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Hindawi Journal of Oncology Volume 2019, Article ID 7035045, 8 pages https://doi.org/10.1155/2019/7035045 Review Article Current and Emerging Targets in Immunotherapy for Osteosarcoma 1 1,2 1 1 Shinji Miwa, Toshiharu Shirai , Norio Yamamoto, Katsuhiro Hayashi, 1 1 1 Akihiko Takeuchi , Kentaro Igarashi, and Hiroyuki Tsuchiya Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa 920-8640, Japan Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan Correspondence should be addressed to Toshiharu Shirai; email@example.com Received 29 August 2018; Accepted 4 December 2018; Published 1 January 2019 Academic Editor: Reza Izadpanah Copyright © 2019 Shinji Miwa 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. Osteosarcoma is the most common primary malignancy of bone. Although outcomes of patients with osteosarcoma have improved since the introduction of chemotherapy, outcomes of metastatic or unresectable osteosarcomas are still unsatisfactory. To improve osteosarcoma outcomes, the development of novel systemic therapies for osteosarcoma is needed. Since the 1880s, various immunotherapies have been utilized in patients with osteosarcoma and some patients have shown response to the treatment. Based on recent studies about the role of the immune system in malignancies, immunotherapies including immune modulators such as interleukin-2 and muramyl tripeptide, dendritic cells, immune checkpoint inhibitors, and engineered T cells have been utilized in patients with malignancies. Although there are limited reports of immunotherapies for osteosarcoma, immunotherapy is thought to be a promising treatment option for treating osteosarcomas. In this review, an overview of various immunotherapies forosteosarcomaisprovidedandtheirpotential asadjuvant therapiesisdiscussed. 1. Introduction for advanced sarcoma including pazopanib, trabectedin, and eribulin , the eca ffi cy of the agents for treating patients Osteosarcoma, the most common primary malignancy of with osteosarcoma remains unclear. er Th efore, novel thera- bone, is thought to originate from mesenchymal stem cells peutic approaches for advanced sarcomas have been sought . Osteosarcoma commonly metastasizes to the lung (more to improve the treatment of osteosarcomas. than 85%) and the bone . Before the introduction of This article reviews immune surveillance for malignancy, chemotherapy, the outcome of patients with osteosarcoma the history of immunotherapy, and recent basic and clin- was poor, and the survival rate of patients with osteosarcoma ical research about immunotherapy for treating osteosar- waslessthan20% before the1970s.Theestablishment coma.Furthermore,wediscuss thefutureperspectivesof of surgical resection with adequate surgical margins and immunotherapy for osteosarcoma treatment. neoadjuvant chemotherapy using methotrexate, doxorubicin, cisplatin, andifosfamideincreased thesurvivalrateupto 2. Role of the Immune System and 60-70% . On the other hand, outcomes of patients with recurrent, metastatic, or unresectable osteosarcomas are still Advancement in Immunotherap unsatisfactory. eTh long-term survival rate for patients with The immune system, a complex organization of immune localizedosteosarcomaisabout 65%,whereasitislessthan cells and mediators, collaborates with other accessory cells 20% for patients with metastatic osteosarcomas [2, 4, 5]. to protect against various pathogens such as viruses and However, no significant improvements have been seen over bacteria.Theinnateimmunesystemconsistsofdendriticcells the last three decades, and recurrent or metastatic osteosar- comas are usually resistant to current standard treatment. (DCs), macrophages, natural killer (NK) cells, neutrophils, Although there are increasing systemic treatment options basophils,andeosinophils.Innateimmunecellsaretheinitial 2 Journal of Oncology defense against foreign antigens (Figure 1). Macrophages and vaccine and inactivated tumor cells can induce antitumor mast cells initiate the inflammatory response by releasing immune responses. cytokines to interact with other immune cells. DCs, strong antigen-presenting cells, play a role in taking foreign antigens 2.2. Macrophage Activator. Muramyl tripeptide (MTP), a and