Immunotherapeutic approaches to sarcoma

Current therapies in advanced sarcomas are primarily based on cytotoxic chemotherapy and have modest efficacy coupled with significant toxicity. Little progress has been made in the field since imatinib was approved for the treatment of gastrointestinal stromal tumor (GIST) in 2002 despite the recent FDA approval of the multi-tyrosine kinase inhibitor pazopanib. Novel therapies are clearly needed. Immunotherapy utilizing checkpoint inhibitors has yielded significant clinical benefit in multiple solid tumors manifesting as durable responses in melanoma, kidney, lung, and bladder cancers, as well as hematologic malignancies. Given the success in several "non-immunogenic" tumors and recent preclinical data, there is sufficient evidence to support the use of immunotherapy in sarcoma. Cytokine-based therapies have shown no benefit in the advanced setting. Two large randomized trials of muramyl tripeptide or of interferon maintenance in resected osteosarcoma patients did not provide unequivocal statistically significant benefit. More promising results have been reported in small studies evaluating vaccines and adoptive T cell therapy in specific subtypes of sarcoma such as synovial sarcoma, which widely expresses the immunogenic cancer testis antigen NY-ESO-1. Emerging approaches with chimeric antigen receptor (CAR)-engineered T cells are hypothesis-generating and thought-provoking. However, the unprecedented clinical activity and excellent safety profile of checkpoint inhibitors targeting programmed death-1 receptor and its ligand (PD-1/PD-L1) have galvanized the field and generated much enthusiasm to harness the power of immunotherapy in pursuit of cures in patients with advanced sarcomas. An ongoing phase II study (SARC028) will hopefully usher an era of investigation of this exciting approach in sarcoma. However, it is unlikely that one agent will carry a universal cure and future approaches need to focus on patient selection as well as on identifying the optimal combination of checkpoint inhibitors with targeted therapy, chemotherapy, or radiation therapy.