Minireviews Open Access
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Apr 10, 2017; 8(2): 145-150
Published online Apr 10, 2017. doi: 10.5306/wjco.v8.i2.145
Immunotherapies in sarcoma: Updates and future perspectives
Marwan Ghosn, Elie El Rassy, Hampig Raphael Kourie, Department of Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut 2038 3054, Lebanon
Author contributions: Ghosn M initiated the review; Ghosn M, El Rassy E and Kourie HR performed the review, analyzed the data and wrote first draft; Ghosn M, El Rassy E and Kourie HR reviewed and commented on the paper and provided final approval.
Conflict-of-interest statement: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Elie El Rassy, MD, Department of Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Monot St, Beirut, PO Box 166830, Beirut 2038 3054, Lebanon. elie.rassy@hotmail.com
Telephone: +961-1-615300 Fax: +961-1-615300
Received: September 20, 2016
Peer-review started: September 23, 2016
First decision: October 20, 2016
Revised: November 15, 2016
Accepted: January 16, 2017
Article in press: January 18, 2017
Published online: April 10, 2017

Abstract

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.

Key Words: Adoptive cell therapy, Cancer vaccines, Immunotherapy, Immune checkpoint inhibitors, Sarcoma

Core tip: This paper is a review that outlines the most recent updates on the immunotherapy treatment of sarcomas. After a brief review of the concept of immunotherapies and the different treatment modalities, we discuss the available data, the limitations and future perspectives of each treatment option.



INTRODUCTION

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).

APPROVED THERAPIES IN SARCOMAS FROM CHEMOTHERAPY TO TARGETED THERAPIES

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].

ADVANCES IN IMMUNO-ONCOLOGY

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].

IMMUNOTHERAPEUTIC MODALITIES EVALUATED IN SARCOMAS

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).

Table 1 Summary of the phase I/II trials of immunotherapies in sarcoma.
Treatment modalityRef.AgentPhase/PatientsIndicationRRSurvival
Adoptive cell therapyRobbins et al[31], 2011Adoptively transferred autologous T cells transduced with a T-cell receptor directed against NY-ESO-1I/6Metastatic synovial cell sarcoma expressing NY-ESO-1RR: 4/6N/A
VaccinesMahvi et al[34], 2002GM-CSF treated tumor cellsI/16Melanoma and sarcomasRR: 1/16N/A
Dillman et al[35], 2004Autologous tumor cell line-derived vaccinesI, II/23Recurrent or metastatic sarcomaNo objective response assessed10 patients lived more than 1 year
Kawaguchi et al[36], 2005Vaccination By SYT-SSX junction peptideI/6Disseminated synovial sarcomaRR: 0/6N/A
Kawaguchi et al[38], 2012SYT-SSX breakpoint peptide vaccinesI, II/21Metastatic synovial sarcomaRR: 1/21 SD: 6/21N/A
Takahashi et al[39], 2013Personalized peptide vaccinationII/20Refractory bone and soft tissue sarcomaSD in all patientsMedian OS: 9.6 mo
Finkelstein et al[40], 2012Combination of external beam radiotherapy with intratumoral injection of dendritic cellsI, II/17Neoadjuvant treatment in high-risk soft tissue sarcomaRR: 9/17One-year PFS: 70.6%
Ghisoli et al[41], 2015FANG autologous immunotherapyI/12Advanced and metastatic Ewing's sarcomaRR: 1/12One-year OS: 75%
Checkpoint inhibitorsMakki et al[44], 2013IpilimumabII/6Advanced synovial sarcomaRR: 0/6 (closed prematurely)Median OS: 8.75 mo
Adoptive cell therapy in sarcomas

Adoptive cell therapy is a new therapeutic strategy based on the modulation, manipulation and selection of autologous T-cells in vitro to overcome the tolerance of the immune system to the tumor cells. Those T-cells may be harvested from tumor infiltrating lymphocytes (TIL) and re-transfused into the same patient after ensuring their expansion. Lymphocyte T-cells may also be harvested from peripheral blood, and those that recognize tumor antigens are selectively expanded. Alternatively, lymphocyte T-cells may be genetically engineered either by modifying a T-cell receptor for cancer antigen (transgenic TCR) or by adding a chimeric antigen receptor (CAR) that recognizes a specific cancer antigen[30,31]. Apart from T-cells, NK ACT has also been proven efficacious with several advantages over the classical T-cell ACT in the absence of MHC/HLA restriction, namely their NKG2D-dependent cytotoxicity against autologous tumor cells[32,33].

