Franz Demane, Dafne Sofia; (2019) Defining and targeting combination immunotherapies in mouse models of cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Checkpoint blockade has achieved long-lasting anti-tumour responses, unfortunately this is limited to a fraction of patients, highlighting the need for more effective therapies. This thesis focuses on the rational proposal and design of new cancer immunotherapies through: (1) proposing a novel immunomodulatory-target for cancer-immunotherapy, Inducible T-cell co-stimulator (ICOS), and studying its efficacy in murine models of cancer; and (2) the description of the immune tumour-microenvironment (TME) of mouse models of lung cancer, to propose strategies that promote increased immunogenicity and tumour rejection. In models of melanoma, the absence of ICOS/ICOSL pathway in ICOS-/- mice, impaired the efficacy of anti-CTLA-4 (Cytotoxic T-lymphocyte antigen-4) therapy. Additionally, patients that received ipilimumab (anti-CTLA-4) monoclonal antibody (mAb) had an increase in the frequency of ICOS+ T-cells. We hypothesised that an agonistic non-depleting anti-ICOS mAb will promote the function of activated T-cells in the TME. Here we show that an agonistic anti-ICOS mAb, with either mIgG1 (non-depleting) or mIgG2a (depleting) isotype, does not promote survival, either as a monotherapy or in combination with other antibody therapies. We also showed that both anti-ICOS isotypes eliminated T-cells in the TME and that anti-ICOS mIgG1 T-cell elimination was Fc-engagement independent. These results were replicated using mice expressing human Fcγ receptors (FcγRs) and anti-ICOS mAb with human (h)IgGs, demonstrating that anti-cancer therapy with anti-ICOS mAbs should be carefully evaluated before use in clinical trials. To design and test new combination therapies, we described the immune-TME of mouse models of lung cancer. Currently, lung cancer has the highest mortality among cancers, with immunotherapy-benefit limited to some patients. Here we described the TME of two mouse models of lung cancer: KPB6.F1 and CMT-167. We did not find significant differences in the TME of the KPB6.F1 model after radiotherapy and chemotherapy. To promote immunogenicity, combination therapy with anti-CD25 mAb and anti-4-1BB mAb was evaluated in both the KPB6.F1 and CMT-167 models. Anti-4-1BB promoted proliferation, granzyme B production and expression of activation markers on effector CD4+ and CD8+ T-cells. Whilst this combination reduced the tumour-burden of the CMT-167 model, no differences were observed in the KPB6.F1 model, suggesting intrinsic differences between them. Further work describing the differential response of both models to specific therapies could provide important information regarding resistant tumours in patients, together with strategies to overcome those resistances. The work presented in this thesis describes variations in the immune-TME following different therapies, suggesting that further investigation is crucial for understanding the biology of the mechanism of action of cancer immunotherapies and to improve their efficacy.

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