Mechanistic and pharmacologic insights on immune checkpoint inhibitors

Abstract

The concept of augmenting the immune system to eradicate cancer dates back at least a century. A major resurgence in cancer immunotherapy has occurred over the past decade since the identification and targeting of negative regulators with antibody therapies to augment the anti-tumor immune response. Unprecedented responses across a broad array of cancer types elevated this class of therapies to the forefront of cancer treatment. The most successful drugs to date target the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) pathways. The immune biology of these pathways was illuminated through thoughtful pre-clinical experiments over the past 20 years. The characterization of these negative immune regulators, also known as immune checkpoints, subsequently led to the successful clinical development four drugs in six different cancer types to date, and progress continues. Despite these successes, significant challenges remain including the development of predictive biomarkers, recognition and management of immune related toxicities, and elucidating and reversing mechanisms of primary and secondary resistance. Ongoing work is expected to build upon recent accomplishments and allow more patients to benefit from this class of therapies.

Keywords: Atezolizumab; CTLA-4; Cancer immunity; Immune checkpoint; Immunotherapy; Ipilimumab; Nivolumab; PD-1; PD-L1; Pembrolizumab.

Figure 1. Binding of the T cell receptor to the peptide:MHC complex alone is not sufficient to activate T cells

Costimulation is necessary from the binding of B7-1/B7-2 to CD28. Inhibitory receptors such as PD-1 and CTLA-4 have been discovered, which blunt costimulation, prevent T cell activation, and result in T cell anergy and/or apoptosis.

Figure 2. Depiction of the non- T cell-inflamed versus T cell-inflamed tumor microenvironment

T cell-inflamed tumors are characterized by the presence of tumor-infiltrating lymphocytes, dendritic cells, chemokines, and type I IFN. The infiltration of tumor-antigen specific T cells results in the development of adaptive immune resistance via negative immune regulatory pathways, such as PD-L1 and other molecules not depicted, which suppress the anti-tumor immune response. Thus, blocking negative regulatory pathways is more likely to lead to T cell activation and regression of tumors. Non-T cell inflamed tumors lack immune infiltrating cells and are unlikely to respond to immune checkpoint blockade, as there is no adaptive resistance present to reverse.