Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs

Abstract

Negative co-stimulatory signaling mediated via cell surface programmed death (PD)-1 expression modulates T and B cell activation and is involved in maintaining peripheral tolerance. In this study, we examined the effects of a fully human PD-1-abrogating antibody on the in vitro expansion and function of human vaccine-induced CD8+ T cells (CTLs) specific for the melanoma-associated antigens glycoprotein 100 (gp100) and melanoma antigen recognized by T cells (MART)-1. PD-1 blockade during peptide stimulation augmented the absolute numbers of CD3+, CD4+, CD8+ and gp100/MART-1 MHC:peptide tetramer+ CTLs. This correlated with increased frequencies of IFN-gamma-secreting antigen-specific cells and augmented lysis of gp100+/MART-1+ melanoma targets. PD-1 blockade also increased the fraction of antigen-specific CTLs that recognized melanoma targets by degranulation, suggesting increased recognition efficiency for cognate peptide. The increased frequencies and absolute numbers of antigen-specific CTLs by PD-1 blockade resulted from augmented proliferation, not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both type-1 and type-2 cytokine accumulation in culture without any apparent skewing of the cytokine repertoire. These findings have implications for developing new cancer immunotherapy strategies.

Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma

“…33 PD-1 is expressed on postvaccination, melanoma antigen-specific, cytotoxic T lymphocytes (CTLs). 34 PD-1 blockade during peptide stimulation augmented the absolute numbers of vaccine peptide tetramer-positive CTLs. 34 Our study also demonstrated that PD-1-bearing, CD8-positive cells were increased in PBMCs and in the tumor microenvironment.…”

“…34 PD-1 blockade during peptide stimulation augmented the absolute numbers of vaccine peptide tetramer-positive CTLs. 34 Our study also demonstrated that PD-1-bearing, CD8-positive cells were increased in PBMCs and in the tumor microenvironment. The number of circulating PD-1-positive/CD8-positive T cells increased further as the disease progressed.…”

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

“…The variable regions of this antibody were sequenced and grafted onto human kappa and IgG4 constant region sequences containing an S228P mutation, and the resulting antibody (nivolumab) was expressed and purified from a transfected CHO cell line. The complete characterization of nivolumab is described below; preliminary data have been reported previously (25,30).…”

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

“…We are currently exploring PD-1 disruption of T cells by generating CTLs targeting on specific tumor antigen, as to solve the problem that continuous treatment to interrupt PD-1/PD-L1 co-stimulation is needed in the process of sustained expansion of PD-1-expressing antigen-specific CTLs. 28 In recent years, a number of studies confirmed PD-L1 expression on the surface of gastric cancer cells 29,30 ; PD-1 expression in peripheral circulating blood lymphocytes, tumor-infiltrating lymphocytes, and its ligands; and PD-L1 in serum and tumor tissue. 31 The expression of PD-L1 and PD-1 was closely related with tumor progression, invasion, …”