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Karches, Clara H.; Benmebarek, Mohamed-Reda; Schmidbauer, Moritz L.; Kurzay, Mathias; Klaus, Richard; Geiger, Martina; Rataj, Felicitas; Cadilha, Bruno L.; Lesch, Stefanie; Heise, Constanze; Murr, Ramona; vom Berg, Johannes; Jastroch, Martin; Lamp, Daniel; Ding, Jian; Duewell, Peter; Niederfellner, Gerhard; Sustmann, Claudio; Endres, Stefan; Klein, Christian and Kobold, Sebastian (2019): Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy. In: Clinical Cancer Research, Vol. 25, No. 19: pp. 5890-5900

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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 CD3 zeta signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII x 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 inmurine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.

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