Sarcomas are a group of aggressive heterogeneous tumors for which more than 100 histological subtypes have been defined. Sarcomas are found in a variety of solid tissues, including bone and gastrointestinal stromal cells. Current treatment options include radiotherapy, surgical resection, targeted therapies, and chemotherapy, but these treatments have had limited efficacy on intermediate to high grade tumors. Investigations into the molecular and cellular mechanisms that drive sarcomas have helped identify potential biomarkers that can serve as potential therapeutic targets. In addition, recent studies have also focused on the tumor microenvironment (TME) within sarcomas and the roles of different immune cell subsets creating an immunosuppressive microenvironment. These observations directly inform novel immunotherapeutic approaches that are being examined in preclinical and clinical studies.
Sarcoma TME and Immune Checkpoint Blockade
In general, sarcoma TMEs are highly immunosuppressive environments, and a recent analysis of the Ewing’s sarcoma family of tumors (ESFT) showed poor overall survival correlated with tumors that had a TME with elevated expression of hypoxia-inducible factor 1-α and were enriched with immunosuppressive M2 macrophages and neutrophils. The presence of tumor-associated macrophages has also been linked to growth and metastasis of sarcomas, and elevated expression of the immune checkpoint molecule PD-L1 also correlated with metastasis and poor overall survival[3,4]. These observations led to clinical trials that evaluated the efficacy of immune checkpoint blockade for treating sarcomas, but treatments that targeted PD-1/PD-L1 or CTLA-4 showed limited clinical efficacy and did not meet primary endpoints for overall survival[5,6].
ICI blockade coupled with chemotherapy has been tested in clinical trials for many cancers that do not respond well to ICI blockade alone. One recent single-center, single-arm phase II study evaluated treatment outcomes in patients with soft tissue sarcoma treated with anti-PD-1 (pembrolizumab) and doxorubicin, and initial results have indicated this combination has manageable toxicity and favorable trends with respect to overall survival and progression-free survival. Another recent retrospective analysis of advanced soft-tissue sarcoma patients treated with pembrolizumab, and cyclophosphamide revealed that the presence of tertiary lymphoid structures within tumors correlated with better treatment outcomes. These findings indicate that ICI blockade has the potential to have therapeutic effects when used in combination with other treatment modalities.
Genomic studies of sarcomas have been critical to identifying mutations associated with tumor growth, angiogenesis, and metastasis. These findings led to clinical trials examining the efficacy of tyrosine kinase inhibitors or inhibitors that target vascular endothelial growth factor or insulin-like growth factor-1, but most of these trials failed to meet overall survival endpoints [9,10]. More recent genomic studies have indicated that mutations associated with different tumors occur in the same genes as some of the targeted therapies, but the mutations differ sufficiently to render these therapies ineffective.
Cell-based immunotherapies have shown great promise in treating hematologic malignancies and are being explored for solid tumors. Chimeric antigen receptor (CAR) T cells have been of particular interest as they are patient-derived T cells engineered to express a tumor-specific receptor, and thus can target tumors without being detected as foreign cells. Preclinical studies suggested that sarcoma-specific CAR T cells may be effective, but clinical trials have failed due to poor penetration and function of CAR T cells in the immunosuppressive TME.
Recent and ongoing studies are exploring the effects of multi-CAR T cell strategies that target different tumor antigens, as well as the effects of using modified dendritic cells or natural killer cells or combining treatment modalities.
Effective and lasting treatment options for sarcomas continue to be elusive but advances in genomic analysis and immune-based treatments are slowly improving outcomes. Like other cancers, clinical studies exploring treatment combinations are also showing promise and may provide critical breakthroughs for some of the most aggressive sarcomas.
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