INVESTIGATING IMMUNE MODULATION TO IMPROVE OUTCOMES AFTER RADIOTHERAPY FOR BLADDER CANCER

UoM administered thesis: Phd

Abstract

There is an urgent clinical need to improve outcomes for patients with muscle-invasive bladder cancer (MIBC). Radiotherapy (RT) plays an important role in the management of many of these patients. Data from pre-clinical studies show that RT may induce anti-tumour immune stimulatory changes in the tumour microenvironment and systemically. However, these effects seldom manifest clinically due to inherent and adaptive immune suppression within tumours. Combination strategies employing standard-of-care anti-PD-1/PD-L1 agents to enhance RT-induced cancer-specific immunity have demonstrated robust anti-tumour effects in pre-clinical models, even leading to systemic ‘abscopal effects’ out of the irradiated field. Despite success in murine models, results from early clinical trials testing this premise in patients with metastatic MIBC have been less impressive. The addition of alternative immune modulatory agents to RT may drive local and systemic anti-tumour immune effects, leading to improved survival outcomes in these patients. BO-112 is a novel, intratumourally-administered dsRNA analogue which has been shown to promote anti-tumour immune effects in murine models, and is being tested in an early phase clinical trial in combination with anti-PD-1 treatment in patients with advanced malignancies. It was hypothesised that the efficacy of RT could be improved by combination with BO-112 in murine models of bladder cancer, and enhanced further by the addition of anti-PD-1 treatment. Here, murine bladder cancer cells exhibited hallmarks of immunogenic cell death and may have induced a weak vaccination effect after RT, as well as upregulating several putative proteins which enhance T cell cytotoxicity. Preliminary data revealed that RT may have increased maturation of dendritic cells (DC) and activation of T cells but did not increase the proportion of CD8+ cells in the immune microenvironment of tumours. The majority of immune cells in non-treated and irradiated tumours were myeloid-derived populations. BO-112 reduced the rate of tumour growth in heterotopic MBT2 and MB49 models. A novel system was developed to administer BO-112 to orthotopic MBT2 tumours, which also slowed tumour growth. BO-112 induced tumour cell death and release of type I interferon in vitro, and a signal emerged that it led to activation of T cells and maturation of DC in vivo. Preliminary data suggest it may have increased the proportion of CD8+ cells in the immune microenvironment, but did not consistently modulate markers associated with macrophage polarisation. A signal emerged from further pilot studies that the addition of BO-112 to RT improved local tumour control in MB49 models after treatment. Dual therapy led to increased maturation of DC and activation of CD8+ cells in tumour-draining lymph nodes. However, the majority of mice developed distant metastases, suggesting a lack of robust systemic anti-tumour immune responses. There was no preliminary evidence that the efficacy of combination treatment was not enhanced by employing alternative sequential scheduling. Although combination treatment led to upregulation of PD-L1 on tumour cells in vitro, and myeloid-derived populations in vivo, there was no preliminary evidence that the addition of anti-PD-1 treatment to dual therapy did not further enhance local tumour control or induce systemic anti-tumour immunity. These results provide compelling preliminary data that justify further pre-clinical work into this novel treatment combination. If these findings are confirmed, this should provide proof-of-principle for future early phase trials investigating the efficacy of BO-112 in combination with RT in patients with MIBC. A clinical study determining the feasibility of cystoscopy-guided intratumoural delivery of BO-112 in patients with MIBC is currently in the final stages of development.

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Original languageEnglish
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Award date1 Aug 2021