Lieping Chen

After proven efficacy in the advanced and metastatic setting in non-small-cell lung cancer (NSCLC), the use of immune checkpoint inhibitors that target the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway is rapidly becoming standard-of-care in the perioperative setting for locally advanced patients. The Checkmate-816 trial changed the treatment paradigm for stage II and stage III disease by demonstrating improvements in complete pathologic response rates and improved event-free survival rates at 24 months among patients treated with 3 cycles of neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone prior to surgical resection. 1 PD-L1 expression and tumor mutational burden (TMB) are commonly used, but imperfect biomarkers, to predict clinical response to anti-PD therapy in NSCLC. 2–4 While increased PD-L1 protein expression in tumors correlates with …

Tumors evade immunity through the overexpression of immune inhibitory molecules in the tumor microenvironment such as PD-L1/B7-H1. An immune inhibitory molecule named PD-1 homolog (also known as V-domain Ig-containing suppressor of T cell activation [VISTA]) functions to control both T cells and myeloid cells. Current clinical trials using anti-VISTA–blocking agents for treatment of cancer are ongoing. We sought to determine the extent of VISTA expression in primary cutaneous melanomas (n = 190), identify the critical cell types expressing VISTA, and correlate its expression with PD-L1 expression using multiplexed quantitative immunofluorescence. Within the tumor subcompartments, VISTA is most highly expressed on CD11b myeloid cells, and PD-L1 is most highly expressed on CD68 myeloid cells in our melanoma cohort. There is little correlation between VISTA and PD-L1 expression intensity …

The invention features methods of diagnosis by assessing B7-H1 expression in a tissue from a subject that has, or is suspected of having, cancer, methods of treatment with agents that interfere with B7-H1-receptor interaction, methods of selecting candidate subjects likely to benefit from cancer immunotherapy, and methods of inhibiting expression of B7-H1.

Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti–programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell–mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML …

Twenty-five years ago, we reported that agonist anti-CD137 monoclonal antibodies eradicated transplanted mouse tumors because of enhanced CD8+ T-cell antitumor immunity. Mouse models indicated that anti-CD137 agonist antibodies synergized with various other therapies. In the clinic, the agonist antibody urelumab showed evidence for single-agent activity against melanoma and non-Hodgkin lymphoma but caused severe liver inflammation in a fraction of the patients. CD137's signaling domain is included in approved chimeric antigen receptors conferring persistence and efficacy. A new wave of CD137 agonists targeting tumors, mainly based on bispecific constructs, are in early-phase trials and are showing promising safety and clinical activity. Significance CD137 (4-1BB) is a costimulatory receptor of T and natural killer lymphocytes whose activity can be exploited in …

B7-H5 costimulatory polypeptides, nucleic acids encoding such polypeptides, and methods for using the polypeptides and nucleic acids to enhance a T cell response are provided herein.

PurposeProgrammed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti–PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates.Patients and MethodsThirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non–small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti–PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy.ResultsAnti–PD-1 was well tolerated: one serious adverse event, inflammatory colitis …

“We thank Beth Cadugan for editing the manuscript, Dr. Zhiyong Guo (The first affiliated hospital, Sun Yat-sen University) for generously sharing the Foxp3 (GFP) knock-in mice, and Mr. Xiaobo Li for providing the technical support of cell sorting. This study partially fulfills the requirement of the Ph. D. degree at the Graduate School of Sun Yat-sen University School of Medicine for Qi Wang and Jianwei He. This work is supported in part by the 985 project grant from Sun Yat-sen University, Guangdong Province Innovative Research Program Project 2011Y035, PRC; National Institutes of Health grants P50 CA177444, P30 CA016359, P50 CA17744415 and P30 CAO16359, and an endowment from the United Technologies Corporation, USA.” should read: