Anti-PDCD1 monoclonal antibody, clone K206 [PE]

Adoptive transfer of T cells genetically engineered to express a tumor-targeting chimeric antigen receptor (CAR) or T-cell receptor (TCR) can mediate cancer regression in some patients. CARs are synthetic single-chain proteins that use antibody domains to target cell surface antigens. TCRs are natural heterodimeric proteins that can target intracellular antigens through recognition of peptides bound to human leukocyte antigens. CARs have shown promise in B-cell malignancies and TCRs in melanoma, but neither approach has achieved clear success in an epithelial cancer. Treatment of epithelial cancers may be particularly challenging because of a paucity of target antigens expressed by carcinomas and not by important healthy tissues. In addition, epithelial cancers may be protected by inhibitory ligands and soluble factors in the tumor microenvironment. One strategy to overcome these negative regulators is to modulate expression of T-cell genes to enhance intrinsic T-cell function. Programmable nucleases, which can suppress inhibitory genes, and inducible gene expression systems, which can enhance stimulatory genes, are entering clinical testing. Other work is delineating whether control of genes for immune checkpoint receptors (e.g., PDCD1, CTLA4) and cytokine and TCR signaling regulators (e.g., CBLB, CISH, IL12, IL15) can increase the antitumor activity of therapeutic T cells. (C) 2016 AACR.

Although many autoimmune diseases are associated with particular HLA/H-2 haplotypes, the mechanisms through which specific HLA/H-2 haplotypes afford autoimmune susceptibility remain enigmatic. Here, we analyzed the effects of the diabetes-associated (H-2(g7)) and an antidiabetogenic (H-2(b)) H-2 haplotypes in NOD mice deficient for programmed cell death-1 (PD-1, Pdcd1), a unique model of type 1 diabetes that confers complete penetrance and rapid onset of the disease. NOD-H2(b/b)Pdcd1(-/-) mice were completely protected from diabetes, confirming that H-2(g7) is indispensable for diabetes even in the absence of PD-1. However, NOD-H2(b/b)Pdcd1(-/-) mice developed autoimmune inflammation in multiple tissues including peripheral nerves, stomachs, and exocrine tissues, demonstrating that autoreactive T cells are generated in the context of H-2(b). These autoreactive T cells damaged target tissues only in the absence of PD-1, confirming that PD-1 deficiency unravels the hidden autoimmune susceptibility of the strain by reducing the threshold of T cell activation. Transfer experiments revealed that CD4 T cells are the effector cells of neuritis, and nerve-infiltrating CD4 T cells are strongly deviated toward Th1. Interestingly, neuritogenic T cells were also generated in the context of H-2(g7), in sharp contrast to the strict requirement of H-2(g7) for diabetes. In addition, 60% of the NOD-H2(b/g7)Pdcd1(-/-) mice developed diabetes, suggesting that H-2(b) does not dominantly suppress diabetes and that H-2(g7) induces diabetes in a dose-dependent fashion.