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BioMed Research International
Volume 2015, Article ID 820813, 11 pages
http://dx.doi.org/10.1155/2015/820813
Review Article

Immunotherapy for Bone and Soft Tissue Sarcomas

1Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
2Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
3Center of Innovative Medicine, Okayama University Hospital, Okayama 700-8558, Japan
4Department of Intelligent Orthopaedic System, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
5Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan

Received 25 July 2014; Accepted 13 November 2014

Academic Editor: Mohammad Owais

Copyright © 2015 Takenori Uehara et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.

1. Introduction

Sarcomas are malignant tumors of mesenchymal origin, including bones, muscles, fat, nerves, and blood vessels. According to the Surveillance Epidemiology and End Results (SEER) database, prevalence of sarcoma accounts for nearly 21% of all pediatric solid malignant tumors and less than 1% of all adult solid malignant tumors [1]. It was estimated that approximately 11,400 Americans would be diagnosed with soft tissue sarcomas and 3,000 with bone sarcoma in 2013 [2]. Based on the survival data obtained from the National Cancer Data Base of the American College of Surgeons, the relative 5-year survival rate is approximately 66% for patients with bone and soft tissue sarcomas, 53.9% for osteosarcomas ( 8,104), 75.2% for chondrosarcoma ( 6,476), and 50.6% for Ewing’s sarcomas ( 3,225) [3]. According to the classification by the World Health Organization, the group of bone and soft tissue sarcomas includes more than 100 histological subtypes [4]. The prognosis of patients with bone and soft tissue sarcomas is associated with histological diagnoses [5]. Standard treatment modalities include surgical resection, chemotherapy, and often radiotherapy [68]. Despite these multimodality therapies, survival rates have not been improved over recent 20 years [9]. Therefore, new effective treatment over conventional therapy is urgently needed.

Historically, Coley reported a case of unresectable small-cell sarcoma of the neck in 1891. The sarcoma completely regressed after a severe episode of erysipelas. He reported that a systemic response against erysipelas influenced the patient’s tumor [10]. The mechanism by which erysipelas caused tumor regression was unclear at that time. However, it is now understood that the activation of innate immunity through Toll-like receptors (TLRs) by erysipelas followed by activation of acquired immunity specific to sarcoma may contribute to the underlying mechanism [11]. Thus, the case described by Coley was the first to demonstrate that the immune system is involved in the spontaneous regression of sarcomas. Over the past 100 years, his work had encouraged many scientists to work on cancer immunology, in an attempt to find a cure for cancers [12, 13].

The dissection of the molecular mechanisms of innate and acquired immunity has enabled medical doctors and scientists to apply various cancer immunotherapies such as vaccines, antibodies, adjuvants, and cell therapies [2931]. Utilizing modern cancer immunotherapies for patients with sarcomas began in the 1980s as a cytokine therapy [32, 33], and more recently antigen-specific cancer vaccines and/or cell therapies have been developed [34, 35].

2. Overview of Cancer Immunology

2.1. Immune System Overview

Knowledge about the immune system is essential for understanding the principles underpinning cancer immunotherapy. There are two types of immune responses against microbes: called innate and adaptive immunity [36]. Innate immunity, whose main components are phagocytic cells (neutrophils and macrophages) and natural killer cells, provides the initial defense against invading microbes during infection [37, 38]. Small molecular proteins called cytokines mediate many activities of the cells involved in innate immunity. In addition to cytokines, pattern recognition molecules such as TLRs expressed on dendritic cells (DCs) and macrophages play critical roles in the activation of innate immunity. These components also have a role in communicating with acquired (adaptive) immunity [39, 40]. The key components of adaptive immunity, following the initial innate immunity, are T and B lymphocytes. The lymphocytes play a central role in eliminating infectious pathogens, virus infected cells, and cancer cells and also in generating antigen-specific memory cells [37].

Adaptive immunity consists of humoral and cell-mediated immunity. T lymphocytes recognize short peptides as antigens presented by major histocompatibility complexes (MHCs) on the cell surface of DCs [41, 42]. CD8 and CD4 T cells recognize antigen in the context of MHC class I and class II molecules, respectively [43, 44]. Primed and activated T cells differentiate into mature effector cells while undergoing clonal expansion. The effector CD8 T cells recognize virus infected cells and tumor cells and eliminate them from the body. The differentiation of naïve CD8 T cells into effector and memory CD8 T cells is mediated by the “help” of CD4 T cells or by a stimulation of TLRs of DC [4345]. “Help” means signals occurring within DCs whose CD40 interacts with CD40L of CD4 T cells to express large amounts of CD80/86 to interact with CD28 of CD8 T cells [4648]. Signals from either CD40 or TLRs activate DCs, and this process then initiates the activation of naïve CD8 T cells following antigen recognition [49].

DCs, B cells, and macrophages are professional antigen-presenting cells (APCs) [50, 51]. Among them, DCs are the most effective APCs [51, 52]. For example, B cells and macrophages present endogenous and internalized exogenous antigens with MHC class I and class II molecules [53], respectively. Therefore, B cells and macrophages can only activate CD4 T cells when they internalize extracellular antigens [54]. On the other hand, DCs are able to process both endogenous and exogenous antigens with MHC class I molecules to activate CD8 T cells. This is referred to as cross-presentation and is essential in fighting against virus infected cells and tumor cells [5557].

2.2. Tumor Immunology and Immune Checkpoint

Tumor antigens recognized by the immune system are categorized into cancer testis antigens (CTAs), melanocyte differentiation antigens, mutated proteins, overexpressed proteins, and viral antigens [58] (Figure 1). Several types of CTAs have been identified in patients with sarcomas (Table 1). Because tumor antigens are potential targets that induce cytotoxic immune responses [59], many clinical trials have utilized tumor antigens as vaccines for decades. The results, however, are limited and the desired therapeutic effect is not achieved [60, 61].

Table 1: Cancer testis antigens in bone and soft tissue sarcomas.
Figure 1: An overview of tumor immunology. Tumor cells are initially attacked by the innate immune system. DCs capture tumor antigens at the tumor site and migrate to the tumor draining lymph nodes. DCs present the tumor antigen to T cells within the lymph node. Antigen-specific CD4 and CD8 T cells are stimulated by DCs. After stimulation, T cells differentiate into effector cells and activate at the tumor site. Effector CD8 T cells kill tumor cells, although their function is regulated by the immune checkpoint mechanism. NK: natural killer cell; MP: macrophage; DC: dendritic cell.