presenting them for recognition by adaptive immune synthetic analog of a component of bacterial cell walls, cells. The adoptive immune cells consist of B lymphocytes, has been developed as a nonspecific immune modula- CD4-positive T helper lymphocytes, and CD8-positive cyto- tor . MTP targets and activates macrophages. Kleiner- toxic T lymphocytes. These cells require direct activation by man reported that treatment with liposome-encapsulated antigen presentation from antigen-presenting cells. Antigen- muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) specific T lymphocytes and B lymphocytes are generated increased levels of TNF-𝛼 and IL-6 . The liposomes by presentation and activation. Furthermore, the innate and encapsulating MTP-PE can deliver the agent selectively to adaptive cells eliminate pathogens and remove damaged cells monocytes and macrophages. After the delivery of MTP-PE [7, 8]. Immunosurveillance for cancer requires the recog- to monocytes and macrophages, these cells become activated nition of tumor-specific antigens, including the products of and tumoricidal [21, 22]. Chemotherapy did not interfere mutated genes, overexpressed normal genes, or genes encod- with L-MTP-PE stimulation of macrophage cytotoxicity in ing viral proteins. In normal conditions, innate immune cells preclinical studies . Meyers reported that adding MTP to and adaptive immune cells detect tumor cells and eliminate conventional chemotherapy improved 6-year overall survival them by activating NK cells, secreting interferons (IFNs), and from 70% to 78% (P = 0.03) in patients with nonmetastatic subsequently activating DCs. However, some tumor cells can osteosarcoma . Furthermore, the risk of death at 6 escape and survive this immune system attack by various years was decreased by 28% for patients receiving MTP. mechanisms including loss of tumor antigens; downregulat- The statistically significant improvement is thought to be ing the major histocompatibility complex (MHC) from the one of the greatest progresses of the treatment of patients surface; altering the tumor microenvironment by recruit- with metastatic osteosarcoma in the last 30 years. On the ing regulatory T cells, myeloid-derived suppressor cells, other hand, a randomized phase 3 trial showed that five- and tumor-associated macrophages; upregulating inhibitory year event-free survival rates for 91 patients with metastatic receptors on T cells, or upregulating inhibitory ligands on osteosarcoma who received L-MTP-PE and those who did tumor cells [9–11]. not were 42% and 26%, respectively . Based on the studies, MTP has been approved by the European Medicine 2.1. Immune Modulator. The stimulation of antitumor Agency for the treatment of patients with osteosarcoma. immune responses by bacterial infection or vaccination has eTh se results suggest a decreased risk of recurrence and been reported for over 100 years (Figure 2). In 1891, Coley metastasis upon treatment with bacterial components in reported that inducing erysipelas and stimulating immune patients with osteosarcoma. reaction by injecting heat-inactivated Streptococcus pyogenes and Serratia marcescens (Coley’s toxin) achieved complete 2.3. Cytokine. Several cytokines have been used for response in approximately 10% of patients with bone and soft immunotherapy in patients with malignancies. IFN-𝛼 tissue sarcomas . In recent studies on the relationship has the ability to induce differentiation and apoptosis, as well between surgical site infection and survival in dogs with as to inhibit proliferation and angiogenesis, and the clinical osteosarcoma, infection had a positive influence on survival efficacy of IFN-𝛼 in several malignancies has been reported [13, 14]. Furthermore, Jeys reported that the 10-year survival [26–29]. In 1977, growth inhibitory effects of IFN- 𝛼 in human for osteosarcoma patients with infection was 85% compared osteosarcoma cells were reported . Furthermore, growth to 63% in patients without infection . These reports inhibitory effects of human IFN- 𝛼 have been reported in of improved survival upon infection suggest that bacteria a mouse model of human osteosarcoma . eTh efficacy have the ability to activate antitumor immune responses. of pegylated IFN-𝛼-2b was investigated in