T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: Towards tumor-directed oligoclonal T cell therapy |
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Authors: | Fatemeh Rahimi Jamnani Fatemeh Rahbarizadeh Mohammad Ali Shokrgozar Fereidoun Mahboudi Davoud Ahmadvand Zahra Sharifzadeh Ladan Parhamifar S. Moein Moghimi |
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Affiliation: | 1. Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran;2. Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran;3. National Cell Bank, Pasteur Institute of Iran, Tehran, Iran;4. School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran;5. Center of Pharmaceutical Nanotechnology and Nanotoxicology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark;6. Hybridoma Laboratory, Department of Immunology, Pasteur Institute of Iran, Tehran, Iran;g NanoScience Center, Faculty of Science, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark |
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Abstract: | BackgroundAdoptive cell therapy with engineered T cells expressing chimeric antigen receptors (CARs) originated from antibodies is a promising strategy in cancer immunotherapy. Several unsuccessful trials, however, highlight the need for alternative conventional binding domains and the better combination of costimulatory endodomains for CAR construction to improve the effector functions of the engineered T cells. Camelid single-domain antibodies (VHHs), which are the smallest single domain antibodies, can endow great targeting ability to CAR-engineered T cells.MethodsWe have developed a method to generate genetically engineered Jurkat T cells armed with a CAR comprising the anti-HER2 VHH as targeting moiety. From an immune camel library, five VHH clones were selected as a set of oligoclonal anti-HER2 VHHs that exhibited diverse binding abilities and joined them to CD28-CD3ζ and CD28-OX40-CD3ζ signaling endodomains. Jurkat T cells expression of VHH-CARs and cell functions were evaluated.ResultsThe oligoclonal engineered T cells showed higher proliferation, cytokine secretion and cytotoxicity than each individual VHH-CAR-engineered Jurkat T cells.ConclusionsThe combination of superior targeting ability of oligoclonal VHHs with the third generation CAR can substantially improve the function of engineered T cells.General significanceAntigen-specific directed oligoclonal T cells are alternatively promising, but safer systems, to combat tumor cells. |
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Keywords: | CAR, chimeric antigen receptor CDR, complementarity determining region HCAb, heavy-chain antibodies IPTG, isopropyl-β-D-thio-galactoside MHC, major histocompatibility complex TAG 72, tumor associated glycoprotein 72 TCR, T cell receptor TMB, 3,3&prime ,5,5&prime -tetramethyl benzidine VHH, variable domain of camel heavy-chain antibody VHH-CAR, VHH-chimeric antigen receptor |
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