One of the best-characterized immune checkpoints involves a protein called PD-L1 (programmed cell death ligand 1), which is often expressed on the surface of tumor cells (Figure 6.30 ). When PD-L1 engages its receptor, PD-1, on CTLs, the CTLs become unresponsive and lose their ability to kill tumor cells. Experimental studies have identified several other immune checkpoint pathways, involving different ligands and receptors, which also have been implicated in immunoevasion by tumors. Of these, the best characterized involves CTLA4, another receptor expressed on T cells that inhibits T cell function.
The discovery of checkpoints that shut off anti-tumor immunity has led to the development of antibodies that block these checkpoints and release the brakes on the immune response. Current checkpoint blockade therapies have resulted in response rates of 10–30% in a variety of solid tumors (melanoma, lung cancer, bladder cancer, and others), and even higher rates in some hematologic malignancies such as Hodgkin lymphoma (Chapter 12). Because these checkpoints evolved to prevent responses to self antigens (Chapter 5), it is not surprising that patients treated with checkpoint blockade therapy develop various autoimmune manifestations, such as colitis and other types of systemic inflammation. Most of these reactions can be controlled with anti-inflammatory agents.
The remarkable response of advanced cancers to immune checkpoint inhibitors has energized other work focused on harnessing the immune system to combat cancer. These include efforts to develop personalized tumor vaccines using neoantigens identified in the tumors of individual patients, as well as new kinds of adoptive immunotherapy. The most advanced of the latter are patient-derived CTLs that are engineered to express chimeric antigen receptors (CARs). CARs have extracellular domains consisting of antibodies that bind tumor antigens and intracellular domains that delivered signals that activate CTLs following their engagement with antigen on the surface of tumor cells. CAR T cells are potent killers of tumor cells and have produced long-term remissions in patients with certain leukemias, such as B cell acute lymphoblastic leukemia (Chapter 12). However, CAR T cells also are associated with serious complications related to cytokines released from the activated CTLs, and it remains to be seen if they will become a routine part of cancer treatment.
Beyond complications of immunotherapy, it also should be recognized that the host immune response to tumors is not an unalloyed blessing. For example, tumors release incompletely characterized factors that alter the function of certain immune cells, such as macrophages and Th2 lymphocytes, in a fashion that is suspected of promoting angiogenesis, tissue fibrosis, and the accumulation of alternatively activated (M2) macrophages, which you will recall from Chapter 5 are associated with suppression of the immune response during wound healing. These types of responses may promote tumor growth, the converse of what one would expect from a protective anti-tumor immune response.
To summarize, while the future appears very bright for cancer immunotherapy, important hurdles remain to be cleared. At present, response and resistance to immune checkpoint inhibitors are unpredictable, and new biomarkers are needed to better tailor therapies for individual patients. This will entail the development of new diagnostic tests to gauge both the host immune response and the likely means of immune evasion in individual cancers. There is reason to believe that immune checkpoint inhibitors may be more effective if given before the patient receives chemotherapy (which is immunosuppressive) or in combination with certain targeted therapies directed against tumor cells, and many well-designed clinical trials will need to be conducted before these questions are answered. Currently available immunotherapies are effective in some cancers but not others. Thus, there is a need for development of safe adaptive therapies that are