Large scale lentiviral vector production
Lead Research Organisation:
King's College London
Department Name: Cancer Studies
Abstract
Lentiviral vectors (LV) are remarkable in their ability to insert their genetic payload into a target cell's genome. This affects a
permanent genetic change in the target which is propagated through to its progeny. While there are several means of
genetic modification, few are capable of permanent modification of target cells. Amongst all vectors for gene delivery, LV
are unique in unparalleled efficiency, safety, lack of toxicity and ability to modify non-dividing target cells. They have
therefore come to be recognised as a key reagent required for the efficient development of the burgeoning cell therapy, as
well as gene therapy industries. However, although LV represent a well understood and robust technology, there is no
manufacturing methodology for very large-scale LV production. This is now an acknowledged bottle-neck both for clinical
trials and for commercial exploitation of many cell and gene therapy products in current development. We propose to
address this unmet need
permanent genetic change in the target which is propagated through to its progeny. While there are several means of
genetic modification, few are capable of permanent modification of target cells. Amongst all vectors for gene delivery, LV
are unique in unparalleled efficiency, safety, lack of toxicity and ability to modify non-dividing target cells. They have
therefore come to be recognised as a key reagent required for the efficient development of the burgeoning cell therapy, as
well as gene therapy industries. However, although LV represent a well understood and robust technology, there is no
manufacturing methodology for very large-scale LV production. This is now an acknowledged bottle-neck both for clinical
trials and for commercial exploitation of many cell and gene therapy products in current development. We propose to
address this unmet need
Technical Summary
* Lentiviral vectors (LV) are used to genetically modify target cells. The main commercial application of LVs is in vitro
production of cellular therapeutics, although they can be used as therapeutic agents in their own right and for generation of
protein producer cells. While small-scale production is well established, a process for very large-scale production has not
been developed. Recently, commercial demand for LV has increased greatly. Large-scale production is a major unmet
need and its lack a bottleneck esp. in the marketing of cellular therapies. The challenge of large-scale LV production is
multifaceted, requiring a deep understanding of lentiviral biology, as well as skilful genetic and cellular engineering,
appreciation of regulatory / GMP considerations, industrial/pharmaceutical scale production issues as well as an
understanding of the down-stream clinical applications.
production of cellular therapeutics, although they can be used as therapeutic agents in their own right and for generation of
protein producer cells. While small-scale production is well established, a process for very large-scale production has not
been developed. Recently, commercial demand for LV has increased greatly. Large-scale production is a major unmet
need and its lack a bottleneck esp. in the marketing of cellular therapies. The challenge of large-scale LV production is
multifaceted, requiring a deep understanding of lentiviral biology, as well as skilful genetic and cellular engineering,
appreciation of regulatory / GMP considerations, industrial/pharmaceutical scale production issues as well as an
understanding of the down-stream clinical applications.
Planned Impact
As described in proposal submitted to IUK
People |
ORCID iD |
| Farzin Farzaneh (Principal Investigator) | |
| Lucas Chan (Co-Investigator) |
Publications
Ana C P
(2020)
Efficient Ex Vivo Expansion of ?d T-Cells from AML Patients Requires Elimination of Circulating Leukemic Blasts
in Advances in Leukemia Research and Treatment
Benjamin R
(2020)
Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies.
in Lancet (London, England)
Bialek-Waldmann JK
(2021)
Induced dendritic cells co-expressing GM-CSF/IFN-a/tWT1 priming T and B cells and automated manufacturing to boost GvL.
in Molecular therapy. Methods & clinical development
Ghorashian S
(2019)
Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR.
in Nature medicine
Kizilors A
(2017)
Retroviral insertional mutagenesis implicates E3 ubiquitin ligase RNF168 in the control of cell proliferation and survival.
