Cancer immunotherapies targeting the PD-1 signaling pathway

Abstract

Immunotherapy has recently emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. While early immunotherapies focused on accelerating T-cell activity, current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses. Successful clinical trials with PD-1 monoclonal antibodies and other immune-checkpoint inhibitors have opened new avenues in cancer immunology. However, the failure of a large subset of cancer patients to respond to these new immunotherapies has led to intensified research on combination therapies and predictive biomarkers. Here we summarize the development of PD-1-blockade immunotherapy and current issues in its clinical use.

Keywords: Cancer immunotherapy; Immune checkpoint; PD-1; PD-L1.

Fig. 1

Costimulatory molecules that positively or negatively regulate immune responses

Fig. 2

History of PD-1 research. Abbreviations: FIM, first in man; approved, FDA-approved; NCT, “National Clinical Trial” registry number in ClinicalTrials.gov in the United States; FIM Pembrolizumab (P07990/MK-3475-001/KEYNOTE-001), NCT01295827; FIM Pidilizumab (CT-011), NCT00532259; FIM BMS-936559 (MDX-1105), NCT00729664; FIM Atezolizumab, NCT01693562; FIM Durvalumab (MEDI4736), NCT01693562; FIM Avelumab, NCT01772004

Fig. 3

Genomic mutations and PD-1 signal inhibitors. (1) Genetic mutations in cancer cells create neo-antigens. (2) Neo-antigens are expressed on the surface of the cancer cells. (3) Recognition of a neo-antigen as a foreign body by an APC induces a T-cell response, and (4) consequently activates T cells and B cells. (5) Activated T cells release IFN-γ. (6) A cancer cell that is exposed to IFN-γ expresses PD-L1, thereby establishing an acquired immune resistance. In this particular tumor microenvironment, PD-1 signal inhibitors appear to be effective; thus, genome-wide mutation analysis (i.e., Mutanome) of cancer cells using next-generation sequencing technology and diversity analysis of the T-cell or B-cell repertoire (i.e., Immunome) are valuable next strategies for identifying predictive biomarkers [75]. APC, antigen-presenting cell