To our knowledge, the use of TIL has never been reported in the treatment of sarcomas whilst the use of NK ACT has been limited to case reports[33]. On the other hand, tumor antigens such as GD2 (93% of sarcomas) and NY-ESO-1 (80% to 100% of different subtype of sarcomas) were found to represent interesting targets for adoptive cells therapies. Moreover, other cancer testis antigens such as LAGE, MAGE-A3 and PRAME were frequently expressed in sarcomas and would be potential immunotherapeutic targets. In this setting, a phase I study evaluated the ability of adoptively transferred autologous T-cells transduced with a T-cell receptor (TCR) directed against NY-ESO-1 to mediate tumor regression in patients with metastatic synovial cell sarcoma expressing NY-ESO-1. The results showed an objective clinical response in 4 out of 6 patients[31].

Two ongoing trials are evaluating genetically engineered NY-ESO-1 T-cells for children and adults in metastatic synovial sarcoma (NCT01343043). Another phase I trial is testing the role of CAR T-cell therapy targeting the GD2 protein in children and young adults with sarcomas and rhabdomyosarcomas (NCT00743496).

Therapeutic vaccines in sarcomas

The therapeutic effects of cancer vaccines rely on the activation of dendritic cells upon the presence of an immunogenic predetermined antigen. However, most of the initial studies of vaccines in sarcomas did not determine specific antigens and used inefficaciously the entirety of the tumor cells[34,35]. Later studies used SYT-SSX, a fusion derived peptide present in 90% of synovial sarcoma, and also failed to demonstrate an objective response[36-38]. Takahashi et al[39] personalized the peptide vaccination patients with refractory sarcoma and administered multiple tumor antigens chosen according to preexisting peptide-specific IgG titers. The median OS was 9.6 mo with disease stabilization occurring in 30% of patients but no objective responses were seen. Another vaccination modality used in situ vaccination through combining preoperative gamma radiation (50 Gy) with intratumoral dendritic cells injection. The studied population was limited to high risk, localized, and resected extremity soft tissue sarcoma and resulted in 71% progression free survival at one year[40].

Major efforts in this field are being conducted namely in children with Ewing sarcomas. Recent data demonstrated a 75% OS at one year with FANG immunotherapy in adolescent patients with Ewing’s sarcoma. The treatment was well tolerated with a favorable OS[41]. A seemingly interesting phase I trial designed for the treatment of pediatric patients with relapsed high-risk Ewing sarcoma, osteogenic sarcoma, rhabdomyosarcoma, synovial sarcoma, and neuroblastoma is using a combination of Decitabine demethylating agent and a cancer vaccine composed of dendritic cells pulsed with overlapping peptides of NY-ESO-1, MAGE-A1, and MAGE-A3 (NCT0 1241162). Another dendritic cell vaccine is also being assessed in combination with Gemcitabine in a phase I trial for adults and children with soft tissue and bone sarcomas (NCT01803152).

Immune checkpoint inhibitors in sarcomas

The concept of ICI relies on deactivating the suppressed activity of the immune system. ICI remove the brakes (PD-1 and CTLA4) thus enhancing the immune function of already sensitized T-cells. Effectively, PD-1 and CTLA4 inhibitors are showing interesting results with acceptable response rates in different cancers, including those considered for a long time as non-immunogenic[42]. Unlike CTLA4 inhibitors, the response to PD1 and PDL-1 inhibitors has been correlated with the expression of PD-1 and PDL-1 on tumor cells and to the mutational load of the tumors[42]. Moreover, PD-1 and PDL-1 expression seems to vary between sarcoma subtypes, a finding that may direct immunotherapy management in patients with sarcomas[43].

