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Title: Development of immunotherapy for classical Hodgkin lymphoma and anaplastic large cell lymphoma using CSF1R re-targeted human T-lymphocytes
Author: Achkova, Daniela Yordanova
ISNI:       0000 0004 7656 2325
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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Classical Hodgkin’s lymphoma (cHL) represents the most common subtype of malignant lymphoma in young people in the Western world. Despite modern treatment strategies, about 20% of patients still die due to relapse or progressive disease. Anaplastic large cell lymphoma (ALCL) is a type of T/null-cell lymphoma that represents about 20-30% of paediatric lymphomas and has an aggressive clinical course with frequent relapse. Recently, high-level expression of CSF-1R on malignant cells in cHL and ALCL has been linked to shorter progression free survival, providing a rationale to test adoptive CSF-1R-targeting chimeric antigen receptor (CAR) T-cell therapy. This approach encompasses the genetic modification of T-cells to express a CAR, a fusion receptor coupling the recognition of CSF-1R on the tumour cell surface to the delivery of tailored T-cell activation signal. To optimize this approach for human translation, a panel of CSF-1R-targeting CARs were designed and co-expressed with the chimeric cytokine receptor 4αβ, which allows for selective expansion and enrichment of CAR-transduced T-cells using IL-4. Successful re-direction of CAR-grafted T-cells against a panel of cHL and ALCL tumour cell lines was confirmed by monitoring target cell destruction, cytokine release and T-cell proliferation. An innovative approach was developed and optimised in which target engagement results in provision of CAR-derived dual co-stimulation in trans (“double targeting”). Data outlined in this thesis suggest that the “double targeting” approach elicits more robust and sustained anti-tumour activity both in vitro and in vivo in comparison to second and third generation CARs. This is accompanied by superior antigen-specific proliferation, cytokine secretion (IL-2 and IFN-γ) and cytotoxicity upon consecutive rounds of antigen stimulation. These results warrant further investigation into the translational potential of “the double targeting” approach. Furthermore, the data detailed in this thesis provide for the first time the basis for successful application of CAR-based immunotherapy against CSF-1R-expressing malignancies.
Supervisor: Maher, John ; Farzaneh, Farzin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available