Immune checkpoint inhibitors in clinical trials

Abstract

Immunology-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. We have learned over the last decade that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints." These checkpoints serve to control or turn off the immune response when it is no longer needed to prevent tissue injury and autoimmunity. Cancer cells have learned or evolved to use these mechanisms to evade immune control and elimination. The development of a new therapeutic class of drugs that inhibit these inhibitory pathways has recently emerged as a potent strategy in oncology. Three sets of agents have emerged in clinical trials exploiting this strategy. These agents are antibody-based therapies targeting cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). These inhibitors of immune inhibition have demonstrated extensive activity as single agents and in combinations. Clinical responses have been seen in melanoma, renal cell carcinoma, non-small cell lung cancer, and several other tumor types. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development.

Figure 1.. Regulatory pathways in immuno-oncology.

The immune system has multiple levels of co-stimulatory (shown in green) and co-inhibitory (shown in red) pathways, helping to maintain immune homeostasis in the midst of responding to antigenic stimulation. Antibodies blocking cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have shown remarkable clinical activity and further development is underway. Agonist antibodies, which directly interact with co-stimulatory pathways such as 41BB and CD40, are also in clinical development. Other means of affecting the immune responses are being explored, including direct actionon regulatory T (Treg) cells and natural killer (NK) cells. MHC, major histocompatibility complex; TCR, T-cell receptor.