Sarcoma immunotherapy: past approaches and future directions

Abstract

Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25-50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease.

Figure 1

Preventing tumorigenesis in sarcoma. The adaptive immune response initiates with presentation of antigens by DC. DC migrates to the lymph node. Antigens are presented to CD4⁺ and CD8⁺ T cells through MHC class I and II, respectively, and costimulatory molecules such as B7 bind to CD28 leading to activation of the lymphocytes. Once stimulated, these lymphocytes are now effector cells with the ability to migrate to the tissue and initiate an immune response against the developing sarcoma (abbreviations: CTL, cytotoxic T lymphocyte; DC, dendritic cell; TH, T helper lymphocyte). Reference: adapted from [25].

Figure 2

Immunoediting. The 3 phases of immunoediting include elimination, equilibrium and escape. (a) Elimination. Cancer cells are transformed (red) but are actively destroyed by the cells of the immune system. (b) Equilibrium. Cancer cells continue to transform (red and teal). Immune system cannot completely remove the transformed cells but controls their growth and there is a dynamic equilibrium that keeps the tumor in check. (c) Escape. Cancer cells continue to grow and transform (red, teal, and pink). These cells now grow unchecked and exhibit immunosuppressive mechanisms (CD4⁺CD25⁺ Treg) which ultimately lead to progressively growing tumors. Abbreviations: CD4⁺, CD8⁺, CD4⁺CD25⁺ Treg, γδ and NKT cells are all types of T cells and NK cells are natural killer cells. Reference: figure modified from [21].

Figure 3

Mechanism of action of CTLA-4 and PDL1 blockade. (a) Activation of T cell requires interaction of MHC bearing tumor antigen with the TCR and interaction of the costimulatory molecule B7 with CD28. CTLA-4 is a negative regulator of the immune response that competes with CD28 binding with B7. Ipilimumab is a monoclonal antibody that binds CTLA-4 and promotes continued T cell activation. (b) The role of the PD-1 receptor is more significant in the peripheral tissue, once T cell activation has already occurred. After antigen exposure, PD-1 receptor is expressed on the T cells. When the PD-1 receptor interacts with its ligands PD-L1 and PD-L2, there is negative regulation of T cells in the tumor microenvironment. Blocking PD-1 or PD-L1 leads to activation of T cells. Reference: figure modified from [57].