Cancer immunotherapy using checkpoint blockade

Abstract

The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.

Fig. 1.

Blockade of CTLA-4 and PD-1/L1 to induce antitumor responses. Left) CTLA-4 is a negative regulator of costimulation that is required for initially activating an antitumor T cell in a lymph node upon recognition of its specific tumor antigen presented by an antigen-presenting cell. The activation immune checkpoint CTLA-4 can be blocked with anti-CTLA-4 antibodies. Right) Once the T cells are activated, they circulate through the body to find their cognate antigen presented by cancer cells. Upon their recognition, the triggering of the T cell receptor (TCR) leads to the expression of the negative regulatory receptor PD-1, and the production of interferon-gamma results in the reactive expression of PD-L1, turning off the antitumor T cell responses. This negative interaction can be blocked by anti-PD-1 or anti-PD-L1 antibodies.

Fig. 2.

Timing of clinical development of anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies from first administration to humans to FDA approval. Thus far, there has been drug regulatory approval for six antibodies blocking immune checkpoints and one combination of two immune checkpoints. The gray shading represents the period of clinical development of each of these antibodies from the dosing of the first patient until their regulatory approval (red checkmarks) in different indications.

Fig. 3.

Mechanism of action of PD-1 blockade therapy. Left) the T cell receptor (TCR) recognition of the cognate antigen presented by MHC molecules on the surface of cancer cells results in T cell activation. T cells then produce interferon-gamma and other cytokines. Cancer cells and other cells in the tumor microenviroment have interferon gamma receptors that signal through the Janus kinases 1 and 2 (JAK1 and JAK2), which phosphorylate and activate signal transducers and activators of transcription (STAT) proteins that dimerize and turn on a series of interferon-response genes, including the interferon regulatory factor 1 (IRF-1), which binds to the promoter of PD-L1 leading to its surface expression. The reactive expression of PD-L1 turns off the T cells that are trying to attack the tumor, and these T cells remain in the margin of the cancer. Right) Blockade of the PD-1:PD-L1 interaction with therapeutic antibodies results in T cell proliferation and infiltration into the tumor, inducing a cytotoxic T cell response that leads to an objective tumor response.