in Bioscience reports
| Description | The single most important contribution of this project has been effective process development and manufacture of reagents (cells and vectors) needed for the production of gamma-retrovirus and lentivirus vectors that are used for various clinical applications of cell and gene therapy. The innovations made for the GMP compliant manufacture of these vectors continues to attract interest and collaborations with both academia and industry. Further direct achievements arising from this project since its completion include more extensive collaborations with industry (Cellectis, Orchard, Lonza and Autolus), including the manufacture of over 50 new lentivirus vectors for early stage clinical trials and a major collaboration with Lonza for the development of their Cocoon platform for the GMP compliant manufacture of lentiviral vectors for highly personalised applications of gene therapy. This award has also culminated in the recent Establishment of one of 3 UK hubs in gene therapy, by MRC/LifeArc/BBSRC at KCL/UCL and Royal Free Hospital NNHS Trust, as well as the establishment of new spinout (ViroCell Biologics (ViroCell.com), which in collaboration with Great Ormond Street Hospital and Royal Free, will double the gene therapy vector manufacturing capacity in UK by the end of 2022. |
| Exploitation Route | The findings of two previous BBSRC grants (BB/E005896/1 and BB/D014301/1) and the current project (BB/N003853/1) and to a smaller extent BB/K013785/1, have underpinned the development of a major manufacturing activity (GMP Production of viral vectors for clinical use) at King's College London. We are now in active collaborations with a number of pharmaceutical (Cellectis, as well as Pfizer and Servier in active discussions for further collaborations) and biotech companies (Autolus and LiFT), as well as the Cell Therapy Catapult, for the further development and commercial exploitation of these manufacturing facilities and expertise, including IP. The collaborations with the industry has culminated in over £3 million additional contracts during 2018, plus IP payments of £2 million pounds to King's College London. There are further milestone payments that may be realised in 2022/23. |
| Sectors | Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| URL | https://virocell.com |
| Description | This research, in combination with BB/K013785/1 and BB/E005896/1 has underpinned a great deal of innovation in the manufacture and production of Lentivirus and retrovirus vectors for clinical trials. This IP, combined with a GLP/GMP facility supported by grants from NIHR and CRUK have enabled the attraction of a number of major research grants including £2.5M from Roche Pharmaceuticals for the evaluation of glycoengineered antibodies and the evaluation of immunological markers in patients receiving these antibodies in phase-i/II clinicaal trials. The IP generated, the facilities and the experience of working on the Roche supported projects have in turn resulted in the attraction of manufacturing contracts from a US Biotech company (Northwest Bio - 1.2M), from a French company focused on the generation of allogeneic T cells expressing Chimeric antigen Receptors (Cellectis, over £11M between 2016 and 2019). The contract with this compnay, Cellectis, is worth in total about £15M over the next 3 years (2016-2019). We are also engaged in a fruther collaborations with a new biotech company in UK (Autolous) for the production of retroviral vectors that are used in the generation of other CAR-T cells for clinical studies. Finally, a recently initiated collaboration with Cell and Gene Therapy Catapult is developing procedures and products for the industrialisation of cell and gene therapy products, including the development of a scalable strategy for suspension cell based manufacture of retrovirus vectors encoding specific T cell receptors. In addition to new industry collaborations and new contracts (over £3 million in 2018) we have received £2 million pounds as milestones for none-exclusive licensing of IP with further milestones that could become due in 2022. |
| First Year Of Impact | 2017 |
| Sector | Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Description | Appointed by the MHRA to the Clinical Trials, Biologicals & Vaccines Expert Advisory Group of the UK Commission on Human Medicines. |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | My participation in the Clinical Trials, Biologicals & Vaccines Expert Advisory Group of MHRA has allowed me to provide advice and comments on over 200 clinical trial applications since 2016, hoping to have made a useful contribution to the outstanding work of MHRA. |
| URL | https://www.gov.uk/government/organisations/commission-on-human-medicines/about/membership#clinical-... |
| Description | Next generation CAR19 studies - Collaboration with Martin Pule et al at UCL |
| Amount | £900,000 (GBP) |
| Funding ID | II-C3-0714-20005 |
