Development of Checkpoint Inhibitors for Sarcomas

Oncology & Hematology Review, 2017;13(1):25–9 DOI:


Sarcomas 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 01, 2017 Accepted April 12, 2017
Correspondence: 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 plateletderived 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 practicechanging 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

In physiologic conditions, antigens or peptides derived from potential pathogens (bacteria, viruses, tumor cells, etc.) are processed and expressed by antigen-presenting cells (dendritic cells, macrophages, and B cells) through the major histocompatibility complex that engages T cells through the TCR, eliciting a complex sequence of events that culminate with the activation of both innate and adaptive immunity.10,11 Key players of cell-mediated adaptive responses are T cells with either helper cells (CD4+ T cells) or cytotoxic capabilities (CD8+ T cells), as well as memory cells involved in sustained immunity.12 Across different steps of this cycle, the magnitude, duration, and, ultimately, efficacy, of the immune response are influenced by modulatory mechanisms, which can result in either amplification or abrogation of this cycle. While essential in avoiding uncontrolled immune responses and autoimmunity in physiologic situations, these negative regulatory pathways can be exploited by tumor cells as immune evasion mechanisms.13,14 As examples of cell surface molecules involved in immunosuppressive singling pathways, cytotoxic T-lymphocyte associated protein-4 (CTLA-4, or CD152) and programmed cell death receptor-1 (PD-1, or CD274) or its ligand (PD-L1) have been successfully targeted by inhibitory monoclonal antibodies, or immune checkpoint inhibitors (ICIs), resulting in a paradigm shift in the management of a growing number of malignancies.15,16 The ICI ipilimumab, a human monoclonal antibody that binds to CTLA-4; pembrolizumab and nivolumab, molecules that target PD-1; and atezoluzimab, an anti-PD-L1 agent, have all been approved for clinical use. In addition to response rates varying from 10% to more than 50%, ICIs have been shown to allow for sustained disease control and long-lasting immune-mediated responses,15–21 and striking activity resulted from combined CTLA-4 and PD-1 blockade.22,23

Interestingly enough, preliminary observations of tumor regressions following wound infections and erysipelas by Busch and Coley alluded to patients with sarcomas.7,8 Antitumor activity has been further demonstrated in sarcomas with the use of various forms of immunotherapy.24 As examples, cytokine therapy with interleukin-2 (Il-2) and interferons lead to occasional responses in patients with heavily pretreated Ewing sarcoma (ES) and osteosarcoma.25–29 Similarly, liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), a muramyl dipeptide analogue associated with enhanced NK-κβ signaling and monocyte/macrophage activation, is approved for clinical use in Europe (although not by the US Food and Drug Administration) based on survival improvements in a randomized trial investigating the addition of this agent to conventional chemotherapy in patients with osteosarcoma receiving adjuvant treatment.30 Trabectedin, a compound with a complex mechanism of action currently approved for the treatment of sarcomas, was shown to affect macrophage viability, differentiation, and the production of CCL2 and IL-6, suggesting an immune-mediated effect that could potentially be involved in antitumor activity.31 Additional proofs of the concept that mobilization of the immune system can result in antitumor effect in sarcoma patients are plentiful in the literature, deriving from different forms of vaccines, tumor antigens/peptides, lysates, and, more recently, TCR-transduced T cells specific to NY-ESO-1 in synovial sarcomas.32–34

Evidence addressing the efficacy of monoclonal antibodies against immune checkpoints begins to emerge, as recent studies have yielded both promising and disappointing results across different histologies. In this review, we revisit the mechanisms underlying the immunogenic potential of sarcomas, the currently available clinical data regarding the efficacy of ICIs in sarcomas, as well as future directions.

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Keywords: Soft tissue sarcomas, immunotherapy, anti-PD-1, immune checkpoint blockade