SYT‐SSX breakpoint peptide vaccines in patients with synovial sarcoma: A study from the Japanese Musculoskeletal Oncology Group

Abstract

In the present study, we evaluated the safety and effectiveness of SYT-SSX-derived peptide vaccines in patients with advanced synovial sarcoma. A 9-mer peptide spanning the SYT-SSX fusion region (B peptide) and its HLA-A*2402 anchor substitute (K9I) were synthesized. In Protocols A1 and A2, vaccines with peptide alone were administered subcutaneously six times at 14-day intervals. The B peptide was used in Protocol A1, whereas the K9I peptide was used in Protocol A2. In Protocols B1 and B2, the peptide was mixed with incomplete Freund's adjuvant and then administered subcutaneously six times at 14-day intervals. In addition, interferon-a was injected subcutaneously on the same day and again 3 days after the vaccination. The B peptide and K9I peptide were used in Protocols B1 and B2, respectively. In total, 21 patients (12 men, nine women; mean age 43.6 years) were enrolled in the present study. Each patient had multiple metastatic lesions of the lung. Thirteen patients completed the six-injection vaccination schedule. One patient developed intracerebral hemorrhage after the second vaccination. Delayed-type hypersensitivity skin tests were negative in all patients. Nine patients showed a greater than twofold increase in the frequency of CTLs in tetramer analysis. Recognized disease progression occurred in all but one of the nine patients in Protocols A1 and A2. In contrast, half the 12 patients had stable disease during the vaccination period in Protocols B1 and B2. Of note, one patient showed transient shrinkage of a metastatic lesion. The response of the patients to the B protocols is encouraging and warrants further investigation. (Cancer Sci 2012; 103: 1625-1630 S ynovial sarcoma is a malignant tumor of soft tissue characterized by biphasic or monophasic histology, specific chromosomal translocation t(X;18), and its resultant SYT-SSX fusion genes.(1,2) Reported 5-year survival rates of patients with synovial sarcoma range from 64% to 77%.(3-7) In contrast, most metastatic or relapsed diseases remain incurable, indicating a need for new therapeutic options other than conventional surgery, radiotherapy, and chemotherapy.Antigen-specific peptide immunotherapy is one such option. (8)(9)(10)(11)(12) Previously, we demonstrated that SYT-SSX fusion gene-derived peptides (wild type and agretope modified) are recognized by circulating CD8 + T cells in HLA-A24 + patients with synovial sarcoma and elicit human leukocyte antigen (HLA)-restricted, tumor-specific cytotoxic responses. (13,14) Subsequent to these preclinical studies, we started a pilot clinical trial with a wild-type SYT-SSX-derived peptide vaccine. (15) In the present study, we evaluated immunologic and clinical outcomes of the vaccination trials using an agretope-modified SYT-SSX peptide and a combination of the peptide vaccine with adjuvant and interferon (IFN)-a.

T‐cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death‐ligand 1 expression in patients with soft tissue sarcomas

“…STS often are divided biologically into 2 categories: genetically “simple” and “complex” tumors. The simple tumors tend to have specific, reliably identifiable oncogenic alterations (such as translocations) and a limited number of mutated neoantigens 13, 14. Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) both are translocation‐driven malignancies and often express high levels of self‐antigens, notably NY‐ESO‐1,15, 16 which has been targeted with promising signals of efficacy 6, 17…”

Current Status of Engineered T-Cell Therapy for Synovial Sarcoma

“…It has been demonstrated that SYT-SSX fusion peptides are recognized by HLA-A24+ synovial sarcoma patients and result in tumor specific cytotoxic responses [17,22]. Further, a pilot trial of a wild-type SYT-SSX derived peptide vaccine confirmed its safety and its ability to evoke in vivo i mmunological responses [23].…”

Potential for immunotherapy in soft tissue sarcoma

“…Recently, the Japanese Musculoskeletal Oncology Group reported their phase I experience using vaccination with a 9-mer SYT-SSX derived peptide with and without systemic interferon-alpha for patients with metastatic synovial sarcoma. 34 The vaccines were well tolerated and antigen-specific cytotoxic T cell responses were seen in vitro. Disease stabilization was observed in 6 out of 12 (50%) of patients who had received vaccine with interferon versus 1 out of 9 (11%) patients who had received the vaccine alone.…”