Although antitumor immunity is induced in patients with cancer vaccines, recent advancements in cancer immunity have revealed the presence of immune-inhibitory mechanisms, referred to as immune checkpoints [62], in the draining of lymph nodes and tumor sites. CTLA-4, a protein receptor expressed on T cells, downregulates T cell activation [63]. The structure of CTLA-4 is similar to CD28, with a T cell costimulatory receptor. Immune inhibition is caused by the competition between CD28 and CTLA-4 to bind CD80/86 on DCs [64]. Regulatory T cells (Tregs) that define CD4+CD25+Foxp3+ T cells highly express CTLA-4 and suppress the activation of cytotoxic lymphocytes [65]. The inhibition of activated T cells via CTLA-4 occurs particularly within draining lymph nodes [66]. Programmed cell death protein 1 (PD1) is also an immune checkpoint receptor expressed on T cells, particularly cytotoxic lymphocytes [67, 68]. Tumor cells upregulate the expression of PD-ligand 1(PD-L1), and the interaction of PD1 with PD-L1 downregulates the function of T cells within the tumor microenvironment [69, 70]. The immune checkpoint is therefore considered to be an important therapeutic target. Anti-CTLA-4 and anti-PD1 antibodies have been introduced for clinical use in some cancers [71]. In addition to CTLA4 and PD-1, there are similar cell surface molecules of activated effector T cells, such as Tim-3 and LAG3, that suppress tumor immunity [72]. Inflammation in the tumor microenvironment induces STAT3 activation within tumors and Tregs. In contrast, STAT3 in certain tumors is constitutively activated by genetic alterations [73, 74]. STAT3 activation leads tumor cells and Tregs to express molecules that are related to immune checkpoints, such as PD-L1, and eventually inhibit T cell function [75, 76].

3. Outcomes of Clinical Trials for Bone and Soft Tissue Sarcomas

Treatments for bone and soft tissue sarcomas include surgery, chemotherapy, and radiotherapy. To date, clinical results of combined therapies have been more successful than those of surgical approaches. However, as described above, the prognosis of bone and soft tissue sarcomas has plateaued since the 1990s. In these recent years, immunotherapies are expected to further improve the prognosis of patients, and several clinical trials have been performed (Tables 2 and 3).

Table 2: Clinical trials stimulating innate immunity against bone and soft tissue sarcomas.
Table 3: Clinical trials stimulating adaptive immunity against bone and soft tissue sarcomas.
3.1. Cytokine Therapies

Cytokines are proteins that regulate the immune system. Interleukin-2 (IL-2) and interferons (IFNs) have been used in the immunotherapy for sarcomas [77], and clinical results are evident. IL-2 leads to the activation and expansion of CD4 and CD8 T cells [78]. Rosenberg et al. established a tumor regression model involving recombinant IL-2 injection for murine melanoma and sarcomas [32]. Then, several studies described the effectiveness of high-dose IL-2 therapy for patients with metastatic melanomas [79, 80]. Therefore, recombinant IL-2 was administered to patients with bone and soft tissue sarcomas [16]. Schwinger et al. reported a positive clinical result using a high-dose IL-2 treatment in two patients with Ewing’s sarcomas and four patients with metastatic osteosarcomas. Patients had already been treated with surgery (1–5 times), chemotherapy (7–43 cycles), and radiation therapy (for patients with Ewing’s sarcoma). Although one patient with metastatic osteosarcoma progressed during the treatment period, two patients with osteosarcoma achieved complete responses with a median follow-up time of 28 months (range: 11–36 months). However, all patients experienced adverse effects such as fatigue, anorexia, diarrhea, nausea, vomiting, and high-grade fever. Two patients could not undergo IL-2 therapy [16]. Furthermore, the other initial study reported treatment related death caused in 1-2% of patients [81]. Consequently, it limited the administration of high-dose IL-2 therapy for its adverse effect [81, 82].

The use of IFN-α as an adjuvant therapy was initiated at the Karolinska Hospital in 1971 [19]. The Karolinska Hospital group reported that 10-year results of adjuvant IFN-α therapy. The clinical outcome was improved by introducing adjuvant IFN-α therapy. The metastasis-free survival rate was 39% and the sarcoma-free survival rate was 43% in adjuvant IFN therapy group. These clinical results were better than the group of surgiral therapy only (15–20%) [83]. COSS-80 study investigated the effectiveness of use of adjuvant chemotherapy with IFN [20]. The 30-month disease-free survival rate of the IFN arm was 77% and that of non-IFN arm 73%. However, there was no significant difference between two groups; EURAMOS-1 study, a recent study in Europe, investigated the efficacy of the use of adjuvant chemotherapy with pegylated-IFNα-2b [21]. In the interim statement, the median follow-up time in EURAMOS-1 study was 3.1 years. The event-free survival rate was 77% in the group with chemotherapy and IFN and 73% in the group without IFN [19]. This difference was also not significant. These observations suggest that conventional chemotherapy with IFN improves the prognosis of bone and soft tissue sarcomas to some extent.

3.2. Mifamurtide

Mifamurtide, liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), is a new agent that is a synthetic analog of a muramyl dipeptide (MDP) [22]. Although its pharmacological behavior is similar to that of MDP, L-MTP-PE has a longer half-life than MDP [84]. The intracellular pattern recognition molecule NOD2 detects MDP and enhances NF-κB signaling [85]. Therefore, recognition of L-MTP-PE by NOD2 stimulates the production of IL-1β, IL-6, and TNF-α via the activation of NF-κB signaling in monocytes and macrophages [86, 87].

The efficacy of L-MTP-PE treatment for osteosarcomas has been examined in dogs. Dogs with postoperative osteosarcomas were treated by intravenous L-MTP-PE injections. The median survival time of dogs treated by L-MTP-PE (222 days) was longer than that of nontreated dogs (77 days) [88]. In human, intergroup study 0133 (INT 0133) began in 1993. 662 patients with osteosarcoma were recruited in this study. The aim of the study was to evaluate the efficacy of supplementation with ifosfamide (IFO) and L-MTP-PE in basic adjuvant chemotherapy (cisplatin, doxorubicin, and high-dose methotrexate (MAP)). Patients were randomly assigned to receive MAP alone, MAP + IFO, MAP + L-MTP-PE, and MAP + IFO + L-MTP-PE. It was observed that the addition of L-MTP-PE to chemotherapy improved the six-year overall survival rate from 70% to 78% (). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI: 0.52–0.96) [22, 89]. Therefore, L-MTP-PE has been approved in Europe for the treatment of osteosarcoma with chemotherapy. However, it has not been approved by FDA in the United States [87].

3.3. Vaccines

Multiple clinical trials using vaccines that target whole cells, lysates, proteins, and peptides have been investigated in patients with sarcomas [9092]. Vaccines are combined with costimulatory adjuvants such as GM-CSF or IL-2 to enhance the immune response [93]. Therapeutic tumor vaccines are presented as antigen epitopes on MHC molecules by APCs. Tumor antigen specific T cells are activated by APCs. The aim of cancer vaccines is to stimulate the patient’s own immune system to eliminate the tumor [94].

Autologous sarcoma cell lysates can be used as a vaccine in patients with sarcomas. A clinical study was performed to treat patients using their autologous tumor cell lysate as vaccines [23]. The study recruited 86 patients with sarcomas and tryed to establish short-term cell lines in vitro. 25 patients, who had an established tumor cell line, were injected with the tumor lysate vaccine. Before vaccine treatment, patients were screened to ensure they were not positive for delayed-type hypersensitivity (DTH) to irradiated tumor cells. After treatment, eight patients became positive for DTH. The median survival time of patients who became positive for DTH (16.6 months) was eight months longer than that of DTH-negative patients (8.2 months). However, objective responses were not recorded [23]. In the result, tumor lysate vaccines improved the survival time, but tumor regression disappeared.

