Modelling the Ability of Targeted Drugs and Immunotherapy to Modulate Anti-Tumour T Cell Activity in Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) is a non-curative B cell malignancy characterised by profound T cell exhaustion and an understudied immunosuppressive tumour microenvironment (TME). Although current therapies such as targeted drugs (BTKis, BCL-2i) alone or in combination with monoclonal antibodies achieve impressive response rates, disease persists and can eventually relapse - highlighting a clinical need to identify additional treatment strategies for these patients. Pre-clinical and early clinical work utilizing immunotherapeutic approaches that harness the ability of the immune system to control disease, opened up new opportunities for cancer therapy. In CLL, the use of immunotherapy to tackle relapse is appealing, although overcoming T cell exhaustion, as well as the inhibitory TME will likely be required. However, it is first desirable in order to optimise the use of immunotherapy, to understand how current therapies like ibrutinib alter the T cell compartment in CLL (immunomodulatory effects of targeted drug therapy). The first project within this thesis investigated how ibrutinib-based therapy versus traditional chemoimmunotherapy modulated T cell subsets and their function during therapy. Analysing patient samples collected from a large Phase 3 trial with flow cytometry and functional assays identified distinct T cell changes and activities during treatment. Importantly, we identified that Ibrutinib-rituximab therapy promoted CD8+ lytic synapse function. In sharp contrast, FCR- treated T cells failed to improve their anti-CLL cytotoxic ability, even with the addition of ex vivo immunotherapy. This study also revealed novel correlations between T cell subset numbers and function and clinical outcomes for both treatment arms, providing novel insight into the role of T cells in contributing to clinical response with these therapies. Next, this thesis evaluated the ability of a novel bispecific antibody combination immunotherapy [CD20-T cell bispecific (TCB) with a CD19-4-1BBL fusion drug] to modulate anti-CLL immune function. Multiple T cell functional assays, co-culture systems, an in vivo xenograft model and organotypic cultures were used to pre-clinically model combination immunotherapy in CLL and non-Hodgkin lymphoma. The results reveal that bispecific antibody pairing induces high levels of T cell cytotoxic function and could help combat TME-mediated immunosuppression in CLL, strengthening the rationale for developing combination immunotherapy to harness the power of cytolytic T cells to deepen therapeutic responses and tackle relapsed disease.