ABSTRACT
Osteosarcoma (OS) is the most common malignant bone tumor and often occurs in children. Chemotherapy with methotrexate, cisplatin, doxorubicin, and ifosfamide has greatly improved the prognosis of patients with OS, and most patients have been able to preserve their limbs. However, no progress has been made in the treatment for OS in the past few decades, and the prognosis of patients with metastasis and/or local recurrence remains poor. Therefore, studies aimed at developing new treatment methods for OS are urgently required. Here, we discuss the current status of immunotherapies for OS as well as the current limitations in the field.
In recent years, immunotherapy has been shown to be effective for treating several cancers, and its indication is continually increasing. Immunotherapy is also expected to be widely used for treating OS, however, the efficacy of immunotherapy for OS has not been established
KEYWORDS:
Commentary
Osteosarcoma (OS) is the most common malignant bone tumor and often occurs in children. Chemotherapy with methotrexate, cisplatin, doxorubicin, and ifosfamide has greatly improved the prognosis of patients with OS, and most patients have been able to preserve their limbs. However, no progress has been made in the treatment for OS in the past few decades, and the prognosis of patients with metastasis and/or local recurrence remains poor. Therefore, studies aimed at developing new treatment methods for OS are urgently required. Here, we discuss the current status of immunotherapies for OS as well as the current limitations in the field.
In recent years, immunotherapy has been shown to be effective for treating several cancers, and its indication is continually increasing. Immunotherapy is also expected to be widely used for treating OS, however, the efficacy of immunotherapy for OS has not been established.
An interesting report related to OS and immunotherapy showed that immune activation due to infection suppressed the progression of OS. Lascelles et al. reported that localized osteomyelitis after surgery results in a significantly longer progression-free survival than without infection in canine OS.Citation1 Jeys et al. reported that the overall survival rate of patients with OS infected after implantation surgery was significantly higher than that of non-infected patients.Citation2 Additionally, we previously demonstrated that systemic immune activation by lipopolysaccharide (LPS) suppressed the progression of OS in a mouse model.Citation3 These reports suggest that host innate immunity plays an important role in the progression of OS and that activation of host innate immunity can suppress the progression of OS. In fact, mifamurtide, a drug that activates innate immunity in cells such as macrophages, improved the survival of patients with OS and has been approved clinically for treating patients with non-metastatic OS in Europe.Citation4
Is there a link between acquired and innate immunity during the progression of OS? Interestingly, the number of CD8 + T cells infiltrating in the tumor is correlated with a favorable prognosis for patients with OS.Citation5 In addition, using a mouse OS model, we found that activation of innate immunity by LPS triggered infiltration of CD8 + T cells into tumor cells and a subsequent reduction in tumor masses; additionally, in vivo depletion of CD8 + T cells exacerbated the effect of LPS.Citation3 Collectively, OS progression may evoke an interaction between innate and acquired immunity in the host with non-negligible effects. However, some issues must be overcome before immunotherapy for OS is used as a clinically effective treatment.
First, OS is a so-called low-immunogenic tumor, and is less likely to induce an immune response in the host compared to cancers for which immunotherapies are effective, such as malignant melanoma and lung cancer. Immunogenicity is defined by the accumulated number of mutations existing in tumors, known as the tumor mutation burden (TMB). It has generally been reported that sarcoma has a lower TMB than other types of cancers, which is also true for OS. Immunogenicity is among the important factors determining the effectiveness of immunotherapy, and low immunogenicity leads to a decrease in tumor-infiltrating immune cells and tumor-specific T cells, making immunotherapy ineffective. Therefore, it may be necessary to enhance the immunogenicity of OS to achieve more effective immunotherapy. For example, doxorubicin and cisplatin, both of which are key drugs for the chemotherapy of OS, have been reported to enhance tumor immunogenicity. Studies of combination therapy using these agents and immunotherapy have been performed in several cancers. It may be necessary to examine the effectiveness of combination therapy of such immunogenicity-improving drugs and immunotherapy for OS.
The second issue that must be addressed is the detailed mechanism causing host immunosuppression in OS. Immune checkpoints molecules such as programmed cell death protein (PD)-1 and PD-1 ligand (PD-L1) are expressed in the tumor microenvironment of OS at relatively high levels.Citation6 The efficacy of PD-1 inhibitors for OS has been reported at the in vitro and preclinical levels, and PD-1 inhibitors are promising drugs for treating OS. However, in a large-scale phase 2 clinical trial of pembrolizumab, the response rate of patients with OS was disappointing.Citation7 Based on these results, in human OS, an immunosuppressive mechanism other than that involving the PD-1 and PD-L1 pathways may exist. Recent studies revealed that other immune checkpoints such as indoleamine 2,3-dioxygenase or T cell immunoglobulin mucin-3 are also expressed in OS, with a correlation observed between expression of the latter protein and poor prognosis in patients with OS.Citation8 In fact, combination therapy with a PD-1 inhibitor and cytotoxic T-lymphocyte-associated protein 4 inhibitor was reported to exert a synergistic effect in some cancers, and it would be difficult to explain the mechanism of immunosuppression by cancer based on only one immune checkpoint system. Similarly, complicated immunosuppressive mechanisms are likely to function in OS. Determining these mechanisms may lead to approaches for improving the efficacy of immunotherapy for OS.
The third issue is that studies are needed to discover an antigen that is specifically or at least relatively exclusively expressed in OS. Two types of immunotherapy have been employed in recent years: non-antigen-specific immunotherapy represented by immune checkpoint inhibitors and antigen-specific immunotherapy represented by adoptive T cells and chimeric antigen receptor (CAR)-T cells. By targeting an antigen expressed in cancer cells but rarely expressed in normal tissues, such as cancer testis antigens, antigen-specific immunotherapy can elicit a very strong immune response confined to tumor cells without negatively affecting normal cells. For example, tisagenlecleucel, a CAR-T therapeutic agent for CD19, is extremely effective against B-cell acute leukemia. Even in OS, identifying an appropriate antigen can lead to the development of promising immunotherapies. Several antigens such as HER2 or GD2 have been studied as target antigen candidates, and their efficacy has been demonstrated in vitro. In addition, several clinical trials of CAR-T therapy for sarcomas, including OS, are underway. Recombinant medicine such as CAR-T cells is expected to further develop through advances in genetic engineering technology. In fact, new generations of CAR-T cells with various functions have been developed; this treatment is expected to be applied clinically not only for OS but also for other sarcomas.
In conclusion, there is currently no immunotherapy that has been clearly demonstrated to be effective against OS. Because OS and the immune system may have complex interactions as in other tumors, immune monotherapy may not be sufficient, and combination therapy with other drugs may be required. Immunotherapy for OS may be less effective than for cancers with high immunogenicity because the TMB of OS is low. However, numerous reports, including our recent findings,Citation3 have suggested that host immunity is involved in the progression of OS.
Thus, determining the roles of the immune system in the biology of OS can lead to the development of promising immunotherapies for OS.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
References
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