Sarcomas are malignant tumors that are characterized by a wide diversity of subtypes with various cytogenetic profiles. Despite major treatment breakthroughs, standard treatment modalities combining chemotherapy, radiotherapy, and surgery failed to improve overall survival. Therefore, high expectations are foreseen with immunotherapy upon its maturation and better understanding of its mechanism of action. This paper presents a targeted review of the published data and ongoing clinical trials in immunotherapies of sarcomas, mainly adoptive cell therapies, cancer vaccines and immune checkpoint inhibitors.

Sarcomas are malignant tumors that derive from embryonic mesodermic tissues including fat, muscles, bones, nerves and blood vessels[1]. Epidemiologic studies report its predominance in the pediatric populations and its rare occurrence in adults[2]. Sarcomas are characterized by a wide diversity of subtypes with various cytogenetic profiles conferring treatment resistances. These findings combined with an advanced stage at diagnosis substantially increase the years of life lost[3]. The standard treatment modalities combining chemotherapy, radiotherapy, and surgery have failed to improve overall survival (OS)[4]. Despite the major breakthroughs in the treatment armamentarium, the recent data reports a relative 5-year survival rate limited to 66% for bone and soft tissue sarcomas, 53.9% for osteosarcomas, 75.2% for chondrosarcomas, and 50.6% for Ewing’s sarcomas[5].

Interestingly, Coley described in 1891 a complete regression of sarcomas secondary to severe episodes of erysipelas but failed to regenerate these results in other patients[6]. The Food and Drug Administration thereafter banned the use of toxin therapy without a new drug-approval process. Fortunately, Coley’s paper has encouraged scientists to analyze the role of the immune system in carcinogenesis[7].

After more than a century since Coley’s research efforts that marked the history of immunotherapy, we present a review on this elegant treatment modality in the management of sarcomas including adoptive cell therapies (ACT), monoclonal antibodies, vaccines, and immune checkpoint inhibitors (ICI).

Specialized centers in the management of sarcomas have demonstrated a better OS and low recurrence rate[8]. Yet, all patients are managed uniformly according to their prognosis dictated by the stage of the disease, which is determined by the grade, depth and size of the tumor[9]. For patients with localized disease, a complete resection with wide 2-3 cm margins followed by adjuvant radiation therapy is the mainstay treatment for a curative approach. However, survival is not only determined by local control since most patients die from systemic disease. The choice of the chemotherapy regimen depends on the tumor chemosensitivity which varies with the tumor subtype and grade, the patient’s performance status, and the timing of metastatic disease[10]. Unfortunately, the benefits of adjuvant chemotherapy are limited to rhabdomyosarcomas, osteosacromas and Ewing’s sarcomas. Moreover, Trabectidine is showing promising results encountered in the adjuvant and neoadjuvant settings of patients with myxoid liposarcomas[11]. The role of adjuvant and neoadjuvant chemotherapy in the management of soft tissue sarcomas is yet to be clearly established. The actual recommendations by NCCN and ESMO are to address this issue on a case by case basis according to the patient’s performance status, comorbid factors, disease location, tumor size, and histologic subtype. In case of advanced and recurrent sarcomas, induction regimens include Cyclophosphamide and Ifosphamide, Vincristine, Doxorubicin, Dactinomycin, and Etoposide[12]. For patients with unresectable or metastatic disease, the management plan is limited to a palliative approach with Trabectedin or Ifosfamide and Doxorubicin based chemotherapy[13,14].

The rationale of using targeted therapies in sarcomas goes back to 1984 when sarcomagenesis was correlated to recurrent translocations[15]. Genetic profiling thus defined two groups of sarcomas. The first group is characterized by a simple karyotype associated with specific tumor genetic alterations that include chromosomal translocations, oncogenetic mutations, and recurrent gene amplifications. The second group is characterized by a complex karyotype associated with nonspecific and nonrecurring genetic alterations[16]. Subsequent to these advances, Pazopanib, a multitargeted tyrosine kinase inhibitor against VEGFR1-3, PDFGRA-B, and KIT was approved for pretreated metastatic nonlipomatous sarcomas based on the phase III PALETTE study[17]. Clinical and preclinical mechanistic studies are being conducted to validate a possible therapeutic role of the various targeted therapies available. Among these novel targeted therapies, we report the trials of Cediranib and Sunitinib in alveolar soft part sarcoma, Tivantinib and Cabozantinib in clear cell sarcoma, Imatinib in dermatofibrosarcoma protuberans, Cabozantinib in endometrial stromal tumors, and Everolimus in perivascular epitheloid cell tumor[18].

