Anti-programmed death receptor 1 immunotherapy in melanoma: rationale, evidence and clinical potential

Abstract

Malignant melanoma is a significant public health problem; according to 2013 Surveillance, Epidemiology, and End Results data, its average incidence rate rose 2.6% each year for the last decade, and it is now the fifth most common cancer diagnosis in the United States. The rising incidence and historical poor response to chemotherapy have led to intense investigation of novel treatments for melanoma, including therapies to improve the immune-mediated destruction of cancer cells. Among the hallmarks of malignancy is the ability to evade this process: while early stages of tumor growth can induce functional CD8+ T-cell responses, cancer cells become increasingly embedded in an immune-suppressive tumor stroma. In the tumor microenvironment, T-cell proliferation and effector function are impaired due to engagement of T-cell programmed death receptor 1 (PD-1) with programmed death receptor ligand (PD-L1) expressed by cancer cells and antigen-presenting cells, which blocks T-cell-mediated cytotoxicity. This receptor-ligand engagement thereby inhibits immunity, allows the tumor to continue to grow, and contributes to the phenomenon of 'T-cell exhaustion'. One immunotherapy strategy currently under investigation is inhibition of the interaction between PD-L1 and PD-1, thereby overcoming a critical immune checkpoint to facilitate destruction of cancer cells. In this review we discuss the preclinical rationale for PD-1 pathway inhibition in cancer, recent results of clinical trials targeting PD-1 and PD-L1, and evaluate its potential as a future anticancer therapy.

PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

“…Therapeutics targeting PD-1:PD-1 ligand interactions have shown tremendous clinical results (17,18). Although T-cell modulation represents a major mechanism by which these therapies elicit their effects, this study raises the exciting possibility that PD-1–directed therapies may also support B-cell responses to TACAs.…”

PD‐1 expression by canine T cells and functional effects of PD‐1 blockade

“…Ipilumimab (Yervoy; CTLA‐4 blocking antibody) was the first checkpoint molecule targeted antibody evaluated clinically, and was approved for use in treatment of human melanoma . More recently, impressive clinical results from PD‐1 and PD‐L1 blocking antibodies have been reported and have stimulated a tremendous amount of excitement around the checkpoint molecule field . PD‐1 targeted antibodies, including pembrolizumab (Keytruda) and nivolumab (Opdiva) were approved in the past 2 years for treatment of melanoma, renal cell carcinoma and non‐small cell lung cancer .…”

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

“…Blockade of the PD-L1/PD-1 pathway has emerged as a major area of cancer therapeutics with profound and durable responses seen in a subset of patients with advanced melanoma, 67 renal cell carcinoma, 7 and non-small cell lung cancer. 9 The presumptive mechanism of this clinical effect is the breaking of tolerance of tumor reactive lymphocytes and the generation of tumor-specific immunity.…”