Sebastian Kobold1, Julius Steffen2, Michael Chaloupka2, Simon Grassmann2, Jonas Henkel2, Raffaella Castoldi2, Yi Zeng2, Markus Chmielewski2, Jan C Schmollinger2, Max Schnurr2, Simon Rothenfußer2, Dolores J Schendel2, Hinrich Abken2, Claudio Sustmann2, Gerhard Niederfellner2, Christian Klein2, Carole Bourquin2, Stefan Endres2. 1. Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany (SK, JS, MiC, SG, JH, YZ, JCS, MS, SR, CB, SE); Roche Pharmaceutical Research and Early Development, Oncology Discovery and Translational Area, Roche Innovation Center Penzberg, Penzberg, Germany (RC, CS, GN); Center for Molecular Medicine Cologne and Department I for Internal Medicine, University Hospital Cologne, Cologne, Germany (MaC, HA); Institute of Molecular Immunology, Helmholtz Zentrum München and Clinical Cooperation Group Immune Monitoring, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany (DJS); Roche Pharmaceutical Research and Early Development, Oncology Discovery and Translational Area, Roche Innovation Center Zurich, Switzerland (CL); Chair of Pharmacology, Department of Medicine, University of Fribourg, Fribourg, Switzerland (CB). sebastian.kobold@med.uni-muenchen.de. 2. Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany (SK, JS, MiC, SG, JH, YZ, JCS, MS, SR, CB, SE); Roche Pharmaceutical Research and Early Development, Oncology Discovery and Translational Area, Roche Innovation Center Penzberg, Penzberg, Germany (RC, CS, GN); Center for Molecular Medicine Cologne and Department I for Internal Medicine, University Hospital Cologne, Cologne, Germany (MaC, HA); Institute of Molecular Immunology, Helmholtz Zentrum München and Clinical Cooperation Group Immune Monitoring, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany (DJS); Roche Pharmaceutical Research and Early Development, Oncology Discovery and Translational Area, Roche Innovation Center Zurich, Switzerland (CL); Chair of Pharmacology, Department of Medicine, University of Fribourg, Fribourg, Switzerland (CB).
Abstract
BACKGROUND: One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy. METHODS: SV40 T antigen-specific T cells from T cell receptor (TCR)-I-transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR-anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40(+) and EpCAM(+)). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met(+) human tumor cell lines. Differences between experimental conditions were analyzed using the Student's t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided. RESULTS: The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR-transduced T cells to immobilized c-Met and recognition of tyrosinase(+) melanoma cells by TCR-, as well as of CEA(+) colon cancer cells by chimeric antigen receptor (CAR)-modified T cells. CONCLUSIONS: BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT.
BACKGROUND: One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy. METHODS: SV40 T antigen-specific T cells from T cell receptor (TCR)-I-transgenic mice were transduced with a truncated humanepidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR-anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murinegastric cancer cell line GC8 (SV40(+) and EpCAM(+)). Anti-EGFR x anti-c-MetBiAb was used for targeting of humantumor-specific T cells to c-Met(+) humantumor cell lines. Differences between experimental conditions were analyzed using the Student's t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided. RESULTS: The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of humanEGFR-transduced T cells to immobilized c-Met and recognition of tyrosinase(+) melanoma cells by TCR-, as well as of CEA(+) colon cancer cells by chimeric antigen receptor (CAR)-modified T cells. CONCLUSIONS:BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT.
Authors: Clara H Karches; Mohamed-Reda Benmebarek; Moritz L Schmidbauer; Mathias Kurzay; Richard Klaus; Martina Geiger; Felicitas Rataj; Bruno L Cadilha; Stefanie Lesch; Constanze Heise; Ramona Murr; Johannes Vom Berg; Martin Jastroch; Daniel Lamp; Jian Ding; Peter Duewell; Gerhard Niederfellner; Claudio Sustmann; Stefan Endres; Christian Klein; Sebastian Kobold Journal: Clin Cancer Res Date: 2019-07-08 Impact factor: 12.531
Authors: Ali Bashiri Dezfouli; Mina Yazdi; Mohamed-Reda Benmebarek; Melissa Schwab; Stefanos Michaelides; Arianna Miccichè; Dirk Geerts; Stefan Stangl; Sarah Klapproth; Ernst Wagner; Sebastian Kobold; Gabriele Multhoff Journal: Front Immunol Date: 2022-06-01 Impact factor: 8.786
Authors: Cornelia Voigt; Peter May; Adrian Gottschlich; Anamarija Markota; Daniel Wenk; Inga Gerlach; Sebastian Voigt; Georgios T Stathopoulos; Kristina A M Arendt; Constanze Heise; Felicitas Rataj; Klaus-Peter Janssen; Melanie Königshoff; Hauke Winter; Isabelle Himsl; Wolfgang E Thasler; Max Schnurr; Simon Rothenfußer; Stefan Endres; Sebastian Kobold Journal: Proc Natl Acad Sci U S A Date: 2017-11-17 Impact factor: 11.205
Authors: Moritz Rapp; Simon Grassmann; Michael Chaloupka; Patrick Layritz; Stephan Kruger; Steffen Ormanns; Felicitas Rataj; Klaus-Peter Janssen; Stefan Endres; David Anz; Sebastian Kobold Journal: Oncoimmunology Date: 2015-10-29 Impact factor: 8.110