Autologous DCs that are pulsed ex vivo with tumor cell lysate can stimulate host antitumor immunity [95, 96]. Adjuvant therapies using tumor lysate-pulsed DCs were investigated for children with solid tumors including bone and soft tissue sarcomas. After tumor lysate-pulsed DC transfer, 70% of patients changed positively in the DTH test. This study resulted in one patient achieving complete remission and in five patients, the disease stabilized during the follow-up period of 16–30 months [97].

Tumor specific or overexpressed peptides are possible for therapeutic targets for antigen-specific immunotherapy [98, 99]. Bone and soft tissue sarcomas can have specific gene mutations and express mutated proteins [100]. Synovial sarcomas are known to have chromosomal translocation and synthesize the SYT-SSX mutated protein [101]. Kawaguchi et al. treated patients who had synovial sarcomas with SYT-SSX fusion gene-derived peptides [102]. The study enrolled 21 patients, who were injected subcutaneously with the 9 mer peptide with or without incomplete Freund’s adjuvant (IFA) and IFN-α. Nine patients were injected with the peptide alone, and later in the study, 12 patients were injected the peptide with IFA and IFN-α. After treatment, in seven patients, the peptide tetramer-positive CD8 T cells appeared in PBMCs. With regard to the clinical result, in six patients, the disease stabilized during vaccination; however, in other patients, the disease progressed [26].

Tumor antigen-specific peptide pulsed DCs can stimulate peptide specific T cells 150 times more efficient than peptide alone [103]. Tumor-specific peptide pulsed DCs have been administered for immunotherapy against sarcoma, leukemia, and glioma [104]. 30 patients with Ewing’s sarcomas and alveolar rhabdomyosarcoma were enrolled in a study for consolidative therapy. Patients were separated into three cohorts that received different dose of IL-2 (high, low, and none). Monocyte-derived DCs were cultured with tumor-derived breakpoint peptides (EWS-FLI1, EWS-FLI2, and PAX3/FKHR), and the E7 peptide was used as control [24]. After treatment, 39% of patients generated immune responses to the vaccinating peptide. The five-year overall survival of the immunotherapy group was 43% and that of the no-immunotherapy group was 31% [24]. Further, this treatment showed no severe adverse effect. For these reasons, vaccines from tumor cell lysate or tumor specific peptide can activate adaptive immune response against tumors. Antigen-specific peptide pulsed DCs can also enhance immune response. Vaccine therapies have validity for bone and soft tissue sarcomas.

CTAs are expressed only in germ line cells in humans; however, they are also expressed in various tumors [105]. More than 40 antigens have been identified [105]. For example, NY-ESO-1 is expressed in many osteosarcomas, leiomyosarcomas, and synovial sarcomas and LAGE-1 is expressed in liposarcomas, leiomyosarcomas, and synovial sarcomas (Table 1) [106]. MAGE-A3 was administered to patients with stage III/IV melanoma [107]. The effectiveness of MAGE-A3 against non-small-cell lung cancer (NSCLC) was reported in a phase II clinical trial [108, 109]. Thus CTAs have a potential to be immunotherapeutic targets against bone and soft tissue sarcomas.

3.4. Adoptive Cell Transfer

Adoptive cell transfer therapy is considered to provide large number of tumor reactive CD8T cells that secrete high levels of cytokines, IFNγ, TNFα, and IL-2 [110]. Tumor infiltrating lymphocytes (TILs) include tumor reactive CD8T cells. Antigen-specific T cells were sorted from patients. T cells were expanded and stimulated ex vivo. After ex vivo treatment, activated effector T cells were transferred to patients [110]. A small study examined six patients with synovial sarcomas or metastatic melanomas expressing NY-ESO-1. For inducing tumor lysis, T cell receptor (TCR) gene-modified T cells redirected towards NY-ESO-1 were generated [28]. Modified TCR displayed T cells were expanded with IL-2 ex vivo and then transferred to patients [111]. Two patients with melanoma showed complete regression, and 1 patient with synovial sarcoma showed disease stabilization for 18 months. Some types of adoptive cell transfer therapies are ongoing for patients with sarcomas, including autologous DC transport therapy for soft tissue sarcomas (NCT01347034) and hematopoietic cell transplantation and natural killer cell transport therapies for Ewing’s sarcomas and rhabdomyosarcomas (NCT02100891).

3.5. Immune Checkpoint Blockade

Immune checkpoint blockade is likely to advance anticancer immunology. Ipilimumab, a fully human monoclonal antibody (IgG1), blocks CTLA-4 and promotes antitumor immunity [112]. Patients with metastatic melanomas treated with ipilimumab showed improved overall survival (from 6.4 months to 10.0 months) [113]. Six patients with advanced synovial sarcoma enrolled in a phase II study were treated with ipilimumab. The overall survival time ranged from 0.77 to 19.7 months (median: 8.75 months). Immunological responses after the treatment were different in each patient, and three patients showed an enhanced titer of CT24 (an uncharacterized CTA). All sarcomas expressed NY-ESO-1; however, NY-ESO-1 titers did not show any remarkable change [114].

Another immune checkpoint blockade agent is a human monoclonal anti-PD-1 antibody, called nivolumab [115]. Nivolumab has demonstrated efficacy against several types of cancers including melanoma, NSCLC, prostate cancer, renal cell carcinoma, and colorectal cancer [116]. The reported clinical outcomes of nivolumab therapies include a cumulative response rate of 18% among patients with NSCLC, 28% among patients with melanoma, and 27% among patients with renal cell carcinoma [116]. Furthermore, a phase I trial of nivolumab combined with ipilimumab enrolled 53 patients with advanced melanoma. This trial reported that 53% of patients experienced grade 3 or 4 adverse effects related to the therapy and 53% of patients had an objective response. Among patients treated with ipilimumab as a control, 20% had an objective response [117]. Thus, immune checkpoint blockade agents demonstrate efficacy in some types of tumors; however, further information is required to confirm the effectiveness of the immune blockade agents ipilimumab and nivolumab for bone and soft tissue sarcomas.