| Organisation | National Institute for Health Research |
| Department | NIHR i4i Invention for Innovation (i4i) Programme |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2016 |
| End | 04/2019 |
| Title | Development of new viral vectors, manufacturing and purification strategies for the production of cell and gene therapy based therapeutics |
| Description | The UKRI supported projects in my group have culminated in the development of a number of different gamma-retro and lenti-virus based vectors and methodologies for their production, purification/concentration under GMP. |
| Type Of Material | Biological samples |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | The most important of these developments are described in our research publications since 2018. Mekkaoui, L., Parekh, F., Kotsopoulou, E., Darling, D., Dickson, G., Cheung, G. W., Chan, L., MacLellan-Gibson, K., Mattiuzzo, G., Farzaneh, F., Takeuchi, Y. & Pule, M (2018). Lentiviral vector purification using genetically encoded biotin mimic in packaging cell. Molecular Therapy Methods Clin Dev. 11:155-165. Doi 10.1016/j.omtm. 2018.10.008. Shi Y, Dincheva L, Cook C, Bergamaschi C, Pavlakis GN, Farzaneh F, Gaensler K (2018). IL-15/IL-15Ra/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice. Blood Advances. 2(22):3177-3192. Doi: 10.1182/bloodadvances.2018019026. Ellison SM, Liao A, Wood S, Taylor J, Youshani AS, Rowlston S, Parker H, Armant M, Biffi A, Chan L, Farzaneh F, Wynn R, Jones SA, Heal P, Gaspar HB, Bigger BW (2019). Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. Mol Ther Methods Clin Dev. 2019 Apr 6;13:399-413. doi: 10.1016/j.omtm.2019.04.001. eCollection 2019 Jun 14. Lwin SM, Syed F, Di WL, Kadiyirire T, Liu L, Guy A, Petrova A, Abdul-Wahab A, Reid F, Phillips R, Elstad M, Georgiadis C, Aristodemou S, Lovell PA, McMillan JR, Mee J, Miskinyte S, Titeux M, Ozoemena L, Pramanik R, Serrano S, Rowles R, Maurin C, Orrin E, Martinez-Queipo M, Rashidghamat E, Tziotzios C, Onoufriadis A, Chen M, Chan L, Farzaneh F, Del Rio M, Tolar J, Bauer JW, Larcher F, Antoniou MN, Hovnanian A, Thrasher AJ, Mellerio JE, Qasim W, McGrath JA (2019). Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa. JCI Insight. 2019 Jun 6;4(11). e126243. doi: 10.1172/jci.insight. 126243. eCollection 2019 Jun 6. Di WL, Lwin SM, Petrova A, Bernadis C, Syed F, Farzaneh F, Moulding D, Martinez AE, Sebire NJ, Rampling D, Virasami A, Zamiri M, Wang W, Hara H, Kadiyirire T, Abdul-Wahab A, Martinez-Queipo M, Harper JI, McGrath JA, Thrasher AJ, Mellerio JE, Qasim W (2019). Generation and Clinical Application of Gene-Modified Autologous Epidermal Sheets in Netherton Syndrome: Lessons Learned from a Phase 1 Trial. Hum Gene Ther. 2019 Aug 5. doi: 10.1089/hum.2019.049. [Epub ahead of print]. Ghorashian S, Kramer AM, Onuoha S, Wright G, Bartram J, Richardson R, Albon SJ, Casanovas-Company J, Castro F, Popova B, Villanueva K, Yeung J, Vetharoy W, Guvenel A, Wawrzyniecka PA, Mekkaoui L, Cheung GW, Pinner D, Chu J, Lucchini G, Silva J, Ciocarlie O, Lazareva A, Inglott S, Gilmour KC, Ahsan G, Ferrari M, Manzoor S, Champion K, Brooks T, Lopes A, Hackshaw A, Farzaneh F, Chiesa R, Rao K, Bonney D, Samarasinghe S, Goulden N, Vora A, Veys P, Hough R, Wynn R, Pule MA, Amrolia PJ (2019). Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019 Sep;25(9):1408-1414. doi: 10.1038/s41591-019-0549-5. Epub 2019 Sep 2. Benjamin R, Graham C, Yallop D, Jozwik A, Mirci-Danicar OC, Lucchini G, Pinner D, Jain N, Kantarjian H, Boissel N, Maus MV, Frigault MJ, Baruchel A, Mohty M, Gianella-Borradori A, Binlich F, Balandraud S, Vitry F, Thomas E, Philippe A, Fouliard S, Dupouy S, Marchiq I, Almena-Carrasco M, Ferry N, Arnould S, Konto C, Veys P, Qasim W; UCART19 Group. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet. 2020 Dec 12;396(10266):1885-1894. doi: 10.1016/S0140-6736(20)32334-5.PMID: 33308471 Sánchez-Fueyo A, Whitehouse G, Grageda N, Cramp ME, Lim TY, Romano M, Thirkell S, Lowe K, Fry L, Heward J, Kerr A, Ali J, Fisher C, Lewis G, Hope A, Kodela E, Lyne M, Farzaneh F, Kordasti S, Rebollo-Mesa I, Jose Lozano J, Safinia N, Heaton N, Lechler R, Martínez-Llordella M, Lombardi G (2020). Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation. Am J Transplant 20 (4): 1125-1136. Doi: 10.1111/ajt.15700. Salehi S, Tavabie OD, Verma S, McPhail MJ, Farzaneh F, Bernal W, Menon K, Agarwal K, Aluvihare VR. Serum miRNA signatures in recovery from acute and chronic liver injury and selection for liver transplantation. Liver Transpl. 2020 Apr 16. doi: 10.1002/lt.25781. Taghikhani A, Farzaneh F, Sharifzad F, Mardpour S, Ebrahimi M, Hassan ZM. Engineered tumour-derived extracellular vesicles: potentials in cancer immune therapy. Front Immunol. 