Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors
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ORIGINAL ARTICLE
Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors Emmet McCormack • Katherine J. Adams • Namir J. Hassan • Akhil Kotian • Nikolai M. Lissin • Malkit Sami Maja Mujic´ • Tereza Osdal • Bjørn Tore Gjertsen • Deborah Baker • Alex S. Powlesland • Milos Aleksic • Annelise Vuidepot • Olivier Morteau • Deborah H. Sutton • Carl H. June • Michael Kalos • Rebecca Ashfield • Bent K. Jakobsen
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Received: 17 August 2012 / Accepted: 28 November 2012 / Published online: 22 December 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract NY-ESO-1 and LAGE-1 are cancer testis antigens with an ideal profile for tumor immunotherapy, combining up-regulation in many cancer types with highly restricted expression in normal tissues and sharing a common HLA-A*0201 epitope, 157–165. Here, we present data to describe the specificity and anti-tumor activity of a bifunctional ImmTAC, comprising a soluble, high-affinity T-cell receptor (TCR) specific for NY-ESO-1157–165 fused
Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1384-4) contains supplementary material, which is available to authorized users. E. McCormack M. Mujic´ B. T. Gjertsen Haematology Section, Institute of Medicine, University of Bergen, Bergen, Norway K. J. Adams N. J. Hassan N. M. Lissin M. Sami D. Baker A. S. Powlesland M. Aleksic A. Vuidepot O. Morteau D. H. Sutton R. Ashfield B. K. Jakobsen (&) Immunocore Ltd, 57C Milton Park, Abingdon, Oxfordshire OX14 4RX, UK e-mail: [email protected] A. Kotian C. H. June M. Kalos Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA T. Osdal KinN Therapeutics AS, Haukeland University Hospital, 9th Floor Laboratory Building, Bergen, Norway B. T. Gjertsen Haematology Section, Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway C. H. June M. Kalos Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
to an anti-CD3 scFv. This reagent, ImmTAC-NYE, is shown to kill HLA-A2, antigen-positive tumor cell lines, and freshly isolated HLA-A2- and LAGE-1-positive NSCLC cells. Employing time-domain optical imaging, we demonstrate in vivo targeting of fluorescently labelled high-affinity NYESO-specific TCRs to HLA-A2-, NYESO-1157–165-positive tumors in xenografted mice. In vivo ImmTAC-NYE efficacy was tested in a tumor model in which human lymphocytes were stably co-engrafted into NSG mice harboring tumor xenografts; efficacy was observed in both tumor prevention and established tumor models using a GFP fluorescence readout. Quantitative RT-PCR was used to analyze the expression of both NY-ESO-1 and LAGE-1 antigens in 15 normal tissues, 5 cancer cell lines, 10 NSCLC, and 10 ovarian cancer samples. Overall, LAGE-1 RNA was expressed at a greater frequency and at higher levels than NY-ESO-1 in the
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