4. Conclusion and Future Directions

Conventional treatment for bone and soft tissue sarcomas consists of surgical resection, chemotherapy, and radiotherapy. However, clinical outcomes by these therapeutic modalities have not significantly improved in recent decades. Under these circumstances, immunotherapy is expected to be a new therapeutic option for treatment. Cytokine therapies were initially regarded as a form of immunotherapy; however, their effectiveness was limited because of their toxicities. Only IFN-α-2 is used for maintenance therapy. Although L-MTP-PE induces antitumor effects via macrophage activation, the FDA has not approved its use because of the limited effectiveness. In Europe, L-MTP-PE efficacy has been confirmed in an international multicenter study. Vaccine therapy using tumor lysates or lysate-derived DCs has been investigated only in small-scale studies and in nonsarcoma patients. CTA peptide and fusion protein peptide therapies are expected to be novel sarcoma-effective vaccines. Addition of L-MTP-PE as an adjuvant may improve the vaccine therapy outcome. Novel microparticle-based drug delivery systems, such as microemulsion, nanoemulsion, nanoparticles, liposomes, and others, can load many kinds of various drugs and improve the drug delivery to target sites [118121]. It has been reported that these systems improve the efficacy of vaccine and reduce adverse effects of cytokines [122124]. Tuftsin, a tetrapeptide (Thr-Lys-Pro-Arg) fraction of immunoglobulin G molecule, binds to neutrophils and macrophages [125127]. Tuftsin stimulates their phagocytic activity and enhances expression of nitric oxide synthase in macrophages. It has been demonstrated that tuftsin improves the efficacy of antibiotics against protozoan, bacterial, and fungal infections. Besides, tuftsin-bearing liposomized etoposide enhanced the therapeutic efficacy in murine fibrosarcoma models [128].

Immune checkpoint mechanism inhibits CD8 T cell function in tumor microenvironment [129]. Although immune checkpoint blockade molecules, anti-CTLA-4 antibody and anti-PD-1 antibody, have not been proven currently to have the effectiveness, there is too little information to decide efficacy of ipilimumab and nivolumab in sarcomas. Thus, immune checkpoint blockade medicines should be evaluated in the future. Adoptive cell transfer approaches are also the subject of new sarcoma treatment trials. Overall, these trials and successes suggest that immunotherapy is moving to the forefront of therapy for bone and soft tissue sarcomas.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

The authors acknowledge a grant-in-aid for Scientific Research on Applying Health Technology from the Ministry of Health, Labor and Welfare of Japan, and a grant-in-aid for Health and Labour Sciences Research Expenses for Commission, Applied Research for Innovative Treatment of Cancer from the Ministry of Health, Labour and Welfare (H26-084).

