Grade 2 TLE1 expression in Schwannoma. Whereas 1case shown grade 2 in Rhabdomyosarcoma. 1case shown grade 2 in Hemangiopericytoma. TLE1 sensitivity for diagnosis of synovial sarcomas was 93.3%, and specificity of 73.3% with positive predictive value of 77.77% and negative predictive value of 91.6%. Conclusion: Specificity can be increased with optimal IHC panel which includes BCL2, Pan Cytokeratin, EMA, CD99 and CD34. Molecular confirmation is the diagnostic gold standard for synovial sarcoma, TLE1, in view of its high sensitivity may be a useful marker within the optimal IHC panel for substantiating a diagnosis of synovial sarcoma. Awareness of TLE1 expression in other tumours and its correct interpretation are necessary.
The Journal of Immunology, 2002
To investigate the immunogenic property of peptides derived from the synovial sarcoma-specific SYT-SSX fusion gene, we synthesized four peptides according to the binding motif for HLA-A24. The peptides, SS391 (PYGYDQIMPK) and SS393 (GYDQIMPKK), were derived from the breakpoint of SYT-SSX, and SS449a (AWTHRLRER) and SS449b (AWTHRLRERK) were from the SSX region. These peptides were tested for their reactivity with CTL precursors (CTLps) in 16 synovial sarcoma patients using HLA-A24/SYT-SSX peptide tetramers and also for induction of specific CTLs from four HLA-A24+ synovial sarcoma patients. Tetramer analysis indicated that the increased CTLp frequency to the SYT-SSX was associated with pulmonary metastasis in synovial sarcoma patients (p < 0.03). CTLs were induced from PBLs of two synovial sarcoma patients using the peptide mixture of SS391 and SS393, which lysed HLA-A24+ synovial sarcoma cells expressing SYT-SSX as well as the peptide-pulsed target cells in an HLA class I-restric...
Cells Tissues Organs, 2002
Soft tissue sarcomas are mesenchymal tumors which respond poorly to systemic therapy. Recent studies suggest a higher response rate with an increased doxorubicin dosage. However, this was parallel with a profound hematotoxicity in 75% of patients. Transfer of the human multidrug resistance 1 (MDR1) gene to normal hematopoietic stem cells and transplantation may significantly reduce the hematotoxicity of anthracyclin-based chemotherapy. To test this concept of supportive gene therapy in advance of a clinical study, we transduced mobilized peripheral blood progenitor cells (PBPC) with the retroviral vector SF91m3 containing the human MDR1 gene, transplanted these cells to immune-deficient mice, allowed 6 weeks for engraftment to occur and treated the animals with MDR1-based chemotherapy. In the MDR1-transduced group the human leukocytes were significantly protected from the toxicity of chemotherapy (p < 0.05). While the gene transfer rate was in the range of 10% and thus comparable...
A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients with Synovial Sarcoma
Sarcoma, 2013
Background. Patients with recurrent synovial sarcomas have few options for systemic therapy. Since they express large amounts of endogenous CT (cancer testis) antigens such as NY-ESO-1, we investigated the clinical activity of single agent anti-CTLA4 antibody ipilimumab in patients with advanced or metastatic synovial sarcoma. Methods. A Simon two-stage phase II design was used to determine if there was sufficient activity to pursue further. The primary endpoint was tumor response rate by RECIST 1.0. Patients were treated with ipilimumab 3 mg/kg intravenously every 3 weeks for three cycles and then restaged. Retreatment was possible for patients receiving an extra three-week break from therapy. Sera and peripheral blood mononuclear cells were collected before and during therapy to assess NY-ESO-1-specific immunity. Results. Six patients were enrolled and received 1-3 cycles of ipilimumab. All patients showed clinical or radiological evidence of disease progression after no more than three cycles of therapy, for a RECIST response rate of 0%. The study was stopped for slow accrual, lack of activity, and lack of immune response. There was no evidence of clinically significant either serologic or delayed type hypersensitivity responses to NY-ESO-1 before or after therapy. Conclusion. Despite high expression of CT antigens by synovial sarcomas of patients treated in this study, there was neither clinical benefit nor evidence of anti-CT antigen serological responses. Assessment of the ability of synovial sarcoma cell lines to present cancer-germ cell antigens may be useful in determining the reason for the observed lack of immunological or clinical activity.
Opposing immune and genetic forces shape oncogenic programs in synovial sarcoma
2019
Synovial sarcoma is an aggressive mesenchymal neoplasm, driven by the SS18-SSX fusion, and characterized by immunogenic antigens expression and exceptionally low T cell infiltration levels. To study the cancer-immune interplay in this disease, we profiled 16,872 cells from 12 human synovial sarcoma tumors using single-cell RNA-sequencing (scRNA-Seq). Synovial sarcoma manifests antitumor immunity, high cellular plasticity and a core oncogenic program, which is predictive of low immune levels and poor clinical outcomes. Using genetic and pharmacological perturbations, we demonstrate that the program is controlled by the SS18-SSX driver and repressed by cytokines secreted by macrophages and T cells in the tumor microenvironment. Network modeling predicted that SS18-SSX promotes the program through HDAC1 and CDK6. Indeed, the combination of HDAC and CDK4/6 inhibitors represses the program, induces immunogenic cell states, and selectively targets synovial sarcoma cells. Our study demonst...