Unfortunately, the efficacy of ICI in sarcomas has been evaluated in only one study so far. It is a phase II study that administered Ipilimumab (3 mg/kg intravenously every 3 wk for 3 cycles), a CTLA-4 inhibitor, to six patients with synovial sarcoma. The median OS was 8.75 mo ranging between 0.8 and 19.7 mo. The study was closed prematurely when none of the patients had an objective tumor response. All patients expressed NY-ESO-1 but its titers did not change after treatment administration[44]. PD-1 and PDL-1 inhibitors present a different mechanism of action compared to anti-CTLA4 agents and consequently may present better response rates[43]. Many ongoing phase I trials are assessing the role of anti-PD1 agents in sarcomas as single agent or in combination with Ipilimumab and Dasatinib (NCT0 1643278).

PERSPECTIVE

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.

CONCLUSION

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.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Oncology

Country of origin: Lebanon

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): C, C

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Leithner A, Mehdi I, Rapidis AD S- Editor: Kong JX L- Editor: A E- Editor: Lu YJ

References
1.  Burningham Z, Hashibe M, Spector L, Schiffman JD. The epidemiology of sarcoma. Clin Sarcoma Res. 2012;2:14.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 396]  [Cited by in F6Publishing: 378]  [Article Influence: 31.5]  [Reference Citation Analysis (0)]
2.  Stat Database: Incidence - SEER 9 Regs Research Data, Nov 2010 Sub (1973-2008) - Linked To County Attributes - Total U.S., 1969-2009. Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2011, based on the November 2010 submission. Surveillance, Epidemiology, and End Results (SEER) Program.  Available from: http://www.seer.cancer.gov.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  National Cancer Institute. A Snapshot of Sarcoma. 2010; Available from: http://www.cancer.gov/aboutnci/servingpeople/cancer-statistics/snapshots.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Mulder RL, Paulides M, Langer T, Kremer LC, van Dalen EC. Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients. Cochrane Database Syst Rev. 2015;CD006300.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 3]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
5.  Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma, and Ewing’s sarcoma: National Cancer Data Base Report. Clin Orthop Relat Res. 2007;459:40-47.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 332]  [Cited by in F6Publishing: 345]  [Article Influence: 20.3]  [Reference Citation Analysis (0)]
6.  Coley WB. II. Contribution to the Knowledge of Sarcoma. Ann Surg. 1891;14:199-220.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Modlin RL. Innate immunity: ignored for decades, but not forgotten. J Invest Dermatol. 2012;132:882-886.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 26]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
8.  Ray-Coquard I, Thiesse P, Ranchère-Vince D, Chauvin F, Bobin JY, Sunyach MP, Carret JP, Mongodin B, Marec-Bérard P, Philip T. Conformity to clinical practice guidelines, multidisciplinary management and outcome of treatment for soft tissue sarcomas. Ann Oncol. 2004;15:307-315.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471-1474.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5537]  [Cited by in F6Publishing: 6120]  [Article Influence: 437.1]  [Reference Citation Analysis (0)]
10.  Van Glabbeke M, van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, Verweij J, Santoro A, Buesa J, Tursz T. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 1999;17:150-157.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 414]  [Cited by in F6Publishing: 442]  [Article Influence: 17.7]  [Reference Citation Analysis (0)]
11.  Mccarter MD, Jaques DP, Brennan MF. Randomized clinical trials in soft tissue sarcoma. Surg Oncol Clin N Am. 2002;11:11-22.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Kolb EA, Kushner BH, Gorlick R, Laverdiere C, Healey JH, La Quaglia MP, Huvos AG, Qin J, Vu HT, Wexler L. Long-term event-free survival after intensive chemotherapy for Ewing’s family of tumors in children and young adults. J Clin Oncol. 2003;21:3423-3430.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J, Benjamin RS. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998;21:317-321.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Yovine A, Riofrio M, Blay JY, Brain E, Alexandre J, Kahatt C, Taamma A, Jimeno J, Martin C, Salhi Y. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol. 2004;22:890-899.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 241]  [Cited by in F6Publishing: 256]  [Article Influence: 12.8]  [Reference Citation Analysis (0)]
