Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer

Abstract

// Anders Handrup Kverneland 1 , * , Magnus Pedersen 1 , * , Marie Christine Wulff Westergaard 1 , Morten Nielsen 1 , Troels Holz Borch 1 , Lars Rønn Olsen 2 , 3 , Gitte Aasbjerg 2 , Saskia J. Santegoets 4 , Sjoerd H. van der Burg 4 , Katy Milne 5 , Brad H. Nelson 5 , 6 , Özcan Met 1 , Marco Donia 1 and Inge Marie Svane 1 1 National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark 2 Section for Bioinformatics, DTU Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark 3 Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark 4 Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands 5 Deeley Research Centre, BC Cancer, Victoria, Canada 6 Department of Medical Genetics, University of British Columbia, Vancouver, Canada * These authors contributed equally to this work Correspondence to: Inge Marie Svane, email: inge.marie.svane@regionh.dk Keywords: adoptive cell therapy; tumor-infiltrating lymphocytes; ovarian cancer; combinational immune therapy; checkpoint inihibors Received: March 27, 2020     Accepted: April 27, 2020     Published: June 02, 2020 ABSTRACT Immune therapy is a promising field within oncology but has been unsuccessful in ovarian cancer (OC). Still, there is rationale and evidence supporting immune therapy in OC. We investigated the potential for adoptive cell therapy (ACT) from in vitro expanded tumor-infiltrating lymphocytes (TILs) in combination with checkpoint inhibitors (ICI) and conducted immunological testing of ex vivo expanded TILs (REP-TILs). Six patients with late-stage metastatic high-grade serous OC were treated with immune therapy consisting of ipilimumab followed by surgery to obtain TILs and infusion of REP-TILs, low-dose IL-2 and nivolumab. One patient achieved a partial response and 5 others experienced disease stabilization for up to 12 months. Analysis of the REP-TILs with flow- and mass-cytometry show primarily activated and differentiated effector memory T cells. REP-TILs showed in vitro reactivity and expression of inhibitory receptors, such as LAG-3 and PD-1. Furthermore, our data indicate that addition of ipilimumab therapy improves the T cell fold expansion during production, increase the level of CD8 T cell tumor reactivity, and favorably affect the T cell phenotype. We show that the combination of ICI and ACT is feasible and safe. With one partial response and one long-lasting SD, we demonstrated the potential of ACT in OC.