In fact, the previous cancer treatment approaches addressed distinctive and complementary hallmarks of carcinogenesis that included sustained proliferative signaling, evasion of growth suppressors, resistance of cell death, enabling of replicative immortality, induction of angiogenesis and activation of invasions and metastasis[19]. The well-known conventional cytotoxic drugs and targeted therapies have reached a plateau in effect that required a re-assessment of the six hallmarks of carcinogenesis. Recent conceptual progress has added two new hallmarks, namely reprogramming of energy metabolism and signaling interactions of the tumor microenvironment[20].

The later resides in the concept of the cancer-immunity cycle and is actually a turning point in the history of cancer therapy[21]. This cycle is the result of a counterbalance between immune-stimulatory and inhibitory factors. It occurs physiologically and starts with the release of cancer cell antigens and ends with the apoptosis of cancer cells via the activated effectors of the immune system[22]. Subsequently, cancer immunoediting may proceed with any of the three following phases[23]. The elimination phase describes an activation of the innate and adaptive immune effectors in response to cytokine secretion. The equilibrium phase occurs in the setting of a balance between tumor immune destruction and proliferation. The immunologic phase takes place when the tumor cells are capable of evading the immune system[23].

Recent advances recommend addressing only one step of the immune cycle to avoid potential unwanted activation of autoimmunity mechanism and normal cells damage. Therefore, immunotherapy aims at initiating or maintaining the cancer-immunity cycle by acting on its rate limiting step. Consequently, ICI often address the immunostar function of the tumor microenvironment[24]. The PD-1/PD-L1 axis is a potential therapeutic target in view of the confirmed expression of PD-L1 in various sarcomas[25]. Inhibition of this axis enables the immune system to quickly adapt to cancer resistances thus allowing durable responses with ICI[26].

Sarcomas mainly occur either secondary to the activation of oncogenes via translocations and inversions, or secondary to the natural expression of germ cell peptides[27,28]. The issuing peptides generate an immune cascade directed against the aberrant cells[29]. Consequently, multiple rationales to immunotherapy including ACT, therapeutic vaccines, and ICI have been assessed in the treatment of sarcomas (Table 1).

The proof of the immunotherapy concept in sarcomas has been undoubtedly validated with the benefits encountered upon the use of liposomal muramyl-tripeptide-phosphatidyl-ethanolamine, an immunoactivator agent derived from BCG. However, its role remains controversial in view of the discordant results between the preliminary data and final results in both the adjuvant and metastatic setting. Even though the actual trend is moving towards immunotherapy as an essential tool in the treatment of cancer, the recent ASCO 2016 meeting was unfortunately disappointing in this regard. Five studies have been presented, of which one trial of chemotherapy (Busulphan and Melphalan), three trials of tyrosine kinase inhibitors, monotherapy (Anlotinib and Regorafenib) or in combination with chemotherapy (Gemcitabine plus Pazopanib), and one study reporting the evident detrimental impact of disease progression and altered quality of life on the long-term care and survival of patients with sarcomas. The ongoing trials including the promising results of immunotherapies are awaited. The available results reported a failure of Pembrolizumab in multiple soft tissue sarcomas (NCT02301039) and Nivolumab in metastatic uterine leiomyosarcoma (NCT0 2428192) despite the promising findings encountered with Nivolumab in retrospective experiences[45]. In fact, the biological preclinical rationale is not fully elucidated in view of the absence of any correlation between PD-L1 expression and OS[46]. Thus, the actual state of knowledge does not predict the patient profile that might benefit from immunotherapy.

The cornerstone treatment for sarcomas consists of complete surgical resection, chemotherapy, and radiotherapy. Unfortunately, these treatment options fall short from achieving an optimal clinical outcome. Immunotherapy is therefore expected to further improve the survival of patients with sarcomas. Until recently, the field of immunotherapy has not yet matured enough to present robust effects. The better understanding of onco-immunotherapy principles is essential to adjust the design of clinical trials and the selection of inclusion criteria. The published data shows that ACT is yet to be more elucidated and evaluated, vaccine therapy requires tailoring and personalization, and ICI, preferably PD-1 and PDL-1 inhibitors, necessitate better patient selection. Such results would allow more understanding of the antitumor immunity mechanisms and improvement of the treatment arsenal against sarcomas.