15.  Aurias A, Rimbaut C, Buffe D, Zucker JM, Mazabraud A. Translocation involving chromosome 22 in Ewing’s sarcoma. A cytogenetic study of four fresh tumors. Cancer Genet Cytogenet. 1984;12:21-25.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Coindre JM. [Molecular biology of soft-tissue sarcomas]. Bull Cancer. 2010;97:1337-1345.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Coens C, van der Graaf WT, Blay JY, Chawla SP, Judson I, Sanfilippo R, Manson SC, Hodge RA, Marreaud S, Prins JB. Health-related quality-of-life results from PALETTE: A randomized, double-blind, phase 3 trial of pazopanib versus placebo in patients with soft tissue sarcoma whose disease has progressed during or after prior chemotherapy-a European Organization for research and treatment of cancer soft tissue and bone sarcoma group global network study (EORTC 62072). Cancer. 2015;121:2933-2941.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 62]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
18.  Linch M, Miah AB, Thway K, Judson IR, Benson C. Systemic treatment of soft-tissue sarcoma-gold standard and novel therapies. Nat Rev Clin Oncol. 2014;11:187-202.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 135]  [Cited by in F6Publishing: 159]  [Article Influence: 15.9]  [Reference Citation Analysis (0)]
19.  Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3297]  [Cited by in F6Publishing: 4123]  [Article Influence: 374.8]  [Reference Citation Analysis (1)]
22.  Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013;39:61-73.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 387]  [Cited by in F6Publishing: 418]  [Article Influence: 38.0]  [Reference Citation Analysis (0)]
23.  Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565-1570.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3828]  [Cited by in F6Publishing: 4149]  [Article Influence: 319.2]  [Reference Citation Analysis (0)]
24.  Predina J, Eruslanov E, Judy B, Kapoor V, Cheng G, Wang LC, Sun J, Moon EK, Fridlender ZG, Albelda S. Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc Natl Acad Sci USA. 2013;110:E415-E424.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 116]  [Cited by in F6Publishing: 123]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
25.  Kim C, Kim EK, Jung H, Chon HJ, Han JW, Shin KH, Hu H, Kim KS, Choi YD, Kim S. Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma. BMC Cancer. 2016;16:434.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 114]  [Article Influence: 14.3]  [Reference Citation Analysis (0)]
26.  Lussier DM, O’Neill L, Nieves LM, McAfee MS, Holechek SA, Collins AW, Dickman P, Jacobsen J, Hingorani P, Blattman JN. Enhanced T-cell immunity to osteosarcoma through antibody blockade of PD-1/PD-L1 interactions. J Immunother. 2015;38:96-106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 122]  [Cited by in F6Publishing: 142]  [Article Influence: 15.8]  [Reference Citation Analysis (0)]
27.  Worley BS, van den Broeke LT, Goletz TJ, Pendleton CD, Daschbach EM, Thomas EK, Marincola FM, Helman LJ, Berzofsky JA. Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations. Cancer Res. 2001;61:6868-6875.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Tseng WW, Somaiah N, Engleman EG. Potential for immunotherapy in soft tissue sarcoma. Hum Vaccin Immunother. 2014;10:3117-3124.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 25]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
29.  Maki RG. Immunity against soft-tissue sarcomas. Curr Oncol Rep. 2003;5:282-287.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Yee C. The use of endogenous T cells for adoptive transfer. Immunol Rev. 2014;257:250-263.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 54]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
31.  Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917-924.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1151]  [Cited by in F6Publishing: 1190]  [Article Influence: 91.5]  [Reference Citation Analysis (0)]
32.  Sangiolo D, Mesiano G, Gammaitoni L, Leuci V, Todorovic M, Giraudo L, Cammarata C, Dell’Aglio C, D’Ambrosio L, Pisacane A. Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas. Cancer Res. 2014;74:119-129.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 59]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
