Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies

Abstract

Despite extensive investigation over the past three decades, cancer immunotherapy has produced limited success, with few agents achieving approval by the Food and Drug Administration and even the most effective helping only a minority of patients, primarily with melanoma or renal cancer. In recent years, immune checkpoints that maintain physiologic self-tolerance have been implicated in the down-regulation of anti-tumor immunity. Efforts to restore latent anti-tumor immunity have focused on antibody-based interventions targeting CTL antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T lymphocytes and its principal ligand (PD-L1) on tumor cells. Ipilimumab, an antibody targeting CTLA-4, appears to restore tumor immunity at the priming phase, whereas anti-PD-1/PD-L1 antibodies restore immune function in the tumor microenvironment. Although ipilimumab can produce durable long-term responses in patients with advanced melanoma, it is associated with significant immune-related toxicities. By contrast, antibodies targeting either PD-1 or PD-L1 have produced significant anti-tumor activity with considerably less toxicity. Activity was seen in patients with melanoma and renal cancer, as well as those with non-small-cell lung, bladder and head and neck cancers, tumors not previously felt to be sensitive to immunotherapy. The tolerability of PD-1-pathway blockers and their unique mechanism of action have made them ideal backbones for combination regimen development. Combination approaches involving cytotoxic chemotherapy, anti-angiogenic agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines and cancer vaccines are currently under clinical investigation. Current efforts focus on registration trials of single agents and combinations in various diseases and disease settings and identifying predictive biomarkers of response.

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

“…Such efficacy is also expected for thymic carcinoma, which responds poorly to various chemotherapeutic agents; however, this has not been examined yet. In some other malignancies, immunotherapy using PD-L1-and PD-1-based antibodies appeared to show enhanced activity, favoring PD-L1-positive tumors over PD-L1-negative tumors (25,44). Although the practical potency is still unknown, these findings support our statement that the clinical use of immunotherapeutic antibodies targeting the PD-1/PD-L1 pathway may be effective for treating thymic carcinoma based on high PD-L1 positivity.…”

“…Anti-PD-1 antibody has already been approved for clinical use in malignant melanoma, non-small cell lung cancer, and renal cell carcinoma, whereas anti-PD-L1 antibody has demonstrated therapeutic efficacy in patients resistant to conventional chemotherapeutic agents in clinical trials (25). Immunotherapy targeting the PD-1/PD-L1 pathway is therefore expected to improve treatments of malignancies, particularly advanced, chemotherapy-resistant, or metastatic cases.…”

Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy

“…More recently, immune checkpoint regulators such as PD-L1 have become exciting new therapeutic targets leading to long-lasting remissions in patients with advanced malignancies ( 60 ). However, in view of the remarkable costs and the toxicity profi les of these therapies, predictive biomarkers able to discriminate responders from nonresponders are urgently needed.…”

Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors

“…Immunotherapy with checkpoint inhibitors that target CTLA-4 and PD-1 is another therapeutic approach that has been successfully applied to the treatment of solid tumors (94). Thus, there is considerable interest in combining immunotherapy with targeted therapy (95,96).…”