References

  1. Z. Burningham, M. Hashibe, L. Spector et al., “The epidemiology of sarcoma,” Clinical Sarcoma Research, vol. 2, no. 1, p. 14, 2012. View at Publisher · View at Google Scholar
  2. National Cancer Institute, A Snapshot of Sarcoma, 2013.
  3. T. A. Damron, W. G. Ward, and A. Stewart, “Osteosarcoma, chondrosarcoma, and Ewing's sarcoma: national cancer data base report,” Clinical Orthopaedics and Related Research, no. 459, pp. 40–47, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. L. A. Doyle, “Sarcoma classification: an update based on the 2013 world health organization classification of tumors of soft tissue and bone,” Cancer, vol. 120, no. 12, pp. 1763–1774, 2014. View at Publisher · View at Google Scholar · View at Scopus
  5. A. Italiano, A. le Cesne, J. Mendiboure et al., “Prognostic factors and impact of adjuvant treatments on local and metastatic relapse of soft-tissue sarcoma patients in the competing risks setting,” Cancer, vol. 120, no. 21, pp. 3361–3369, 2014. View at Google Scholar
  6. M. A. Tucker, G. J. D'Angio, J. D. Boice Jr. et al., “Bone sarcomas linked to radiotherapy and chemotherapy in children,” The New England Journal of Medicine, vol. 317, no. 10, pp. 588–593, 1987. View at Publisher · View at Google Scholar · View at Scopus
  7. A. N. van Geel, U. Pastorino, K. W. Jauch et al., “Surgical treatment of lung metastases: the European organization for research and treatment of cancer-soft tissue and bone sarcoma group study of 255 patients,” Cancer, vol. 77, no. 4, pp. 675–682, 1996. View at Publisher · View at Google Scholar
  8. S. S. Bielack, B. Kempf-Bielack, G. Delling et al., “Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols,” Journal of Clinical Oncology, vol. 20, no. 3, pp. 776–790, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. L. Mulder Renée, M. Paulides, T. Langer, L. C. Kremer, and E. C. van Dalen, “Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients,” Cochrane Database of Systematic Reviews, vol. 17, no. 2, Article ID CD006300, 2012. View at Publisher · View at Google Scholar
  10. W. B. Coley, “II. Contribution to the knowledge of sarcoma,” Annals of Surgery, vol. 14, no. 3, pp. 199–220, 1891. View at Google Scholar
  11. J. Kluwe, A. Mencin, and R. F. Schwabe, “Toll-like receptors, wound healing, and carcinogenesis,” Journal of Molecular Medicine, vol. 87, no. 2, pp. 125–138, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. F. Balkwill, “Tumour necrosis factor and cancer,” Nature Reviews Cancer, vol. 9, no. 5, pp. 361–371, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. R. L. Modlin, “Innate immunity: ignored for decades, but not forgotten,” Journal of Investigative Dermatology, vol. 132, no. 3, pp. 882–886, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. J. F. M. Jacobs, F. Brasseur, C. A. Hulsbergen-van de Kaa et al., “Cancer-germline gene expression in pediatric solid tumors using quantitative real-time PCR,” International Journal of Cancer, vol. 120, no. 1, pp. 67–74, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. K. M. Skubitz, S. Pambuccian, J. C. Carlos, and A. P. N. Skubitz, “Identification of heterogeneity among soft tissue sarcomas by gene expression profiles from different tumors,” Journal of Translational Medicine, vol. 6, article 23, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. W. Schwinger, V. Klass, M. Benesch et al., “Feasibility of high-dose interleukin-2 in heavily pretreated pediatric cancer patients,” Annals of Oncology, vol. 16, no. 7, pp. 1199–1206, 2005. View at Publisher · View at Google Scholar · View at Scopus
  17. H. Ito, K. Murakami, T. Yanagawa et al., “Effect of human leukocyte interferon on the metastatic lung tumor of osteosarcoma: case reports,” Cancer, vol. 46, no. 7, pp. 1562–1565, 1980. View at Google Scholar
  18. J. H. Edmonson, H. J. Long, S. Frytak, W. A. Smithson, and L. M. Itri, “Phase II study of recombinant alfa-2a interferon in patients with advanced bone sarcomas,” Cancer Treatment Reports, vol. 71, no. 7-8, pp. 747–748, 1987. View at Google Scholar · View at Scopus
  19. C. R. Müller, S. Smeland, H. C. F. Bauer, G. Sæter, and H. Strander, “Interferon-α as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series,” Acta Oncologica, vol. 44, no. 5, pp. 475–480, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. K. Winkler, G. Beron, R. Kotz et al., “Neoadjuvant chemotherapy for osteogenic sarcoma: Results of a cooperative German/Austrian study,” Journal of Clinical Oncology, vol. 2, no. 6, pp. 617–624, 1984. View at Google Scholar · View at Scopus
  21. S. S. Bielack, S. Smeland, J. Whelan et al., “MAP plus maintenance pegylated interferon alpha-2b (MAPIfn) versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 “good response” randomization,” Journal of Clinical Oncology, vol. 31, no. 18, 2013. View at Google Scholar
  22. L. Kager, U. Potschger, and S. Bielack, “Review of mifamurtide in the treatment of patients with osteosarcoma,” Therapeutics and Clinical Risk Management, vol. 6, no. 279–286, 2010. View at Google Scholar
  23. R. Dillman, N. Barth, S. Selvan et al., “Phase I/II trial of autologous tumor cell line-derived vaccines for recurrent or metastatic sarcomas,” Cancer Biotherapy and Radiopharmaceuticals, vol. 19, no. 5, pp. 581–588, 2004. View at Publisher · View at Google Scholar · View at Scopus
  24. C. L. Mackall, E. H. Rhee, E. J. Read et al., “A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas,” Clinical Cancer Research, vol. 14, no. 15, pp. 4850–4858, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. A. Suminoe, A. Matsuzaki, H. Hattori, Y. Koga, and T. Hara, “Immunotherapy with autologous dendritic cells and tumor antigens for children with refractory malignant solid tumors,” Pediatric Transplantation, vol. 13, no. 6, pp. 746–753, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Kawaguchi, T. Tsukahara, K. Ida et al., “SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: a study from the Japanese Musculoskeletal Oncology Group,” Cancer Science, vol. 103, no. 9, pp. 1625–1630, 2012. View at Publisher · View at Google Scholar · View at Scopus
  27. R. G. Maki, A. A. Jungbluth, S. Gnjatic et al., “A pilot study of anti-CTLA4 antibody ipilimumab in patients with synovial sarcoma,” Sarcoma, vol. 2013, Article ID 168145, 8 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  28. P. F. Robbins, R. A. Morgan, S. A. Feldman et al., “Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1,” Journal of Clinical Oncology, vol. 29, no. 7, pp. 917–924, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. G. Schuler, B. Schuler-Thurner, and R. M. Steinman, “The use of dendritic cells in cancer immunotherapy,” Current Opinion in Immunology, vol. 15, no. 2, pp. 138–147, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. L. Gattinoni, D. J. Powell Jr., S. A. Rosenberg, and N. P. Restifo, “Adoptive immunotherapy for cancer: building on success,” Nature Reviews Immunology, vol. 6, no. 5, pp. 383–393, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. S. A. Rosenberg, N. P. Restifo, J. C. Yang, R. A. Morgan, and M. E. Dudley, “Adoptive cell transfer: a clinical path to effective cancer immunotherapy,” Nature Reviews Cancer, vol. 8, no. 4, pp. 299–308, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. S. A. Rosenberg, J. J. Mule, P. J. Spiess, C. M. Reichert, and S. L. Schwarz, “Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2,” The Journal of Experimental Medicine, vol. 161, no. 5, pp. 1169–1188, 1985. View at Publisher · View at Google Scholar · View at Scopus
