Checkpoint Blockade in Cancer Immunotherapy

Abstract

The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade.

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

“…Although the immune system is the principal mechanism of cancer prevention, transformed cells counteract immunosurveillance. Natural control mechanisms that limit T-cell activation, thereby preventing collateral damage from unrestrained T-cell activity, may be exploited by tumors to evade immune responses (1). Restoring the capacity of immune effector cells-especially T cells-to recognize and eliminate cancer is the goal of immunotherapy.…”

Stimulating immune responses to fight cancer: Basic biology and mechanisms

“…52,58 • Activation in the effector phase of T-cell response in peripheral tissues 53 Stimulating immune responses…”

Cancer-Immune Equilibrium: Questions Unanswered

“…A DC vaccine derived from patients loaded tumor antigens can be an efficient method for stimulating anticancer immunity. A vaccination strategy may be used in combination with other approaches like enhancement of T cell costimulation by administering agonistic antibodies or by antagonistic antibodies specific for coinhibitory receptors such as CTLA-4 [34,56,57]. Equally important would be to develop interventions that counter the propensity of tumors to evade immune elimination, such as removing Treg or immunizing against the tumor stroma.…”