A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release
| Autor: | Stephan A. Grupp, Cheng Liu, Bryan Zimdahl, Horan Lucas, Pengbo Zhang, Hong Liu, David M. Barrett, Yiyang Xu, Jingwei Lu, Liu Lianxing, Vivien W. Chan, Shon Green, Javier Morales, Zhiyuan Yang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
biology Chemistry lcsh:Cytology medicine.medical_treatment CD137 T-cell receptor Degranulation CD28 Cell Biology Biochemistry Chimeric antigen receptor Article 03 medical and health sciences 030104 developmental biology Cytokine Genetics biology.protein medicine Cancer research Cytotoxic T cell Antibody lcsh:QH573-671 Molecular Biology |
| Zdroj: | Cell Discovery Cell Discovery, Vol 4, Iss 1, Pp 1-13 (2018) |
| ISSN: | 2056-5968 |
| Popis: | The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti-CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA-approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the γ and δ chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3ζ CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model. |
| Databáze: | OpenAIRE |
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