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Clin Cancer Res. 2019 Oct 1;25(19):5890-5900. doi: 10.1158/1078-0432.CCR-18-3927. Epub 2019 Jul 8.

Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy.

Author information

1
Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Munich, Germany, Member of the German Center for Lung Research (DZL).
2
Roche Innovation Center Zurich, Schlieren, Switzerland.
3
Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.
4
Helmholtz Diabetes Center and German Diabetes Center (DZD), Helmholtz Zentrum München, Neuherberg, Germany.
5
TCR Therapeutics, Cambridge, Massachusetts.
6
Roche Innovation Center Munich, Penzberg, Germany.
7
Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Munich, Germany, Member of the German Center for Lung Research (DZL). Sebastian.kobold@med.uni-muenchen.de.
#
Contributed equally

Abstract

PURPOSE:

Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing.

EXPERIMENTAL DESIGN:

BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell-induced lysis were characterized in three murine and human tumor models in vitro and in vivo.

RESULTS:

Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3ζ signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII × anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo.

CONCLUSIONS:

We describe a novel ACT platform with antitumor activity in murine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.

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