2020 Mar 6;11:221. doi: 10.3389/fimmu.2020.00221 Koks S, Williams RW, Quinn J, Farzaneh F, Conran N, Tsai S-J , Awandare G, Goodman SR (2020). COVID-19: Time for precision epidemiology. Experimental Biology and Medicine 2020; 245: 677-679. DOI: 10.1177/1535370220919349 Parente-Pereira AC, Krishnamurthy P, Whilding LM, Ioannou K,Ciprut S, Potter V, Ghulam J Mufti GJ, Barber L, Farzaneh F, Maher J (2020). Efficient ex vivo expansion of ?d T-Cells from AML patients requires elimination of circulating AML. Advances Leuk Res Treat 2(1):28-33. Bialek-Waldmann JK, Domning S, Esser R, Glienke W, Mertens M, Aleksandrova K, Arseniev L,Kumar S, Schneider A, Koenig J, Theobald SJ,Tsay H-C, Cornelius ADA, Bonifacius A, Eiz-Vesper B, Figueiredo C, Schaudien D, Talbot SR, Bleich A, Spineli LM, von Kaisenberg C, Clark C, Blasczyk R, Heuser M, Ganser A, Köhl U, Farzaneh F, Stripecke R (2021). Induced dendritic cells co-expressing GM-CSF/IFN-a/tWT1 priming T and B cells and automated manufacturing to boost GvL. Molecular Therapy: Methods & Clinical Development Vol. 21 June 2021 p621-641. van Schalkwyk MCI, van der Stegen SJC, Bosshard-Carter L, Graves H, Papa S, Parente-Pereira AC, Farzaneh F, Fisher CD, Hope A, Adami A and Maher J (2021). Development and Validation of a Good Manufacturing Process for IL-4-Driven Expansion of Chimeric Cytokine Receptor-Expressing CAR T-Cells. Cells 2021, 10(7),1797, PMCID: PMC8307141. Graham CE, Jozwik A, Quartey-Papafio R, Ioannou N, Metelo AM, Scala C, Dickson G, Stewart O, Almena-Carrasco M, Peranzoni E, Ramsay AG, Patten PEM, Pertel T, Farzaneh F, Dupouy S, Pepper A, Benjamin R (2021). Gene-edited healthy donor CAR T cells show superior anti-tumour activity compared to CAR T cells derived from patients with lymphoma in an in vivo model of high-grade lymphoma. Leukemia https://doi.org/10.1038/s41375-021-01324-z Roddie C, Dias J, O'Reilly MA, Abbasian M, Cadinanos-Garai A, Vispute K, Bosshard-Carter L, Mitsikakou M, Mehra V, Roddy H, Hartley JA, Spanswick V, Lowe H, Popova B, Clifton-Hadley L, Wheeler G, Olejnik J, Bloor A, Irvine D, Wood L, Marzolini MAV, Domning S, Farzaneh F, Lowdell MW, Linch DC, Pule MA, Peggs KS (2021). Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or refractory B-Cell Acute Lymphoblastic Leukemia. J. Clin Oncology 39, 30, p3352-3363. Mohseni YR, Saleem A, Tung SL, Dudreuilh C, Lang C, Peng Q, Volpe A, Adigbli G, Cross A, Hester J, Farzaneh F, Scotta C, Lechler RI, Issa F, Fruhwirth GO & Lombardi G (2021). Chimeric antigen receptor-modified human regulatory T cells that constitutively express IL-10 maintain their phenotype and are potently suppressive. European J Immunol. 51 (10) 2522-2530. Cordoba S, Onuoha S, Thomas S, Pignataro DS, Hough R, Ghorashian S, Vora A, Bonney D, Veys P, Rao K, Lucchini G, Chiesa R, Chu J, Clark L, Fung MM, Smith K, Peticone C, Al-Hajj M, Baldan V, Ferrari M, Srivastava S, Jha R, Arce Vargas F, Duffy K, Day W, Virgo P, Wheeler L, Hancock J, Farzaneh F, Domning S, Zhang Y, Khokhar NZ, Peddareddigari VGR, Wynn R, Pule M, Amrolia PJ (2021). CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Nature Medicine 27 (10): 1797-1805. Tonge, D. P., Darling, D., Farzaneh, F. & Williams, G. T., (2022). Whole-genome-scale identification of novel non-protein coding RNAs controlling cell proliferation and survival through a functional forward genetics strategy. Scientific Reports. 12, 1, 182 |
| Description | Autolus - Novel GMP Production of Retroviral Vectors |
| Organisation | Autolus Limited |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Development of a novel procedure for the substantially faster GMP manufacture of retrovirus vectors, thus reducing the time from pre-clinical studies to the first-in-man clinical studies of gene therapy studies using retrovirus vectors. |
| Collaborator Contribution | Funding of the study and the contribution of expertise to the GMP manufacture of lentivirus vectors, including the placement of 3 Autolus members of staff for over a year at King's College London. |
| Impact | New GMP manufacture of retrovirus vectors Multiple clinical trials, the first of which is due to start within the next 3 months. |
| Start Year | 2016 |
| Description | Cellectis: Production of viral vectors (primarily lentivirus), and gene modified cells, for clinical applications of cell and gene therapy |
| Organisation | Cellectis |
| Country | France |
| Sector | Private |
| PI Contribution | Development and production of multiple lentivirus and retrovirus vectors for a range of clinical studies in collaboration with both academic and industry partners, the largest of which is the collaboration with Cellectis culminating in over £1.6 million of funding todate, plus a new contract for £10.1 million over the next 3 years. |
| Collaborator Contribution | Provision of funding and know-how in specific areas (e.g. site directed endonuclease mediated inhibition of endogenous T cell receptors, in order to allow the generation of allogeneic (off-the-shelf) Chimeric Antigen Receptor (CAR) T cells for the treatment of malignant disease. This project is directly supported by BB/N003853/1 and assisted by the outputs from our previous BBSRC grants: BB/E005896/1, BB/D014301/1 and BB/K013785/1. |