  33. W. H. West, K. W. Tauer, J. R. Yannelli et al., “Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer,” The New England Journal of Medicine, vol. 316, no. 15, pp. 898–905, 1987. View at Publisher · View at Google Scholar · View at Scopus
  34. S. A. Rosenberg, P. Spiess, and R. Lafreniere, “A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes,” Science, vol. 233, no. 4770, pp. 1318–1321, 1986. View at Publisher · View at Google Scholar · View at Scopus
  35. S. A. Rosenberg, J. C. Yang, and N. P. Restifo, “Cancer immunotherapy: moving beyond current vaccines,” Nature Medicine, vol. 10, no. 9, pp. 909–915, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. K. E. de Visser, A. Eichten, and L. M. Coussens, “Paradoxical roles of the immune system during cancer development,” Nature Reviews Cancer, vol. 6, no. 1, pp. 24–37, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. R. Medzhitov and C. A. Janeway Jr., “Innate immunity: the virtues of a nonclonal system of recognition,” Cell, vol. 91, no. 3, pp. 295–298, 1997. View at Publisher · View at Google Scholar · View at Scopus
  38. C. A. Janeway Jr. and R. Medzhitov, “Innate immune recognition,” Annual Review of Immunology, vol. 20, no. 1, pp. 197–216, 2002. View at Publisher · View at Google Scholar · View at Scopus
  39. T. Kawai and S. Akira, “TLR signaling,” Cell Death & Differentiation, vol. 13, no. 5, pp. 816–825, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. K. Takeda and S. Akira, “TLR signaling pathways,” Seminars in Immunology, vol. 16, no. 1, pp. 3–9, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. H. R. MacDonald and M. Nabholz, “T-cell activation,” Annual Review of Cell Biology, vol. 2, pp. 231–253, 1986. View at Publisher · View at Google Scholar · View at Scopus
  42. J. E. Smith-Garvin, G. A. Koretzky, and M. S. Jordan, “T cell activation,” Annual Review of Immunology, vol. 27, pp. 591–619, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Grakoui, S. K. Bromley, C. Sumen et al., “The immunological synapse: a molecular machine controlling T cell activation,” Science, vol. 285, no. 5425, pp. 221–227, 1999. View at Publisher · View at Google Scholar · View at Scopus
  44. S. M. Kaech, E. J. Wherry, and R. Ahmed, “Effector and memory T-cell differentiation: implications for vaccine development,” Nature Reviews Immunology, vol. 2, no. 4, pp. 251–262, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. S. M. Kaech, S. Hemby, E. Kersh, and R. Ahmed, “Molecular and functional profiling of memory CD8 T cell differentiation,” Cell, vol. 111, no. 6, pp. 837–851, 2002. View at Publisher · View at Google Scholar · View at Scopus
  46. D. Mauri, T. Wyss-Coray, H. Gallati, and W. J. Pichler, “Antigen-presenting T cells induce the development of cytotoxic CD4+ T cells. I. Involvement of the CD80-CD28 adhesion molecules,” The Journal of Immunology, vol. 155, no. 1, pp. 118–127, 1995. View at Google Scholar · View at Scopus
  47. I. S. Grewal and R. A. Flavell, “A central role of CD40 ligand in the regulation of CD4+ T-cell responses,” Immunology Today, vol. 17, no. 9, pp. 410–414, 1996. View at Publisher · View at Google Scholar · View at Scopus
  48. S. R. M. Bennett, F. R. Carbone, F. Karamalis, R. A. Flaveli, J. F. A. P. Miller, and W. R. Heath, “Help for cytotoxic-T-cell responses is mediated by CD40 signalling,” Nature, vol. 393, no. 6684, pp. 478–480, 1998. View at Publisher · View at Google Scholar · View at Scopus
  49. K. Murali-Krishna, J. D. Altman, M. Suresh et al., “Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection,” Immunity, vol. 8, no. 2, pp. 177–187, 1998. View at Publisher · View at Google Scholar · View at Scopus
  50. R. M. Steinman, “The dendritic cell system and its role in immunogenicity,” Annual Review of Immunology, vol. 9, pp. 271–296, 1991. View at Publisher · View at Google Scholar · View at Scopus
  51. J. Banchereau and R. M. Steinman, “Dendritic cells and the control of immunity,” Nature, vol. 392, no. 6673, pp. 245–252, 1998. View at Publisher · View at Google Scholar · View at Scopus
  52. M. L. Albert, B. Sauter, and N. Bhardwaj, “Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLS,” Nature, vol. 392, no. 6671, pp. 86–89, 1998. View at Publisher · View at Google Scholar · View at Scopus
  53. M. Corr, A. E. Slanetz, L. F. Boyd et al., “T cell receptor-MHC class I peptide interactions: affinity, kinetics, and specificity,” Science, vol. 265, no. 5174, pp. 946–949, 1994. View at Publisher · View at Google Scholar · View at Scopus
  54. P. R. Scholl, P. R. Scholl, R. S. Geha, and R. S. Geha, “MHC class II signaling in B-cell activation,” Immunology Today, vol. 15, no. 9, pp. 418–422, 1994. View at Publisher · View at Google Scholar · View at Scopus
  55. W. R. Heath and F. R. Carbone, “Cross-presentation, dendritic cells, tolerance and immunity,” Annual Review of Immunology, vol. 19, no. 1, pp. 47–64, 2001. View at Publisher · View at Google Scholar · View at Scopus
  56. H. Udono, T. Yamano, Y. Kawabata, M. Ueda, and K. Yui, “Generation of cytotoxic T lymphocytes by MHC class I ligands fused to heat shock cognate protein 70,” International Immunology, vol. 13, no. 10, pp. 1233–1242, 2001. View at Publisher · View at Google Scholar · View at Scopus
  57. A. L. Ackerman and P. Cresswell, “Cellular mechanisms governing cross-presentation of exogenous antigens,” Nature Immunology, vol. 5, no. 7, pp. 678–684, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Chiriva-Internati, A. Pandey, R. Saba et al., “Cancer testis antigens: a novel target in lung cancer,” International Reviews of Immunology, vol. 31, no. 5, pp. 321–343, 2012. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Stockert, E. Jäger, Y.-T. Chen et al., “A survey of the humoral immune response of cancer patients to a panel of human tumor antigens,” Journal of Experimental Medicine, vol. 187, no. 8, pp. 1349–1354, 1998. View at Publisher · View at Google Scholar · View at Scopus
  60. C. Coppin, F. Porzsolt, J. Kumpf, A. Coldman, and T. Wilt, “Immunotherapy for advanced renal cell cancer,” Cochrane Database of Systematic Reviews, 2004. View at Google Scholar · View at Scopus
  61. A. D. Sasse, E. C. Sasse, L. G. O. Clark, L. Ulloa, and O. A. C. Clark, “Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma,” Cochrane Database of Systematic Reviews, Article ID CD005413, 2007. View at Publisher · View at Google Scholar · View at Scopus
  62. G. A. Rabinovich, D. Gabrilovich, and E. M. Sotomayor, “Immunosuppressive strategies that are mediated by tumor cells,” Annual Review of Immunology, vol. 25, pp. 267–296, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. T. L. Walunas, D. J. Lenschow, C. Y. Bakker et al., “CTLA-4 can function as a negative regulator of T cell activation,” Immunity, vol. 1, no. 5, pp. 405–413, 1994. View at Publisher · View at Google Scholar · View at Scopus
  64. P. S. Linsley, J. L. Greene, W. Brady et al., “Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors,” Immunity, vol. 1, no. 9, pp. 793–801, 1994. View at Google Scholar
  65. K. Wing, Y. Onishi, P. Prieto-Martin et al., “CTLA-4 control over Foxp3+ regulatory T cell function,” Science, vol. 322, no. 5899, pp. 271–275, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. E. R. Kearney, T. L. Walunas, R. W. Karr et al., “Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4,” The Journal of Immunology, vol. 155, no. 3, pp. 1032–1036, 1995. View at Google Scholar · View at Scopus
  67. D. L. Barber, E. J. Wherry, D. Masopust et al., “Restoring function in exhausted CD8 T cells during chronic viral infection,” Nature, vol. 439, no. 7077, pp. 682–687, 2006. View at Publisher · View at Google Scholar · View at Scopus
