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Review Sarcoma Development of Checkpoint Inhibitors for Sarcomas Rodrigo R Munhoz, 1,2 William D Tap, 3,4 and Sandra P D’Angelo 3,4 1. Oncology Center, Hospital Sírio Libanês, São Paulo, Brazil; 2. Instituto do Cancer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil; 3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, US; 4. Weill Cornell Medical College, New York, US S arcomas comprise a rare and heterogeneous group of malignancies of bone and soft tissue origin. Despite optimal approach, a significant proportion of patients will develop recurrent/metastatic disease. Although advances have been achieved, therapeutic options for these patients are limited and prognosis remains poor. Over the past century, the characterization of mechanisms involved in the interaction between tumor cells and the immune system has paved the way for the development of different forms of cancer immunotherapy, including cytokines, vaccines, cell therapies, and, more recently and successfully, monoclonal antibodies against molecules involved in the modulation of immune response, or immune checkpoint inhibitors. While the clinical applicability of this approach has been limited in sarcomas, the immunogenic potential of this group of malignancies was demonstrated more than 100 years ago. In this article, we review aspects associated with the immunogenicity of sarcomas and how the use of checkpoint inhibitors is being explored for this group of patients. Keywords Soft tissue sarcomas, immunotherapy, anti-PD-1, immune checkpoint blockade Disclosure: Rodrigo R Munhoz, William D Tap, and Sandra P D’Angelo have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: March 1, 2017 Accepted: April 12, 2017 Citation: Oncology & Hematology Review, 2017;13(1):25–9 Corresponding Author: Sandra P D’Angleo, Sarcoma Medical Oncology Service, 300 East 66th Street, New York, NY 10065, US. E: Sarcomas consist of a highly diverse group of malignancies of mesenchymal origin, encompassing more than 80 distinct subtypes and diagnosed in approximately 15,000 patients every year in the US. 1 Surgery still represents the mainstay of therapy for patients with localized disease. Although the use of multimodal treatment with curative intent remains debatable in soft tissue sarcomas (STS), radiation therapy and chemotherapy are often used in the neo- or adjuvant settings in select situations; for bone sarcomas, combination regimens in association with surgical resection remain the standard treatment. 2 For patients with advanced (unresectable or metastatic) disease, however, the prognosis remains poor, and median survival rarely exceeds 12–15 months. 2 Alternatives for patients with sarcomas not amenable to treatment with curative intent still rely on cytotoxic agents; standard chemotherapy such as doxorubicin, ifosfamide, and dacarbazine result in objective responses in 10–30% of the patients, usually of short duration, and the efficacy of these agents is largely influenced by the histologic subtype and tumor grade. 3,4 During the past years, new options became available for clinical use, including pazopanib, trabectedin, eribulin, and olaratumab. Of note, olaratumab, a monoclonal antibody against the subunit alpha of the platelet- derived growth factor receptor (PDGFR), resulted in an 11.8 month-overall survival improvement (hazard ratio [HR] 0.46; 95% confidence interval [CI] 0.30–0.71; p=0.0003) when used in combination with doxorubicin, versus doxorubicin alone, in a randomized, phase II trial. 5 Although survival gains have indeed been achieved, 5,6 improvements have been modest and short lived in most scenarios and the therapeutic development has been slower in comparison to other solid tumors, highlighting the need for new, effective treatment options for this group of patients. Manipulation of the immune system has emerged as a new hallmark of cancer therapeutics during the past decade, although observations of tumor regressions mediated by what is now characterized as an anticancer immune response date back to the nineteenth century. 7,8 Different approaches to harness the immune system have been investigated: while cytokines, vaccines, and adoptive cell therapy with artificially engineered antigen receptors (or chimeric antigen receptor [CAR] T cells) or modified T cell receptors (TCRs) resulted in variable degrees of antitumor effect, the most practice- changing and clinically applicable development in the management of solid tumors resulted from the use of monoclonal antibodies targeting molecules involved in the modulation of immune activation and response, or checkpoints. 9,10 TOU CH MED ICA L MEDIA 25