Abstract
Gene therapies including CAR-T cell immunotherapy have shown very promising results in clinical trials particularly haematological malignancies. Viral vector manufacture, used for producing CAR-T cells, represents a major bottleneck limiting the number of patients treated from individual cGMP vector batches. A major obstacle is the absence of a rapid and quantitative detection method for viral vectors that would enable accurate monitoring and feedback into the production process. This project aims to address this challenge by harnessing a unique type of optical biosensor based on a novel yet inexpensive optical metamaterial.
References
1 Stambrook, P. J., Maher, J. & Farzaneh, F. Cancer Immunotherapy: Whence and Whither. Mol Cancer Res 15, 635-650, doi:10.1158/1541-7786.MCR-16-0427 (2017).
2 Chan, L. et al. IL-2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML. Molecular therapy : the journal of the American Society of Gene Therapy 11, 120-131, doi:10.1016/j.ymthe.2004.09.006 (2005).
3 Ghorashian, S. et al. A Novel Second Generation CD19 CAR for Therapy of High Risk/Relapsed Paediatric CD19 Acute Lymphoblastic Leukaemia and Other Haematological Malignancies: Preliminary Results from the Carpall Study. Blood 128, 4026 (2016).
4 Qasim, W. et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Science Translational Medicine 9, eaaj2013, doi:10.1126/scitranslmed.aaj2013 (2017).
5 Nesbeth, D. et al. Metabolic Biotinylation of Lentiviral Pseudotypes for Scalable Paramagnetic Microparticle-Dependent Manipulation. Molecular Therapy 13, 814-822, doi:https://doi.org/10.1016/j.ymthe.2005.09.016 (2006).
6 Hughes, C., Galea-Lauri, J., Farzaneh, F. & Darling, D. Streptavidin Paramagnetic Particles Provide a Choice of Three Affinity-Based Capture and Magnetic Concentration Strategies for Retroviral Vectors. Molecular Therapy 3, 623-630, doi:https://doi.org/10.1006/mthe.2001.0268 (2001).
7 Mekkaoui, L. et al. Lentiviral Vector Purification Using Genetically Encoded Biotin Mimic in Packaging Cell. Molecular Therapy – Methods & Clinical Development 11, 155-165, doi:https://doi.org/10.1016/j.omtm.2018.10.008 (2018).
8 Chen, R. et al. Affinity recovery of lentivirus by diaminopelargonic acid mediated desthiobiotin labelling. Journal of Chromatography B 878, 1939-1945, doi:https://doi.org/10.1016/j.jchromb.2010.05.019 (2010).
9 Chan, L. et al. Conjugation of Lentivirus to Paramagnetic Particles via Nonviral Proteins Allows Efficient Concentration and Infection of Primary Acute Myeloid Leukemia Cells. Journal of Virology 79, 13190, doi:10.1128/JVI.79.20.13190-13194.2005 (2005).
10 Darton, N. J. et al. Lentivirus capture directly from cell culture with Q-functionalised microcapillary film chromatography. Journal of Chromatography A 1251, 236-239, doi:https://doi.org/10.1016/j.chroma.2012.06.072 (2012).
11 McNally, D. J., Darling, D., Farzaneh, F., Levison, P. R. & Slater, N. K. H. Optimised concentration and purification of retroviruses using membrane chromatography. Journal of Chromatography A 1340, 24-32, doi:https://doi.org/10.1016/j.chroma.2014.03.023 (2014).
12 Córdova-Castro, R. M., Krasavin, A. V., Nasir, M. E., Zayats, A. V. & Dickson, W. Nanocone-based plasmonic metamaterials. Nanotechnology 30, 055301, doi:10.1088/1361-6528/aaea39 (2018).
13 Nasir, M. E., Dickson, W., Wurtz, G. A., Wardley, W. P. & Zayats, A. V. Hydrogen Detected by the Naked Eye: Optical Hydrogen Gas Sensors Based on Core/Shell Plasmonic Nanorod Metamaterials. Advanced Materials 26, 3532-3537, doi:10.1002/adma.201305958 (2014).
14 Wang, P., Krasavin, A. V., Nasir, M. E., Dickson, W. & Zayats, A. V. Reactive tunnel junctions in electrically driven plasmonic nanorod metamaterials. Nat Nanotechnol 13, 159-164, doi:10.1038/s41565-017-0017-7 (2018).
15 Yakovlev, V. V. et al. Ultrasensitive Non-Resonant Detection of Ultrasound with Plasmonic Metamaterials. Advanced Materials 25, 2351-2356, doi:10.1002/adma.201300314 (2013).
16 Wang, Y., Keller, K. & Cheng, X. Tangential Flow Microfiltration for Viral Separation and Concentration. Micromachines 10, doi:10.3390/mi10050320 (2019).
17 Frostell, Å., Vinterbäck, L. & Sjöbom, H. in Protein-Ligand Interactions: Methods and Applications (eds Mark A. Williams & Tina Daviter) 139-165 (Humana Press, 2013).
18 Wurtz, G. A. et al. Guided plasmonic modes in nanorod assemblies: strong electromagnetic coupling regime. Opt. Express 16, 7460-7470, doi:10.1364/OE.16.007460 (2008).