  68. C. Petrovas, J. P. Casazza, J. M. Brenchley et al., “PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection,” The Journal of Experimental Medicine, vol. 203, no. 10, pp. 2281–2292, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. K. Sakuishi, L. Apetoh, J. M. Sullivan, B. R. Blazar, V. K. Kuchroo, and A. C. Anderson, “Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity,” Journal of Experimental Medicine, vol. 207, no. 10, pp. 2187–2194, 2010. View at Publisher · View at Google Scholar · View at Scopus
  70. Y. Latchman, C. R. Wood, T. Chernova et al., “PD-L2 is a second ligand for PD-1 and inhibits T cell activation,” Nature Immunology, vol. 2, no. 3, pp. 261–268, 2001. View at Publisher · View at Google Scholar · View at Scopus
  71. M. K. Callahan and J. D. Wolchok, “At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy,” Journal of Leukocyte Biology, vol. 94, no. 1, pp. 41–53, 2013. View at Publisher · View at Google Scholar · View at Scopus
  72. D. M. Pardoll, “The blockade of immune checkpoints in cancer immunotherapy,” Nature Reviews Cancer, vol. 12, no. 4, pp. 252–264, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Chaudhry, D. Rudra, P. Treuting et al., “CD4+ regulatory T cells control TH17 responses in a stat3-dependent manner,” Science, vol. 326, no. 5955, pp. 986–991, 2009. View at Publisher · View at Google Scholar · View at Scopus
  74. J. R. Brahmer, S. S. Tykodi, L. Q. M. Chow et al., “Safety and activity of anti-PD-L1 antibody in patients with advanced cancer,” The New England Journal of Medicine, vol. 366, no. 26, pp. 2455–2465, 2012. View at Publisher · View at Google Scholar · View at Scopus
  75. Y. Iwai, M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, and N. Minato, “Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 19, pp. 12293–12297, 2002. View at Publisher · View at Google Scholar · View at Scopus
  76. L. M. Francisco, V. H. Salinas, K. E. Brown et al., “PD-L1 regulates the development, maintenance, and function of induced regulatory T cells,” Journal of Experimental Medicine, vol. 206, no. 13, pp. 3015–3029, 2009. View at Publisher · View at Google Scholar · View at Scopus
  77. S. Lee and K. Margolin, “Cytokines in cancer immunotherapy,” Cancers, vol. 3, no. 4, pp. 3856–3893, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. J.-P. Shaw, P. J. Utz, D. B. Durand, J. J. Toole, E. A. Emmel, and G. R. Crabtree, “Indentification of a putative regulator of early T cell activation genes,” Science, vol. 241, no. 4862, pp. 202–205, 1988. View at Publisher · View at Google Scholar · View at Scopus
  79. M. T. Lotze, A. E. Chang, C. A. Seipp, C. Simpson, J. T. Vetto, and S. A. Rosenberg, “High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity, and histologic findings,” The Journal of the American Medical Association, vol. 256, no. 22, pp. 3117–3124, 1986. View at Publisher · View at Google Scholar · View at Scopus
  80. M. B. Atkins, M. T. Lotze, J. P. Dutcher et al., “High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993,” Journal of Clinical Oncology, vol. 17, no. 7, pp. 2105–2116, 1999. View at Google Scholar · View at Scopus
  81. R. N. Schwartz, L. Stover, and J. Dutcher, “Managing toxicities of high-dose interleukin-2,” Oncology, vol. 16, no. 11, pp. 11–20, 2002. View at Google Scholar · View at Scopus
  82. D. J. Schwartzentruber, “Guidelines for the safe administration of high-dose interleukin-2,” Journal of Immunotherapy, vol. 24, no. 4, pp. 287–293, 2001. View at Publisher · View at Google Scholar · View at Scopus
  83. M. P. Link, A. M. Goorin, A. W. Miser et al., “The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity,” The New England Journal of Medicine, vol. 314, no. 25, pp. 1600–1606, 1986. View at Publisher · View at Google Scholar · View at Scopus
  84. K. Ando, K. Mori, N. Corradini, F. Redini, and D. Heymann, “Mifamurtide for the treatment of nonmetastatic osteosarcoma,” Expert Opinion on Pharmacotherapy, vol. 12, no. 2, pp. 285–292, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. P. M. Anderson, M. Tomaras, and K. McConnell, “Mifamurtide in osteosarcoma-a practical review,” Drugs of Today, vol. 46, no. 5, pp. 327–337, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. K. Geddes, J. G. Magalhães, and S. E. Girardin, “Unleashing the therapeutic potential of NOD-like receptors,” Nature Reviews Drug Discovery, vol. 8, no. 6, pp. 465–479, 2009. View at Publisher · View at Google Scholar · View at Scopus
  87. J. E. Frampton, P. M. Anderson, A. J. Chou et al., “Mifamurtide: a review of its use in the treatment of osteosarcoma,” Pediatric Drugs, vol. 12, no. 3, pp. 141–153, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. E. G. MacEwen, I. D. Kurzman, R. C. Rosenthal et al., “Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide,” Journal of the National Cancer Institute, vol. 81, no. 12, pp. 935–938, 1989. View at Publisher · View at Google Scholar · View at Scopus
  89. P. A. Meyers, C. L. Schwartz, M. D. Krailo et al., “Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the children's oncology group,” Journal of Clinical Oncology, vol. 26, no. 4, pp. 633–638, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. M. Ayyoub, R. N. Taub, M. L. Keohan et al., “The frequent expression of cancer/testis antigens provides opportunities for immunotherapeutic targeting of sarcoma,” Cancer Immunity, vol. 4, no. 7, 2004. View at Google Scholar
  91. R. Takahashi, Y. Ishibashi, K. Hiraoka et al., “Phase II study of personalized peptide vaccination for refractory bone and soft tissue sarcoma patients,” Cancer Science, vol. 104, no. 10, pp. 1285–1294, 2013. View at Publisher · View at Google Scholar · View at Scopus
  92. S. E. Finkelstein, M. Fishman, A. P. Conley, D. Gabrilovich, S. Antonia, and A. Chiappori, “Cellular immunotherapy for soft tissue sarcomas,” Immunotherapy, vol. 4, no. 3, pp. 283–290, 2012. View at Publisher · View at Google Scholar · View at Scopus
  93. C. Harrison, “Vaccines: nanorings boost vaccine adjuvant effects,” Nature Reviews Drug Discovery, vol. 13, no. 7, pp. 496–496, 2014. View at Google Scholar
  94. M. Vergati, C. Intrivici, N.-Y. Huen, J. Schlom, and K. Y. Tsang, “Strategies for cancer vaccine development,” Journal of Biomedicine and Biotechnology, vol. 2010, Article ID 596432, 13 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. F. J. Hsu, C. Benike, F. Fagnoni et al., “Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells,” Nature Medicine, vol. 2, no. 1, pp. 52–58, 1996. View at Publisher · View at Google Scholar · View at Scopus
  96. C. M. Celluzzi, J. I. Mayordomo, W. J. Storkus, M. T. Lotze, and L. D. Falo Jr., “Peptide-pulsed dendritic cells induce antigen-specific, CTL-mediated protective tumor immunity,” Journal of Experimental Medicine, vol. 183, no. 1, pp. 283–287, 1996. View at Publisher · View at Google Scholar · View at Scopus
  97. J. D. Geiger, R. J. Hutchinson, L. F. Hohenkirk et al., “Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression,” Cancer Research, vol. 61, no. 23, pp. 8513–8519, 2001. View at Google Scholar · View at Scopus
  98. H. L. Chen and D. P. Carbone, “p53 as a target for anti-cancer immunotherapy,” Molecular Medicine Today, vol. 3, no. 4, pp. 160–167, 1997. View at Publisher · View at Google Scholar · View at Scopus
  99. S. Gnjatic, H. Nishikawa, A. A. Jungbluth et al., “NY-ESO-1: review of an immunogenic tumor antigen,” Advances in Cancer Research, vol. 95, pp. 1–30, 2006. View at Publisher · View at Google Scholar · View at Scopus
  100. S. A. Rosenberg, “A new era for cancer immunotherapy based on the genes that encode cancer antigens,” Immunity, vol. 10, no. 3, pp. 281–287, 1999. View at Publisher · View at Google Scholar · View at Scopus