patients with Larsson investigated the effects of immunotherapy using osteosarcoma by an international randomized controlled irradiated tumor cells and the Bacillus Calmette-Guerin trial . The study patients were treated with methotrexate, (BCG) vaccine in a mouse model of osteosarcoma . doxorubicin, and cisplatin (MAP), with or without pegylated In the study, injecting irradiated tumor cells significantly IFN-𝛼-2b. In the study, the 5-year overall survival rates prevented tumor incidence aer ft the injection of living tumor in patients with MAP and MAP + IFN-𝛼-2b were 81% cells, whereas BCG injection had no significant effect on and 84%, respectively. Although the report with a short osteosarcoma. Eilber reported the effect of immunotherapy follow-up period suggests little effect of adjuvant IFN-𝛼-2b, consisting of BCG and an allogenic tumor cell vaccine the follow-up continues to determine long-term survival. . In the study, three of 17 patients (18%) treated with IL-2 induces the activation of lymphocytes and their BCG and tumor vaccine remained alive and disease-free, differentiation into lymphokine-activated killer (LAK) cells whereas 0 of 12 patients without treatment were disease-free. which can recognize and eliminate various tumor cells . Karbach reported that the bacterial vaccine increased levels Although responsestoIL-2havebeenreportedinclinical of immunoregulatory cytokines including interleukin (IL)-6, trials in patients with various malignancies, only clinical tumor necrosis factor (TNF)-𝛼,IFN- 𝛾,and IL1- 𝛽,which trials for renal cell carcinoma and melanoma observed may be involved in inducing tumor regression . Based efficacy of IL-2 . Only a few clinical trials of IL-2 on these studies, it is thought that treatment with a bacterial for sarcomas have been reported [35, 36]. In a clinical Journal of Oncology 3 Figure 1: Interactions between tumor cells and microenvironmen t. Antitumor immune system includes dendritic cells (DCs), CD4 Tcells, CD8 T cells, natural killer (NK) cells, and tumor-suppressing killer B cells. Tumor cells escape immune surveillance by expression of immune checkpoint proteins, regulatory T (Treg) cells, and myeloid-derived suppressor cells (MDSCs). trial using IL-2 with or without reinfusion of LAK for serum IFN-𝛾 levels, reduced pulmonary metastases, and patients with metastatic osteosarcoma, 3-year event-free increased numbers of CD8-positive T lymphocytes in the and overall survival rates were 34% and 45%, respectively metastatic areas . Kawano  reported the eeff ct of . Immunotherapy using a monoclonal antibody against combination treatment with tumor lysate-pulsed DCs and an the tumor-associated disialoganglioside GD2, granulocyte anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody macrophage colony-stimulating factor (GM-CSF), and IL- in a mouse model of osteosarcoma. In the study, treatment 2 was associated with a significantly improved outcome as with either the anti-CTLA-4 antibody or tumor lysate- compared with standard treatment in patients with neu- pulsed DCsresultedinanincreased numberof CD8+T roblastoma . In a study of high-dose IL-2 treatment in lymphocytes, inhibition of primary and metastatic lesion relapsed pediatric sarcoma, two of the four patients with growth, prolonged survival, reduced number of regulatory osteosarcoma showed a complete response, although severe T lymphocytes, and increased levels of serum IFN-𝛾,and side effects were observed, including increases in white blood the combination of these treatments enhanced the systemic cells (WBC), creatinine, 𝛾-glutamyltransferase, C-reactive immune response. Furthermore, they reported that combi- protein, glucose, and body weight and decreases of red blood nation treatment with tumor lysate-pulsed DCs and anti- cells, platelets, protein, albumin, and cholinesterase . glucocorticoid-induced tumor necrosis factor receptor (anti- Basedonthe resultsofpaststudies,IFN-𝛼 and IL-2 can acti- GITR) antibodies enhanced the systemic immune response vate antitumor immune responses, although no significant . improvement in osteosarcoma treatment outcomes has been In our phase 1/2 clinical trial of DC-based immunother- observed in the previous trials. apy, 37 patients with bone and soft tissue sarcoma