Advances in immune checkpoint inhibitors for bone sarcoma therapy

Abstract

Bone sarcomas are a collection of sporadic malignancies of mesenchymal origin. The most common subtypes include osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. Despite the use of aggressive treatment protocols consisting of extensive surgical resection, chemotherapy, and radiotherapy, outcomes have not significantly improved over the past few decades for osteosarcoma or Ewing sarcoma patients. In addition, chondrosarcoma and chordoma are resistant to both chemotherapy and radiation therapy. There is, therefore, an urgent need to elucidate which novel new therapies may affect bone sarcomas. Emerging checkpoint inhibitors have generated considerable attention for their clinical success in a variety of human cancers, which has led to works assessing their potential in bone sarcoma management. Here, we review the recent advances of anti-PD-1/PD-L1 and anti-CTLA-4 blockade as well as other promising new immune checkpoint targets for their use in bone sarcoma therapy.

Keywords: Anti-CTLA-4; Anti-PD-1/PD-L1; Bone sarcoma; Immune checkpoint; Immunotherapy.

Fig. 1

Histologic subtypes of common bone sarcomas in pediatric and adolescent populations (A), and adults (B) , .

Fig. 2

Anatomical distribution of common bone sarcomas , , , , , , .

Fig. 3

Overview of immune checkpoints under investigation in bone sarcomas. Sarcoma cells are initially attacked by macrophages of the innate immune system. Dendritic cells capture tumor-associated antigens at the tumor site and present them to T cells within the lymph node. After activation, the T cells return and kill tumor cells. This anti-tumor immune response is regulated by the immune checkpoint mechanism. The PD-1/PD-L1 axis inhibits T cell activation, while the inhibitory effect of CTLA-4 is caused by competition between CD28 and CTLA-4 binding to B7-1/2 (CD80/86). Similarly, B7-H3 competitively binds CD28 and inhibits T cell activation. On the natural killer (NK) cells, NKG2D/NKG2DL stimulates cytotoxic activity leading to tumor cells apoptosis. Various antibodies which affect these inhibitory and co-stimulatory immune checkpoints may enhance the anti-tumor immune response in bone sarcoma patients. , , , . Abbreviations: Antigen-presenting cell (APC), B7 homolog 3 (B7-H3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), major histocompatibility complex (MHC), natural killer cell (NK), natural killer group 2D (NKG2D), natural killer group 2D ligand (NKG2DL), natural killer group 2D chimeric antigen receptor (NKG2D CAR), program cell death receptor-1 (PD-1), program cell death receptor-1/2 ligand (PD-L1/PD-L2), tumor-associated antigen (TAA), T cell receptor (TCR).