Hazelton, Warren; (2022) The development of multi-antigen targeting chimeric antigen receptors to treat acute myeloid leukaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Patients with acute myeloid leukaemia (AML) are faced with low survival rates and high relapse rates due to the relative chemo-insensitivity of leukaemic stem cells (LSC), highlighting the need for improved targeted therapies. CD19 directed Chimeric Antigen Receptor (CAR) T-cell therapy has shown unprecedented levels of success in the setting of acute lymphoblastic leukaemia (ALL), with two products currently approved by the FDA, and efforts are ongoing to develop similar strategies for AML. Identifying target antigens for AML stem cells is challenging as they can arise from many stages of myelopoiesis and are both genetically and phenotypically diverse. To address these issues, we have developed multi-antigen targeting CAR T-cell strategies, targeting CD33, CD123, and CLL1 for their broad expression on AML blasts and LSCs, to be used as a bridging strategy for allogeneic haematopoietic stem cell transplants (allo-HSCT) with curative intent. Using in vitro pre-clinical models, we have demonstrated multi-antigen targeting Tandem (Multiplexed binders on a single CAR molecule) and Compound (Multiple complete CARs in a single vector) CAR T-cell strategies were able to demonstrate antigen-specific cytotoxicity, proliferation, and cytokine production upon interaction with AML tumour cell lines. In subsequent, comparative in vivo experiments Compound CAR T-cells demonstrated the potent anti-tumour efficacy, even at low doses. In a model of heterogeneous tumour, where different blast populations expressed different AML antigens, Compound CAR T-cells demonstrated complete tumour clearance and improved efficacy compared to that noted in Tandem CAR (TanCAR) T-cell treated mice. Overall, we have developed multi-antigen targeting CAR T-cell strategies that can destroy and clear tumour cells upon interaction with three different AML associated antigens, even when expression of one antigen is lost. This approach has the potential to be used alongside chemotherapy as an induction therapy prior to allo-HSCT and overcome the inter-and intra-patient variability observed in patients with AML.

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