were included in the study . eTh study patients were treated 2.4. Dendritic Cell. Recently, various kinds of cellular with DCs stimulated by tumor lysate, TNF-𝛼,andOK-432. immunotherapy for advanced sarcomas have been developed The patients showed increased levels of IFN- 𝛾 and IL-12 . Treatment of DCs pulsed with tumor lysate significantly without severe toxicity. Among the 35 patients who were increased induction of cytotoxic T lymphocyte (CTL) activity assessed for clinical responses, one patient (3%) showed par- tial response, 6 patients (17%) showed stable disease, and 28 andincreased theserum levelIFN-𝛾 . DCs have been used to enhance tumor-specific immune responses because patients (80%) showed progression of the disease . On the DCs are major antigen-presenting cells initiating cellular other hand, a phase 1 trial using a vaccine of autologous DCs matured with tumor lysate and keyhole limpet hemocyanin immune responses in vivo . DCs pulsed with tumor lysate andreimplantationofcryo-treatedtumorsinducedincreased (KLH) in 13 patients with relapsed osteosarcoma showed 4 Journal of Oncology Immune checkpoint Cytokine therapy: inhibitors IFN-, IL-2 (PD-L, PD-L1, CTLA-4) Immune modulator: Nonspeciﬁc immunotherapy Coley toxin, BCG Lymphokine activated killer T cells Dendritic cells Tumor speciﬁc immunotherapy Peptide vaccine Genetically modiﬁed T cells: (TCR T cells, CAR T cells) 1880 1980 2000 2010 Figure 2: Development of immunotherapy for malignancies. no significant toxicity, although only 2 out of 12 patients therapy for synovial sarcoma using a peptide spanning SYT- exhibited induction of specific T-cell immune response to the SSX fusion region (B peptide) and its HLA-A∗2402 anchor tumor . In a phase 1 study of immunotherapy using tumor substitute, 6 of 12 patients treated with a mixture of the lysate and KLH, 2 of 12 patients with relapsed osteosarcoma peptides had stable disease during the vaccination period, showed induction of specific T cell immune response against although one of the study patients developed intracerebral the tumor although no patients had a clinical response . hemorrhage aer ft the vaccination . In a phase 1 study of immunotherapy using DCs pulsed with tumor lysate, 5 of 10 pediatric patients with solid 2.6. Genetically Modified T Cells. The development of gene- tumors showed progression control and 1 patient showed transfer technology has enabled the genetic transduction of T tumor regression . Merchant et al. reported that 62% of cell receptor (TCR) or chimeric antigen receptor (CAR) into patients with metastatic and/or recurrent pediatric sarcomas conventional T cells. who were treated with immunotherapy using autologous Genes encoding 𝛼 and 𝛽 chains of TCR are introduced lymphocytes, tumor lysate/KLH-pulsed DC vaccinations, into T cells to generate TAA-specicfi TCR T cells . HLA- and/or recombinant human IL7, showed T cell responses A2-restricted TCRs which recognize several antigens, includ- and responders showed prolonged survival period . ing MART-1, gp100, MAGE-A3, and NY-ESO-1, have been In clinical studies of DC-based immunotherapy, no severe cloned [52–55]. TCR cell therapy demonstrated favorable adverse effects have been reported. These studies indicate outcomes in patients with melanoma and synovial sarcoma that the strategy of DC vaccination in relapsed osteosarcoma [56, 57]. Eleven of 18 patients with NY-ESO-1 positive appears safe and resulted in an immunological response in synovialsarcoma(61%) whoreceivedautologousTcells patients with sarcoma, although it resulted in an improved transduced with an NY-ESO-1 reactive TCR demonstrated clinical outcome in only some patients. To improve cellular objective clinical responses, and the vfi e-year survival rate immunotherapy for osteosarcoma, further investigations for was 14% . tumor-associated antigen (TAA) as target of the treatment, Chimeric antigen receptor therapy is an adoptive combination therapy, and favorable indication are needed. immunotherapy utilizing T lymphocytes engineered with chimeric antigen receptors. CAR-T cells can recognize 2.5. Peptide Vaccine. Variousvaccinestargeting tumor tumor antigens in an MHC-independent fashion. Chimeric lysates, proteins, and peptides have been used in clinical trials