| Impact | The development of allogeneic CAR-T cells (referred to as UniCAR-T) for the treatment of malignant disease. There has also been substantial inward investment (over £11,000,000 between 2016 and 2019 from Cellectis alone) underpining further developments that we expect to culminate in substantially larger collaborations with other pharmaceuticaal companies (active discussions in progress with Cell Therapy Catapult, Pfizer and Servier). This collaboration has also resulted in a separate collaboration with a UK based start-up company - Autolus (reported as a separate collaboration). |
| Start Year | 2015 |
| Description | Collaboration with the University fo Lausanne for the development and production of lentivirus lectors |
| Organisation | University of Lausanne |
| Country | Switzerland |
| Sector | Academic/University |
| PI Contribution | We have set up a new collaboration with the University of Lausanne for the development of lentivirus vectors and their GMP manufacture over the next 3 years (2018 to 2020). University of Lausanne has provided a contract of £2.6M of which the first instalment of 20% has already been paid. |
| Collaborator Contribution | The development of vectors that they have produced for a number of gene therapy based clinical studies, and the use of the vectors made under GMP at King's College London, in these clinical trials. |
| Impact | Contracts of Collaboration Signed |
| Start Year | 2018 |
| Description | Several new collaborations with UK, US and European biotech/pharma the details of which I cannot provide identification due to NDA. Each of these initiatives has been directly facilitated by this BBSRC award (BB/N003853) |
| Organisation | Autolus Limited |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | These Collaborations, constituting various projects on the development of viral vectors fro clinical trials have a total value of over £10 million for the period since 2015. These industrial collaboration on the development and GMP manufacture of viral vectors is in addition to collaborative research grants awarded by the Wellcome Trust. |
| Collaborator Contribution | By enlarge the collaborators have provided either the vector payload or the earlier generations of vectors to which we have added improvements by R&D activities and then incorporated new manufacturing strategies supported by our R&D activities by improving vector design, assessing the impact of the improvements and incorporating these improvements into the GMP manufacture of vectors that have then to first-0in-man clinical trials. |
| Impact | Awards by Industry: - Servier Pharmaceutical Group, France. Development and GMP manufacture of vectors for clinical trials in Universal CAR T cell therapies. 01/09/2017 to 31/12/2018. Value: >€871,051.14 - Orchard Therapeutics / University of Manchester. Clinical grade lentivirus vectors: PI: F Farzaneh. Duration: 2018. Value: £632,000. - Cellectis. Development of lentivirus vectors. PI: F Farzaneh. Duration: 2016/21. Value: >£10,300,000. - Autolus Pharmaceuticals. GMP Manufacture of retroviral vectors by a novel procedure. PI: F Farzaneh. Duration 2018-2020. Value: £4,750,000 Awards by Research Councils/Governmental Agencies/Charities: - Cell Therapy Catapult. Development of viral vector industrialisation processes. PI: F Farzaneh Duration 2015/18. Value: £130,000. - NIHR Invention for Innovation Programme (i4i). Next generation CAR19 studies. Collaborative project with UCL, ICH and UCH. PIs Martine Pule, Karl Peggs, David Linch and Paul Smith (UCL), Waseem Qaseem and Adrian Thrasher (ICH), Farzin Farzaneh (KCL), Mike Watts (UCH). Duration 1/11/2015 to 30/04/2019. Value: 3,754,000 (£840,421 at KCL). Ref: II-C3-0714-20005 - Wellcome Trust. Next generation engineered T-cell therapy for brain lymphoma. PI: Martin Pule. Applicants: Karl Peggs, David Linch, Farzin Farzaneh, Mark Lythgoe, Mark Lowdell, Erik Arstad, Paul Smith, Irfan Kayani, Ashley Groves. Duration 2016/2021. Value: £2,733,673. - Wellcome Trust. Pre-clinical development of a stem cell based gene therapy protocol and clinical proof of principle for Duchenne Muscular Dystrophy. PI: G Cossu. Applicants: I Hughes, F Muntoni, F Farzaneh, G McCullagh, L Chan, S Kimber. Duration: 01/06/2016 to 31/05/2020. Value: £827,583 (Approx £250,000 at KCL). - Department of Health/CRUK (Experimental Cancer Medicine Centre). GMP Facility Core Funding - 50% Contribution to Quality Manager's salary. PI: F Farzaneh. Duration: 2017/22. Value £150,000. - Cancer Research UK King's Health Partners Centre. PI: Parker, P., Ciccarelli, F., Dazzi, F., Farzaneh, F., Hayday, A., Maher, J., Ng, T., Papa, S., Purushotham, A., Sarker, D. & Spicer, J. Duration: 01/04/2017 to 30/09/2022. Value: £2,464,067 Includes: GMP Facility Core Funding - 50% Contribution to Quality Manager's salary. PI: Farzin Farzaneh. Duration: 2017/22. Value £150,000. - Greater London Authority (GLA). Adaptation of former HeLa based Cancer-Killing Assay of human leukocytes to be based on Pancreatic Cancer cells in order to increase the specificity of the assay in Pancreatic Cancer. PI: Farzaneh, F. Duration 01/04/2017 to 31/03/2019. Value: £100,000 - University of Lauzanne, Switzerland. Development of viral vector for clinical applications of gene therapy. PI: Faith Green & Farzin Farzaneh. 