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Kinetic segregation gated Chimeric Antigen Receptors

Kong, Khai Jien; (2017) Kinetic segregation gated Chimeric Antigen Receptors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chimeric Antigen Receptor (CAR) T cell therapy has had unprecedented success in the treatment of haematological malignancies, this is especially true in clinical trials targeted against CD19 for the treatment of paediatric Acute Lymphoblastic Leukaemia (ALL) and Chronic Lymphocytic Leukaemia (CLL). However, clinical evidence of on-target off-tumour toxicity was observed in anti-CD19 CAR trials as well as other CAR trials. Here I have developed a CARs platform that can potentially discriminate a cancerous tissue from normal tissue by recognizing multiple antigens presented on each cell type. Using Boolean logic we have programmed the T cell to only activate when two antigens are present (Boolean’s AND gate); only in the absence of one antigen (Boolean’s ANDNOT gate); or when both or either antigens is present (Boolean’s OR gate). We engineered the mechanism through co-localisation or kinetic segregation of the dual CARs inspired by how TCR and co-receptors work. We further found that CAR triggering responses are governed by a local balance in kinase/phosphatase activity. This platform increases the specificity and safety of the engineered T cells through the recognition of a profile of antigens rather than relying on the restricted expression of one tumour associated antigen (TAA). Logic gated CARs could reduce on-target off-tumour toxicity and open the therapy to numerous cancerous tissues where no appropriate TAAs have yet been identified.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Kinetic segregation gated Chimeric Antigen Receptors
Event: UCL (University College London)
Language: English
Keywords: Chimeric Antigen Receptor, Logic gate, CAR, T cell Engineering, OR gate, ANDNOT gate, AND gate
URI: http://discovery.ucl.ac.uk/id/eprint/1535164
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