antigen receptor is composed by an extracellular antigen in patients with sarcoma [47–50]. To eliminate tumor cells, recognition domain, which is called the single-chain variable tumor vaccines have been used to stimulate patients’ immune fragment, and an intracellular signaling domain. CAR-T systems. In treating malignancy, TAA-specific T cells are acti- cell therapy has been used for patients with leukemia vated by antigen-presenting cells as the tumor vaccines are andthisimmunotherapy hasbeenpromising forsarcoma presented on MHC-molecules. Various vaccines have been treatment. A phase 1/2 clinical study using HER2-specific investigated as candidates for vaccine therapy. Tsukahara et CAR-T cells in patients with recurrent/refractory sarcoma al. reported that high expression of papillomavirus binding demonstrated that 4 of 17 patients had stable disease for 12 factor was observed in osteosarcoma cell lines and tumor weeks to 14 months without severe toxicity . On the other tissues . On the other hand, Tsuda et al. reported that hand,CAR-Tcelltherapyisassociatedwithseveraladverse high levels of SART3 were detected in osteosarcoma cell lines effects including cytokine release syndrome and “on-target, and osteosarcoma tissues, and SART3 induced HLA-A24- off-tumor” toxicity, and some of the adverse effects are restricted tumor-specicfi cytotoxic T lymphocytes . In a life-threatening. Cytokine release syndrome is caused by phase 2 trial of four HLA-matched peptides from 31 pooled intensive responses to tumor cell elimination mediated by peptides in 20 patients with refractory bone and soft tissue activated lymphocytes . Excessive levels of cytokines sarcoma, 6 patients had stable disease and 14 patients exhib- including C-reactive protein, IL-6, and IFN-𝛾 are observed in ited disease progression, although no severe adverse effect patients, and high levels cause clinical syndromes including was observed in the study . In a clinical trial of vaccine hypotension, fever, and neurological changes. “On-target, Journal of Oncology 5 off-tumor” toxicity is caused by recognition of tumor- of PD-L1 was correlated with tumor-infiltrating lymphocytes associated antigens on the surface of normal cells, and (TILs).In thestudy,medianoverall survivalforpatients lymphocytes subsequently attack, causing damage to normal with low PD-L1 expression was 89 months compared with tissue. CAR-Tcellsmaykillnormalcellswithtargetantigen 28 months for patients with high PD-L1 expression. Hin- even if the expression of the target antigen is at low level. gorani et al. reported that increased expression of CTLA- eTh refore, CAR-T cell therapy can be applied for cancers 4 in T cells and increased immunosuppressive monocytes with specicfi expression of the antigen. were observed in patients with pediatric sarcoma . A Although further studies of TAAs with high specificity are recent study reported that high levels of PD-1 expression needed for the use of tumor-specific immunotherapies, adop- on peripheral CD4+ and CD8+ T cells were observed in tive cell therapy using TCR or CAR targeting TAAs represents patients with osteosarcoma, and the expression levels of PD-1 a new and promising therapeutic approach for patients with on CD4+ T cells in patients with metastasis were significantly sarcomas. Randomized clinical trials are demanded to assess higher than those without metastasis . Lussier et al. the efficacies and safety of adoptive cell therapies in patients reported that T cells infiltrating PD-L1 antibody-resistant with sarcomas. tumors upregulated inhibitory receptors such as CTLA-4 . Furthermore, combination immunotherapy using anti- 2.7. Immune Checkpoint Inhibitors. Recent studies have CTLA-4 and anti-PD-L1 antibodies improved overall survival in a mouse model of osteosarcoma, whereas no benefit was focused on the association of immune checkpoints with inhibition of the tumor immune system. Although immune observed upon treatment with an anti-CTLA-4 antibody checkpoints are necessary for maintaining self-tolerance alone . Based on a study of immune checkpoints in patients with osteosarcoma, PD-1, PD-L1, and CTLA-4 influ- and for limiting immune responses to prevent autoimmune disorders, immune checkpoints can allow immune tolerance