01/01/2018 to 31/12/2021. Value: £2,830,000. - MRC DPFS. Engineered Potassium Channel gene therapy for epilepsy. PI: Stephanie Schorge et al (at UCL), F Farzaneh at KCL. Duration; 01/03/2018 to 28/02/2021. Value: £1,945,483 (at KCL >£464,903). - JP Moulton Charitable Trust. AML-2: CD80/IL-2 immune gene therapy for poor prognosis Acute Myeloid Leukaemia. Duration 2020-2022. Value: £595,000. |
| Start Year | 2015 |
| Description | Several new collaborations with UK, US and European biotech/pharma the details of which I cannot provide identification due to NDA. Each of these initiatives has been directly facilitated by this BBSRC award (BB/N003853) |
| Organisation | Cellectis |
| Country | France |
| Sector | Private |
| PI Contribution | These Collaborations, constituting various projects on the development of viral vectors fro clinical trials have a total value of over £10 million for the period since 2015. These industrial collaboration on the development and GMP manufacture of viral vectors is in addition to collaborative research grants awarded by the Wellcome Trust. |
| Collaborator Contribution | By enlarge the collaborators have provided either the vector payload or the earlier generations of vectors to which we have added improvements by R&D activities and then incorporated new manufacturing strategies supported by our R&D activities by improving vector design, assessing the impact of the improvements and incorporating these improvements into the GMP manufacture of vectors that have then to first-0in-man clinical trials. |
| Impact | Awards by Industry: - Servier Pharmaceutical Group, France. Development and GMP manufacture of vectors for clinical trials in Universal CAR T cell therapies. 01/09/2017 to 31/12/2018. Value: >€871,051.14 - Orchard Therapeutics / University of Manchester. Clinical grade lentivirus vectors: PI: F Farzaneh. Duration: 2018. Value: £632,000. - Cellectis. Development of lentivirus vectors. PI: F Farzaneh. Duration: 2016/21. Value: >£10,300,000. - Autolus Pharmaceuticals. GMP Manufacture of retroviral vectors by a novel procedure. PI: F Farzaneh. Duration 2018-2020. Value: £4,750,000 Awards by Research Councils/Governmental Agencies/Charities: - Cell Therapy Catapult. Development of viral vector industrialisation processes. PI: F Farzaneh Duration 2015/18. Value: £130,000. - NIHR Invention for Innovation Programme (i4i). Next generation CAR19 studies. Collaborative project with UCL, ICH and UCH. PIs Martine Pule, Karl Peggs, David Linch and Paul Smith (UCL), Waseem Qaseem and Adrian Thrasher (ICH), Farzin Farzaneh (KCL), Mike Watts (UCH). Duration 1/11/2015 to 30/04/2019. Value: 3,754,000 (£840,421 at KCL). Ref: II-C3-0714-20005 - Wellcome Trust. Next generation engineered T-cell therapy for brain lymphoma. PI: Martin Pule. Applicants: Karl Peggs, David Linch, Farzin Farzaneh, Mark Lythgoe, Mark Lowdell, Erik Arstad, Paul Smith, Irfan Kayani, Ashley Groves. Duration 2016/2021. Value: £2,733,673. - Wellcome Trust. Pre-clinical development of a stem cell based gene therapy protocol and clinical proof of principle for Duchenne Muscular Dystrophy. PI: G Cossu. Applicants: I Hughes, F Muntoni, F Farzaneh, G McCullagh, L Chan, S Kimber. Duration: 01/06/2016 to 31/05/2020. Value: £827,583 (Approx £250,000 at KCL). - Department of Health/CRUK (Experimental Cancer Medicine Centre). GMP Facility Core Funding - 50% Contribution to Quality Manager's salary. PI: F Farzaneh. Duration: 2017/22. Value £150,000. - Cancer Research UK King's Health Partners Centre. PI: Parker, P., Ciccarelli, F., Dazzi, F., Farzaneh, F., Hayday, A., Maher, J., Ng, T., Papa, S., Purushotham, A., Sarker, D. & Spicer, J. Duration: 01/04/2017 to 30/09/2022. Value: £2,464,067 Includes: GMP Facility Core Funding - 50% Contribution to Quality Manager's salary. PI: Farzin Farzaneh. Duration: 2017/22. Value £150,000. - Greater London Authority (GLA). Adaptation of former HeLa based Cancer-Killing Assay of human leukocytes to be based on Pancreatic Cancer cells in order to increase the specificity of the assay in Pancreatic Cancer. PI: Farzaneh, F. Duration 01/04/2017 to 31/03/2019. Value: £100,000 - University of Lauzanne, Switzerland. Development of viral vector for clinical applications of gene therapy. PI: Faith Green & Farzin Farzaneh. 01/01/2018 to 31/12/2021. Value: £2,830,000. - MRC DPFS. Engineered Potassium Channel gene therapy for epilepsy. PI: Stephanie Schorge et al (at UCL), F Farzaneh at KCL. Duration; 01/03/2018 to 28/02/2021. Value: £1,945,483 (at KCL >£464,903). - JP Moulton Charitable Trust. AML-2: CD80/IL-2 immune gene therapy for poor prognosis Acute Myeloid Leukaemia. Duration 2020-2022. Value: £595,000. |