33.  Ratnavelu K, Subramani B, Pullai CR, Krishnan K, Sugadan SD, Rao MS, Veerakumarasivam A, Deng X, Hiroshi T. Autologous immune enhancement therapy against an advanced epithelioid sarcoma: A case report. Oncol Lett. 2013;5:1457-1460.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
34.  Mahvi DM, Shi FS, Yang NS, Weber S, Hank J, Albertini M, Schiller J, Schalch H, Larson M, Pharo L. Immunization by particle-mediated transfer of the granulocyte-macrophage colony-stimulating factor gene into autologous tumor cells in melanoma or sarcoma patients: report of a phase I/IB study. Hum Gene Ther. 2002;13:1711-1721.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 27]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
35.  Dillman R, Barth N, Selvan S, Beutel L, de Leon C, DePriest C, Peterson C, Nayak S. Phase I/II trial of autologous tumor cell line-derived vaccines for recurrent or metastatic sarcomas. Cancer Biother Radiopharm. 2004;19:581-588.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 20]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
36.  Kawaguchi S, Wada T, Ida K, Sato Y, Nagoya S, Tsukahara T, Kimura S, Sahara H, Ikeda H, Shimozawa K. Phase I vaccination trial of SYT-SSX junction peptide in patients with disseminated synovial sarcoma. J Transl Med. 2005;3:1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 74]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
37.  Sato Y, Nabeta Y, Tsukahara T, Hirohashi Y, Syunsui R, Maeda A, Sahara H, Ikeda H, Torigoe T, Ichimiya S. Detection and induction of CTLs specific for SYT-SSX-derived peptides in HLA-A24(+) patients with synovial sarcoma. J Immunol. 2002;169:1611-1618.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Kawaguchi S, Tsukahara T, Ida K, Kimura S, Murase M, Kano M, Emori M, Nagoya S, Kaya M, Torigoe T. SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: a study from the Japanese Musculoskeletal Oncology Group. Cancer Sci. 2012;103:1625-1630.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 83]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
39.  Takahashi R, Ishibashi Y, Hiraoka K, Matsueda S, Kawano K, Kawahara A, Kage M, Ohshima K, Yamanaka R, Shichijo S. Phase II study of personalized peptide vaccination for refractory bone and soft tissue sarcoma patients. Cancer Sci. 2013;104:1285-1294.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 31]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
40.  Finkelstein SE, Iclozan C, Bui MM, Cotter MJ, Ramakrishnan R, Ahmed J, Noyes DR, Cheong D, Gonzalez RJ, Heysek RV. Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. Int J Radiat Oncol Biol Phys. 2012;82:924-932.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 97]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
41.  Ghisoli M, Barve M, Schneider R, Mennel R, Lenarsky C, Wallraven G, Pappen BO, LaNoue J, Kumar P, Nemunaitis D. Pilot Trial of FANG Immunotherapy in Ewing’s Sarcoma. Mol Ther. 2015;23:1103-1109.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 38]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
42.  Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8900]  [Cited by in F6Publishing: 9330]  [Article Influence: 777.5]  [Reference Citation Analysis (0)]
43.  Kim JR, Moon YJ, Kwon KS, Bae JS, Wagle S, Kim KM, Park HS, Lee H, Moon WS, Chung MJ. Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS One. 2013;8:e82870.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 195]  [Cited by in F6Publishing: 227]  [Article Influence: 20.6]  [Reference Citation Analysis (0)]
44.  Maki RG, Jungbluth AA, Gnjatic S, Schwartz GK, D’Adamo DR, Keohan ML, Wagner MJ, Scheu K, Chiu R, Ritter E. A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients with Synovial Sarcoma. Sarcoma. 2013;2013:168145.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 98]  [Cited by in F6Publishing: 132]  [Article Influence: 12.0]  [Reference Citation Analysis (0)]
45.  Paoluzzi L, Ghesani MV, Cacavio A, Rapkiewicz A, Rosen G. Anti-PD1 therapy with nivolumab in sarcoma. J Clin Oncol. 2016;34 suppl:abstr 11047. [accessed 2016 Sep 3] Available from: http://meetinglibrary.asco.org/content/166876-176.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  D’Angelo SP, Shoushtari AN, Agaram NP, Kuk D, Qin LX, Carvajal RD, Dickson MA, Gounder M, Keohan ML, Schwartz GK. Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol. 2015;46:357-365.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 185]  [Cited by in F6Publishing: 220]  [Article Influence: 22.0]  [Reference Citation Analysis (0)]