ence osteosarcoma progression. Therefore, immune check- against tumors. CTLA-4 and programmed death receptor- points are promising targets for treating various malignancies 1 (PD-1), the main inhibitory receptors expressed on T including osteosarcoma. The recent studies of osteosarcoma cells, have been considered as an important part in immune indicate that immune checkpoint can be promising treat- ment for patients with osteosarcoma. It is reported that suppression induced by tumor cells, and these molecules are thought to be candidates as new therapeutic targets in var- the expression of checkpoint molecules such as PD-L1 on ious types of advanced malignancies . Activated T cells osteosarcoma cells correlates with metastases and overall normally express PD-1 on the surface and suppress excessive survival . A multicenter, phase 2 trial of the anti-PD-1 immune responses, including autoimmune reactions. PD-L1, mAb pembrolizumab demonstrated that seven of 40 patients the ligand of PD-1, is expressed in various cells including with bone and soft tissue sarcoma (18%) and two of 40 macrophages and tumor cells, and the interaction between patients (5%) had objective responses ; treatment-related PD-1 and PD-L1 is usually inu fl enced by tumor tissues. Dhup- serious adverse events occurred in 11% of patients. eTh kar P et al. reported that anit-PD-1 therapy redirecting M2 study included 22 patients with osteosarcoma; one patient macrophages (immunosuppressive and tumor promoting) to (5%) had a partial response, 6 patients (27%) had stable M1 (anti-tumor) resulted in regression of lung metastasis in disease, and 15 patients (68%) exhibited disease progression. mouse model of osteosarcoma . It is considered that immune checkpoints play some roles BlockadeofPD-1byanti-PD-1 nivolumaboranti- in sarcoma development, and immune checkpoints can be PD-L1 BMS-936559 has demonstrated objective responses promising targets for osteosarcoma treatment. Further basic and improved oncological survival in patients with lung and clinical studies will determine the efficacy of immune cancer, melanoma, renal cell cancer, and ovarian cancer checkpoint inhibitors. [62, 63]. Furthermore, ipilimumab, a monoclonal antibody (mAb)targeting CTLA-4,showedsignicfi antimprovement 2.8. Conclusions. Based on recent studies of the tumor of overall survival in patients with metastatic melanomas microenvironment, mechanisms of tumor invasion and . However, no correlation with immune checkpoints has metastasis, antitumor immune system, and immune check- been reported in some types of sarcoma. In sarcomas with points in malignancies, significant improvements in out- high PD-1 expression, PD-1 inhibitors are considered to be come have been seen for some malignancies. Therefore, promising, while tumor antigen-specicfi treatments, such immunotherapy is an increasingly attractive treatment option as dendritic cell-based immunotherapy, can be a candidate in patients with osteosarcoma. Although the introduction treatment in sarcomas with a high expression of tumor- of chemotherapy dramatically improved the outcomes of specific antigen. osteosarcoma treatment, no marked improvement of the Murine studies suggest activity of checkpoint inhibitors treatment for osteosarcoma has been seen in the last three in osteosarcoma . In patients with osteosarcoma, PD-1 decades. eTh main reasons for the lack of development of and PD-L1 levels negatively correlate with prognosis . osteosarcoma treatment include this type of cancer’s rarity, Zheng investigated the efficacy of nivolumab in a mouse heterogeneity, and the lack of discovery of a tumor-specific model of osteosarcoma and reported that nivolumab-treated antigen. For successful osteosarcoma immunotherapy, eluci- mice had significantly fewer metastatic lung lesions, although dation of the condition of immunosurveillance, discovery of nivolumab had no effect on primary tumor volume and tumor-specific antigen for osteosarcoma, and collaborative growth . Shen et al. reported that high expression of PD-L1 was observed in osteosarcoma patients and expression multicenter studies are necessary. 6 Journal of Oncology Conflicts of Interest  D. E. Thrall, S. J. Withrow, B. E. 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