| Start Year | 2015 |
| Description | Several new collaborations with UK, US and European biotech/pharma the details of which I cannot provide identification due to NDA. Each of these initiatives has been directly facilitated by this BBSRC award (BB/N003853) |
| Organisation | Servier Laboratories |
| Country | France |
| Sector | Private |
| PI Contribution | These Collaborations, constituting various projects on the development of viral vectors fro clinical trials have a total value of over £10 million for the period since 2015. These industrial collaboration on the development and GMP manufacture of viral vectors is in addition to collaborative research grants awarded by the Wellcome Trust. |
| Collaborator Contribution | By enlarge the collaborators have provided either the vector payload or the earlier generations of vectors to which we have added improvements by R&D activities and then incorporated new manufacturing strategies supported by our R&D activities by improving vector design, assessing the impact of the improvements and incorporating these improvements into the GMP manufacture of vectors that have then to first-0in-man clinical trials. |
| Impact | Awards by Industry: - Servier Pharmaceutical Group, France. Development and GMP manufacture of vectors for clinical trials in Universal CAR T cell therapies. 01/09/2017 to 31/12/2018. Value: >€871,051.14 - Orchard Therapeutics / University of Manchester. Clinical grade lentivirus vectors: PI: F Farzaneh. Duration: 2018. Value: £632,000. - Cellectis. Development of lentivirus vectors. PI: F Farzaneh. Duration: 2016/21. Value: >£10,300,000. - Autolus Pharmaceuticals. GMP Manufacture of retroviral vectors by a novel procedure. PI: F Farzaneh. Duration 2018-2020. Value: £4,750,000 Awards by Research Councils/Governmental Agencies/Charities: - Cell Therapy Catapult. Development of viral vector industrialisation processes. PI: F Farzaneh Duration 2015/18. Value: £130,000. - NIHR Invention for Innovation Programme (i4i). Next generation CAR19 studies. Collaborative project with UCL, ICH and UCH. PIs Martine Pule, Karl Peggs, David Linch and Paul Smith (UCL), Waseem Qaseem and Adrian Thrasher (ICH), Farzin Farzaneh (KCL), Mike Watts (UCH). Duration 1/11/2015 to 30/04/2019. Value: 3,754,000 (£840,421 at KCL). Ref: II-C3-0714-20005 - Wellcome Trust. Next generation engineered T-cell therapy for brain lymphoma. PI: Martin Pule. Applicants: Karl Peggs, David Linch, Farzin Farzaneh, Mark Lythgoe, Mark Lowdell, Erik Arstad, Paul Smith, Irfan Kayani, Ashley Groves. Duration 2016/2021. Value: £2,733,673. - Wellcome Trust. Pre-clinical development of a stem cell based gene therapy protocol and clinical proof of principle for Duchenne Muscular Dystrophy. PI: G Cossu. Applicants: I Hughes, F Muntoni, F Farzaneh, G McCullagh, L Chan, S Kimber. Duration: 01/06/2016 to 31/05/2020. Value: £827,583 (Approx £250,000 at KCL). - Department of Health/CRUK (Experimental Cancer Medicine Centre). GMP Facility Core Funding - 50% Contribution to Quality Manager's salary. PI: F Farzaneh. Duration: 2017/22. Value £150,000. - Cancer Research UK King's Health Partners Centre. PI: Parker, P., Ciccarelli, F., Dazzi, F., Farzaneh, F., Hayday, A., Maher, J., Ng, T., Papa, S., Purushotham, A., Sarker, D. & Spicer, J. Duration: 01/04/2017 to 30/09/2022. Value: £2,464,067 Includes: GMP Facility Core Funding - 50% Contribution to Quality Manager's salary. PI: Farzin Farzaneh. Duration: 2017/22. Value £150,000. - Greater London Authority (GLA). Adaptation of former HeLa based Cancer-Killing Assay of human leukocytes to be based on Pancreatic Cancer cells in order to increase the specificity of the assay in Pancreatic Cancer. PI: Farzaneh, F. Duration 01/04/2017 to 31/03/2019. Value: £100,000 - University of Lauzanne, Switzerland. Development of viral vector for clinical applications of gene therapy. PI: Faith Green & Farzin Farzaneh. 01/01/2018 to 31/12/2021. Value: £2,830,000. - MRC DPFS. Engineered Potassium Channel gene therapy for epilepsy. PI: Stephanie Schorge et al (at UCL), F Farzaneh at KCL. Duration; 01/03/2018 to 28/02/2021. Value: £1,945,483 (at KCL >£464,903). - JP Moulton Charitable Trust. AML-2: CD80/IL-2 immune gene therapy for poor prognosis Acute Myeloid Leukaemia. Duration 2020-2022. Value: £595,000. |
| Start Year | 2015 |
| Description | Vector Industrialisation Project |
| Organisation | Cell Therapy Catapult |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | The aim of this recently initiated project is the development of GMP compatible procedures for the industrialisation of gene therapy products. The main focus of this specific project is the development of cell line/s with characteristics needed for large scale manufacture of a retrovirus vector encoding a specific T cell receptor (TCR). |
