Cancer: Antitumour immunity gets a boost.

Abstract

Five papers extend the list of cancers that respond to therapies that restore antitumour immunity by blocking the PD-1 pathway, and characterize those patients who respond best. See Letters p.558, p.563, p.568, p.572 & p.577 Thomas Powles et al. report the results of a clinical phase I study in metastatic urothelial bladder cancer treated with the anti-PDL1 antibody MPDL3280A. The transmembrane protein PD-L1 (programmed death-ligand 1) is upregulated in many different types of cancer and protocols targeting its interactions have shown promise in pre-clinical studies. This paper shows MPDL3280A to be particularly active against tumours with PD-L1-positive tumour-infiltrating immune cells. In addition, PD-L1-negative patients achieved a 11% response, which could be of significance given the historical rates of response in this type of cancer. The transmembrane protein PD-L1 (programmed death-ligand 1) is upregulated in many different types of cancer and protocols targeting its interactions have shown promise in pre-clinical studies. Here Roy Herbst et al. present clinical and correlative biomarker results from a phase I clinical trial in patients with solid tumours of various types treated with the engineered anti-PD-L1 antibody MPDL3280A. The findings indicate that PD-L1 expression on tumour-infiltrating immune cells is associated with clinical response to MPDL3280A. Therapies that target the human cell-surface programmed death-1 (PD-1) receptor have shown unprecedented clinical responses in a variety of cancer types. Here Paul Tumeh et al. investigate the dynamics of T-cell responses in tumour tissues of patients with advanced melanoma treated with pembrolizumab, a humanized monoclonal antibody directed against human PD-1. Clinical efficacy is shown to correlate with increased frequencies of pre-existing CD8+ T cells and PD-1 and PD-L1 expression at the invasive tumour margin and within tumours. Mahesh Yadav et al. use a combination of genome-wide exome and transcriptome analysis, mass spectrometry and computational structural modelling to identify immunogenic neo-antigens in two mouse tumour cell lines. Mice vaccinated with predicted immunogenic peptides yielded therapeutically useful cytotoxic T-lymphocyte responses. In many individuals, immunosuppression is mediated by T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), immunomodulatory receptors expressed on T cells. Matthew Gubin et al. use the MCA mouse sarcoma model to show that mutant tumour antigens serve as targets for CD8+ T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy with anti-PD-1 and/or anti-CTLA-4. The authors demonstrate that these antigens can be used effectively in therapeutic vaccines, suggesting a possible route to personalized cancer vaccines.