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Specific tumor targeting and activation of Vγ9Vδ2 T cells by bi-specific nanobodies
© Stam et al.; licensee BioMed Central Ltd. 2014
- Published: 6 November 2014
- Epidermal Growth Factor Receptor
- Colon Carcinoma
- Susceptible Tumor
- Specific Trigger
- Isopentenyl Pyrophosphate
Gamma delta T cells expressing the Vγ9Vδ2 T cell receptor (TCR) are the most predominant γδ-T cell subset in peripheral blood accounting for approximately 1-5 % of all T cells. Vγ9Vδ2 T cells recognize phosphoantigens (pAg) such as isopentenyl pyrophosphate (IPP), a naturally occurring pAg that can accumulate in tumor cells, resulting in activation, cytokine release and anti-tumor activity of Vγ9Vδ2 T. The use of Vγ9Vδ2 T cells in clinical trials, either via adoptive transfer of ex vivo expanded Vγ9Vδ2 T cells or through in vivo activation by aminobisphosphonates or synthetic pAg, has led to promising results. Anti-tumor responses were observed in some patients, but overall results lack consistency. This might be related to systemic activation of Vγ9Vδ2 T cells in these trials, not providing a specific trigger for these cells to accumulate at the tumor site.
In order to improve the efficacy of Vγ9Vδ2 T cell based immunotherapy, we focused on the design of a tumor-targeting construct that binds both the TCR of Vγ9Vδ2 T cells and the Epidermal Growth Factor Receptor (EGFR), which is over-expressed by many tumor types, including Vγ9Vδ2 T cell susceptible tumors like colon carcinoma and head and neck cancer. For this bi-specific construct an antagonistic anti-EGFR single domain antibody fragment (VHH or Nanobody) and an agonistic anti-Vγ9Vδ2 TCR VHH were identified, characterized and constructed into a bi-specific targeting molecule. Only when bound to both EGFR expressing tumor cells and Vγ9Vδ2 T cells, this bi-specific targeting molecule induced Vγ9Vδ2 T cell activation, release of IFN-γ and TNF-α as well as up-regulated expression of cytolytic molecules such as perforin-and granzyme B. Importantly, tumor targeted Vγ9Vδ2 T cells were able to efficiently lyse EGFR expressing tumor cells in vitro.
This study shows that bi-specific anti-Vγ9Vδ-T-anti-EGFR-nanobodies can specifically and efficiently lyse EGFR-expressing tumor cells and are promising candidates for cancer immunotherapy.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.