| Collaborator Contribution | Funding of the initial studies, providing the vector manufacturing cell line and expertise in project management, accurate calculation of costs of goods. Cell and Gene Therapy Catapult is also providing expertise in the development of strategies aimed at reducing the cost of goods, risk-reduction for manufacturing campaigns and strategies for efficient large scale manufacture of clinical grade vectors. This project is underpinned by two previous BBSRC grants and directly affected by our current BBSRC supported project. |
| Impact | This project is contributing to the development of new therapies and therapeutic strategies, particularly with respect of the industrial scale manufacture of cell and gene therapy vectors, thus contributing both to better health care and to creation of wealth, including inward investment from outside the UK. |
| Start Year | 2016 |
| Title | Development of GMP compliant manufacturing strategies for the production of clinical grade viral vectors |
| Description | The production of viral vectors, in particular lentivirus and gamma-retrovirus in sufficient quantities and able to meet the regulatory standards of quality is particularly challenging. Using the technologies that were developed as part of our BBSRC supported projects, we have established a range of manufacturing, purification and concentration strategies that have enabled us to manufacture the largest number (academia or industry) of retroviral and lentivirus vectors for regulatory approved clinical trials in Europe. This extensive research and development programme has now culminated in over £15 million pound of income (2012 to 2019) for King's College London from overseas based companies. |
| IP Reference | |
| Protection | Protection not required |
| Year Protection Granted | 2016 |
| Licensed | Yes |
| Impact | The background manufacturing IP and know-how is licensed (non-exclusive) to Cellectis and to Cell Therapy Catapult. Discussions are in progress with other organisations in taking similar non-exclusive licenses. |
| Title | The processes developed in the course of this study have directly contributed to the success of subsequent contracts with the Industry, including Autolus and Cellectis (biotech and pharmaceutical companies. |
| Description | We have developed procedures for the fast manufacture of retrovirus and lentivirus vectors in compliance with the regulatory requirements for clinical use (GMP compliant procedures). These highly optimised procedures have enabled the production of high titre vectors (about 50,000 million infectious units of vector) from relatively small scale cultures (circa 10 litres), with greater than 50% recovery (frequently in excess of 70%) and minimal quantities of contaminating proteins and nucleic acids. This knowhow has recently been licensed on non-exclusive deals to the industry (Cellectis) in contracts producing in excess of £15 million pounds of income over the next 3 years. |
| IP Reference | |
| Protection | Protection not required |
| Year Protection Granted | 2016 |
| Licensed | Yes |
| Impact | We have produced, for regulatory approved clinical trials, the largest number of lenti- and retroviral vectors in Europe. Each of the 4 BBSRC supported projects have contributed to this outcome. We are now extending this expertise with a view to similarly innovative manufacture of Adeno Associated Virus (AAV) manufacture for clinical use. |
| Title | CAR T cells |
| Description | The GMP vectors produced with the support of this BBSRC grant are now being used in a range of clinical trials based at Uuniversity College Hospital, Great Ormod Street Hospital and King's College Hospital |
| Type | Therapeutic Intervention - Cellular and gene therapies |
| Current Stage Of Development | Early clinical assessment |
| Year Development Stage Completed | 2016 |
| Development Status | Under active development/distribution |
| Clinical Trial? | Yes |
| Impact | The vectors produced with the support of this project are now being used in multiple clinical trials - all Phase-1, all first-in-man |
| Description | 14th Annual World Advanced Therapies & Regenerative Medicine Congress & Expo 2019 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Gave scientific presentation on the development of new viral vectors and their GMP manufacture for novel applications of gene therapy in human clinical studies. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.smartbank.it/wp-content/uploads/2019/04/Advanced-Therapies-and-Regenerative-Medicine-Con... |
| Description | 3rd International Conference on Genetics an Molecular Biology |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A large in person conference in Miami Use (April 18-19, 2022) in which I was part of the Organising Committee. I also gave a presentation and participated in a very interesting public debate. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://molecularbiology.conferenceseries.com/organizing-committee.php |