  101. A. Kawai, J. Woodruff, J. H. Healey, M. F. Brennan, C. R. Antonescu, and M. Ladanyi, “SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma,” The New England Journal of Medicine, vol. 338, no. 3, pp. 153–160, 1998. View at Publisher · View at Google Scholar · View at Scopus
  102. S. Kawaguchi, T. Wada, K. Ida et al., “Phase I vaccination trial of SYT-SSX junction peptide in patients with disseminated synovial sarcoma,” Journal of Translational Medicine, vol. 3, article 1, 2005. View at Publisher · View at Google Scholar · View at Scopus
  103. L. He, H. Feng, A. Raymond et al., “Dendritic-cell-peptide immunization provides immunoprotection against bcr-abl-positive leukemia in mice,” Cancer Immunology, Immunotherapy, vol. 50, no. 1, pp. 31–40, 2001. View at Publisher · View at Google Scholar · View at Scopus
  104. R. Yamanaka, N. Yajima, T. Abe et al., “Dendritic cell-based glioma immunotherapy (review),” International Journal of Oncology, vol. 23, no. 1, pp. 5–15, 2003. View at Google Scholar · View at Scopus
  105. A. J. G. Simpson, O. L. Caballero, A. Jungbluth, Y.-T. Chen, and L. J. Old, “Cancer/testis antigens, gametogenesis and cancer,” Nature Reviews Cancer, vol. 5, no. 8, pp. 615–625, 2005. View at Publisher · View at Google Scholar · View at Scopus
  106. R. L. Jones, S. M. Pollack, E. T. Loggers, E. T. Rodler, and C. Yee, “Immune-based therapies for sarcoma,” Sarcoma, vol. 2011, Article ID 438940, 7 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  107. C. Roeder, B. Schuler-Thurner, S. Berchtold et al., “MAGE-A3 is a frequent tumor antigen of metastasized melanoma,” Archives of Dermatological Research, vol. 296, no. 7, pp. 314–319, 2005. View at Publisher · View at Google Scholar · View at Scopus
  108. W. Sienel, C. Varwerk, A. Linder et al., “Melanoma associated antigen (MAGE)-A3 expression in Stages I and II non-small cell lung cancer: results of a multi-center study,” European Journal of Cardio-Thoracic Surgery, vol. 25, no. 1, pp. 131–134, 2004. View at Publisher · View at Google Scholar · View at Scopus
  109. O. L. Caballero and Y.-T. Chen, “Cancer/testis (CT) antigens: potential targets for immunotherapy,” Cancer Science, vol. 100, no. 11, pp. 2014–2021, 2009. View at Publisher · View at Google Scholar · View at Scopus
  110. M. E. Dudley and S. A. Rosenberg, “Adoptive-cell-transfer therapy for the treatment of patients with cancer,” Nature Reviews Cancer, vol. 3, no. 9, pp. 666–675, 2003. View at Publisher · View at Google Scholar · View at Scopus
  111. D. W. Lee, D. M. Barrett, C. Mackall, R. Orentas, and S. A. Grupp, “The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer,” Clinical Cancer Research, vol. 18, no. 10, pp. 2780–2790, 2012. View at Publisher · View at Google Scholar · View at Scopus
  112. J. Weber, “Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events,” The Oncologist, vol. 12, no. 7, pp. 864–872, 2007. View at Publisher · View at Google Scholar · View at Scopus
  113. F. S. Hodi, S. J. O'Day, D. F. McDermott et al., “Improved survival with ipilimumab in patients with metastatic melanoma,” The New England Journal of Medicine, vol. 363, no. 8, pp. 711–723, 2010. View at Publisher · View at Google Scholar · View at Scopus
  114. K. Wiater, T. Witaj, J. Mackiewicz et al., “Efficacy and safety of ipilimumab therapy in patients with metastatic melanoma: a retrospective multicenter analysis,” Contemporary Oncology, vol. 17, no. 3, pp. 257–262, 2013. View at Publisher · View at Google Scholar · View at Scopus
  115. E. D. Deeks, “Nivolumab: a review of its use in patients with malignant melanoma,” Drugs, vol. 74, no. 11, pp. 1233–1239, 2014. View at Publisher · View at Google Scholar
  116. S. L. Topalian, F. S. Hodi, J. R. Brahmer et al., “Safety, activity, and immune correlates of anti-PD-1 antibody in cancer,” The New England Journal of Medicine, vol. 366, no. 26, pp. 2443–2454, 2012. View at Publisher · View at Google Scholar · View at Scopus
  117. J. D. Wolchok, H. Kluger, M. K. Callahan et al., “Nivolumab plus Ipilimumab in advanced melanoma,” The New England Journal of Medicine, vol. 369, no. 2, pp. 122–133, 2013. View at Publisher · View at Google Scholar · View at Scopus
  118. M. Farazuddinm, B. Sharma, A. A. Khan, B. Joshi, and M. Owais, “Anticancer effcacy of perillyl alcohol-bearing PLGA microparticles,” International Journal of Nanomedicine, vol. 7, pp. 35–47, 2012. View at Google Scholar · View at Scopus
  119. A. Khan, Y. Shukla, N. Kalra et al., “Potential of diallyl sulfide bearing pH-sensitive liposomes in chemoprevention against DMBA-induced skin papilloma,” Molecular Medicine, vol. 13, no. 7-8, pp. 443–451, 2007. View at Publisher · View at Google Scholar · View at Scopus
  120. M. Farazuddin, B. Dua, Q. Zia, A. A. Khan, B. Joshi, and M. Owais, “Chemotherapeutic potential of curcumin-bearing microcells against hepatocellular carcinoma in model animals,” International Journal of Nanomedicine, vol. 9, no. 1, pp. 1139–1152, 2014. View at Publisher · View at Google Scholar
  121. A. Chauhan, S. Zubair, A. Nadeem, S. A. Ansari, M. Y. Ansari, and O. Mohammad, “Escheriosome-mediated cytosolic delivery of PLK1-specific siRNA: potential in treatment of liver cancer in BALB/c mice,” Nanomedicine, vol. 9, no. 4, pp. 407–420, 2014. View at Publisher · View at Google Scholar · View at Scopus
  122. A. Chauhan, S. Zubair, S. Tufail et al., “Fungus-mediated biological synthesis of gold nanoparticles: potential in detection of liver cancer,” International Journal of Nanomedicine, vol. 6, pp. 2305–2319, 2011. View at Google Scholar · View at Scopus
  123. H. Singha, A. I. Mallick, C. Jana, N. Fatima, M. Owais, and P. Chaudhuri, “Co-immunization with interlukin-18 enhances the protective efficacy of liposomes encapsulated recombinant Cu-Zn superoxide dismutase protein against Brucella abortus,” Vaccine, vol. 29, no. 29-30, pp. 4720–4727, 2011. View at Publisher · View at Google Scholar · View at Scopus
  124. M. A. Khan, A. Aljarbou, A. Khan, and M. Owais, “Immune stimulating and therapeutic potential of tuftsin-incorporated nystatin liposomes against Cryptococcus neoformans in leukopenic BALB/C mice,” FEMS Immunology and Medical Microbiology, vol. 66, no. 1, pp. 88–97, 2012. View at Publisher · View at Google Scholar · View at Scopus
  125. M. A. Khan, A. Khan, and M. Owais, “Prophylactic use of liposomized tuftsin enhances the susceptibility of Candida albicans to fluconazole in leukopenic mice,” FEMS Immunology and Medical Microbiology, vol. 46, no. 1, pp. 63–69, 2006. View at Publisher · View at Google Scholar · View at Scopus
  126. M. A. Khan and M. Owais, “Toxicity, stability and pharmacokinetics of amphotericin B in immunomodulator tuftsin-bearing liposomes in a murine model,” Journal of Antimicrobial Chemotherapy, vol. 58, no. 1, pp. 125–132, 2006. View at Publisher · View at Google Scholar · View at Scopus
  127. M. A. Khan, S. M. Faisal, and O. Mohammad, “Safety, efficacy and pharmacokinetics of tuftsin-loaded nystatin liposomes in murine model,” Journal of Drug Targeting, vol. 14, no. 4, pp. 233–241, 2006. View at Publisher · View at Google Scholar · View at Scopus
  128. A. Khan, A. A. Khan, V. Dwivedi, M. G. Ahmad, S. Hakeem, and M. Owais, “Tuftsin augments antitumor efficacy of liposomized etoposide against fibrosarcoma in Swiss albino mice,” Molecular Medicine, vol. 13, no. 5-6, pp. 266–276, 2007. View at Publisher · View at Google Scholar · View at Scopus
  129. J. Crespo, H. Sun, T. H. Welling, Z. Tian, and W. Zou, “T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment,” Current Opinion in Immunology, vol. 25, no. 2, pp. 214–221, 2013. View at Publisher · View at Google Scholar · View at Scopus