American Association for Cancer Research
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10780432ccr183927-sup-213188_2_supp_5559533_pyrd6y_eps_zip.zip (2.7 MB)

Supplementary Figure 4 from Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy

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posted on 2023-03-31, 21:31 authored by 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

Supplementary Figure 4: Human SAR T cells are specifically stimulated by anti-human mesothelin x anti-EGFRv3 2 + 1 BiAb and redirect lysis to mesothelin+ target cells in vitro and in vivo

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Elite Network of Bavaria

Melanoma Research Alliance

H2020

European Research Council

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ARTICLE ABSTRACT

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. 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. 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. 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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