Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer

Abstract

Previously, clinical approaches to using the immune system against cancer focused on vaccines that intended to specifically initiate or amplify a host response against evolving tumours. Although vaccine approaches have had some clinical success, most cancer vaccines fail to induce objective tumour shrinkage in patients. More-recent approaches have centred on a series of molecules known as immune checkpoints-whose natural function is to restrain or dampen a potentially over-exuberant response. Blocking immune checkpoint molecules with monoclonal antibodies has emerged as a viable clinical strategy that mediates tumour shrinkage in several cancer types. In addition to being part of the current treatment armamentarium for metastatic melanoma, immune checkpoint blockade is currently undergoing phase III testing in several cancer types.

Figure 1

Mechanism of action of cancer vaccines. Cancer vaccines work by providing a target antigen or antigens to a specialized cell known as the dendritic cell (DC). These cells reside at the site of antigen injection (usually intradermal), where they take up and process antigen. Immunostimulatory molecules in the vaccine preparation (adjuvants) activate DCs, which respond by upregulating the molecules they need to interact with (T cells), and migrating to a lymph node. Once in a lymph node, activated DCs present antigen to T cells; if the T cell recognizes its cognate antigen in the proper context, it is then activated. Upon activation, CD4⁺ T cells produce cytokines that help CD8 T cells to fully mature. Upon full maturation, CD8⁺ T cells in turn proliferate and then leave the lymph node to traffic widely throughout the body. When an activated T cell senses a cell bearing its target antigen (tumour antigen) in the periphery, it can then lyse that cell, potentially mediating an antitumour response.

Figure 2

Immune checkpoint blockade. This approach to immunotherapy is exemplified by antibodies directed against CTLA-4 (ipilimumab, tremilimumab), which block the immunosupression mediated by the interaction between B7 family members (on antigen-presenting cells) and CTLA-4 (on CD8⁺ and CD4⁺ T cells). A second major checkpoint, mediated by the interaction between PD-1 on T cells and its ligand PD-L1 on either antigen-presenting cells or tumour cells, has been the subject of several recent clinical trials, and has shown evidence of efficacy in both non-small-cell lung cancer and renal cell carcinoma.