PD-1 and PD-L1 antibodies in cancer: current status and future directions

Abstract

Immunotherapy has moved to the center stage of cancer treatment with the recent success of trials in solid tumors with PD-1/PD-L1 axis blockade. Programmed death-1 or PD-1 is a checkpoint molecule on T cells that plays a vital role in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host. In cancer patients, PD-1 expression is very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironment. While PD-L1 expression on tumors is often regarded as a negative prognostic factor, it is clearly associated with a positive outcome for treatment with PD-1/PD-L1 blocking antibodies, and has been used to select patients for this therapy. Responses of long duration, a minority of patients with atypical responses in which progression may precede tumor shrinkage, and a pattern of autoimmune side effects often seen with this class of drugs characterize therapy with PD-1/PD-L1 blocking drugs. While excellent efficacy has been seen with a limited number of tumor types, most epithelial cancers do not show responses of long duration with these agents. In the current review, we will briefly summarize the scientific background data supporting the development of PD-1/PD-L1 blockade, and then describe the track record of these antibodies in multiple different histologies ranging from melanoma and lung cancer to less common tumor types as well as discuss biomarkers that may assist in patient selection.

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

“…With the discovery of this mechanism, immune check-point inhibitors have been shown to carry great promise. However, its efficacy has only been recognized still in a small number of patients, and PD-L1 expression on tumor cells has been regarded as a negative prognostic factor [4,5] .…”

“…Moreover cancer-specific-antigen loaded DC vaccines are also utilized to induce more types of cancer-specific T lymphocytes. [76] The more recent discovery of immune check-point inhibitors achieved outstanding progress in cancer immunotherapy by showing sensational longterm benefits in patients with advanced cancer [4,5] . The purpose of this medicine is to inhibit immune suppressive signals between cancer cells and T-cells; thus the agent that eliminates a cancer during the final phase is T-cells [36,37] .…”

“…Recent progress has been made in cancer immunotherapy, a fourth cancer therapeutic method, including activated T-cell therapy and dendritic cell (DC) vaccines; however, their therapeutic efficacy is still limited [2,3] . The more recent discovery of immune check-point inhibitors has demonstrated sensational long-term benefits in patients with advanced cancer and has highlighted the importance of immune responses to cancer, but its efficacy has been recognized only in a minority of patients [4,5] . Hence, current therapeutic methods need to be improved or new therapeutic cancer therapy developed for single or combination use.…”

Negative Predictive Biomarkers of Checkpoint Inhibitors in Hyper-Progressive Tumors

“…PD-1 and PD-L1 inhibitors led to distinguished clinical responses in patients with different types of cancer ranging from 20 to 30% when used in monotherapy. Anti-PD1 and anti-PDL1 agents are approved by the US FDA in the treatment of multiple malignancies from renal cell carcinoma, classical Hodgkin lymphoma, non-small-cell lung cancer, squamous cell carcinoma of head and neck, metastatic melanoma and urothelial carcinoma of the bladder [1].Defining predictive biomarker of treatment response and toxicity represents one of the challenges of these new agents. In fact, several biomarkers were evoked in order to explain the response to ICI such as PD-L1 expression/amplification, high tumor mutational burden and mismatch repair gene defect [2].…”

“…PD-1 and PD-L1 inhibitors led to distinguished clinical responses in patients with different types of cancer ranging from 20 to 30% when used in monotherapy. Anti-PD1 and anti-PDL1 agents are approved by the US FDA in the treatment of multiple malignancies from renal cell carcinoma, classical Hodgkin lymphoma, non-small-cell lung cancer, squamous cell carcinoma of head and neck, metastatic melanoma and urothelial carcinoma of the bladder [1].…”