Immunotherapy for sarcomas: new frontiers and unveiled opportunities

Abstract

Sarcomas are a rare malignancy of mesenchymal tissues, comprizing a plethora of unique subtypes, with more than 60 types. The sheer heterogeneity of disease phenotype makes this a particularly difficult cancer to treat. Radiotherapy, chemotherapy and surgery have been employed for over three decades and, although effective in early disease (stages I-II), in later stages, where metastatic tumors are present, these treatments are less effective. Given the spectacular results obtained by cancer immunotherapy in a variety of solid cancers and leukemias, there is now a great interest in appliying this new realm of therapy for sarcomas. The widespread use of immunotherapy for sarcoma relies on immuno-profiling of subtypes, immunomonitoring for prognosis, preclinical studies and insight into the safety profile of these novel therapies. Herein, we discuss preclinical and clinical data highlighting how immunotherapy is being used in soft tissue sarcoma and bone sarcomas.

Keywords: immunotherapy; sarcoma.

Figure 1

Harnessing the immune system against sarcoma. (1) Immune checkpoint inhibitors restore the ability of immune cells (eg, cytotoxic T cells) to mediate anti-cancer immunity. (2) Autologous T cells transduced with a T cell receptor specific for tumor antigens are expanded and reinfused in patients where they exert cytotoxic functions. (3) CAR T cells against several sarcoma specific antigens can be designed to further boost adoptive T cell therapy. (4) Universal donor NK cells administered with ALT803 may enhance the therapeutic effects of NK cells. (5) Therapeutic cancer vaccines are designed to stimulate a patient’s immune system against cancer and typically target a tumor antigen. Vaccine approaches evaluated in sarcoma include peptide vaccines, or dendritic cell vaccines loaded with tumor lysate or pulsed with antigenic peptide. (6) Oncolytic viruses T-VEC and Pexa-VEC are being evaluated in sarcoma, and promote tumor destruction by direct lysis of tumor cells, transgene expression (eg, GM-CSF) and stimulation of adaptive and innate immune responses. (7) Anti-tumor immunity can be promoted by antibodies targeting tumor antigens (eg, GD2) eliciting antibody-mediated or complement-mediated cytotoxicity. (8) Molecules preventing polarization of anti-cancer M1 macrophages to tumor-promoting M2 macrophages can potentiate anti-cancer immunity in sarcoma. CAR, chimeric antigen receptors; CSF1R, colony stimulating factor 1 receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; NK, natural killer; T-VEC, talimogene laherparepvec.