Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC

• Authors: Benjamin Besse, Gustave Roussy Cancer Campus; Melinda Charrier, Gustave Roussy Cancer Campus; Valerie Lapierre, Gustave Roussy Cancer Campus; Eric Dansin, CLCC Oscar Lambret; Olivier Lantz, Centre d'Investigation Clinique en Biothérapies; David Planchard, Gustave Roussy Cancer Campus; Thierry Le Chevalier, Gustave Roussy Cancer Campus; Alain Livartoski, Institut Curie; Fabrice Barlesik, Aix Marseille University; Agnes Laplanche, Gustave Roussy Cancer Campus; Stephanie Ploix, Centre d'Investigation Clinique en Biothérapies; Nadege Vimond, Gustave Roussy Cancer Campus; Isabelle Peguillet, Centre d'Investigation Clinique en Biothérapies; Clotilde Thery, University of Paris-Sud 11; Ludovic Lacroix, Gustave Roussy Cancer Campus; Inka Zoernig, National Center for Tumor Diseases; Kavita Dhodapkar, Emory University; Madhav Dhodapkar, Emory University; Sophie Viaud, Gustave Roussy Cancer Campus; Jean-Charles Soria, Gustave Roussy Cancer Campus; Katrin S. Reiners, University Hospital Cologne; Elke Pogge von Strandmann, University Hospital Cologne; Frederic Vely, Aix Marseille University; Sylvia Rusakiewicz, Gustave Roussy Cancer Campus; Alexander Eggermont, Gustave Roussy Cancer Campus; Jonathan M. Pitt, Gustave Roussy Cancer Campus; Laurence Zitvogel, Gustave Roussy Cancer Campus; Nathalie Chaput, Gustave Roussy Cancer Campus
• Journal Title: OncoImmunology
• Volume: Volume 5, Number 4
• Publisher: Taylor & Francis: STM, Behavioural Science and Public Health Titles | 2016-01-01, Pages e1071008-e1071008
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1080/2162402X.2015.1071008
• Subjects: Health Sciences, Oncology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Immunology; cancer vaccine; exosomes; immunotherapy; NSCLC; NK cell; phase II trial; IMMUNE-SYSTEM; PROGNOSTIC VALUE; CLINICAL GRADE; CHAPERONE; RECEPTOR; HSP70; EXPRESSION; RESPONSES; NKP30

Abstract

ABSTRACT: Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.