Investigation into next generation immunotherapy candidates and the anti-tumour immune response

Describe background to the work including that carried out in the supervisor's own team and previous work. [This informationwill be used by the reviewers to understand the context of the proposed study].TAMs are one of the most abundant stromal cell populations in cancer. The 'stroma' describes the heterogeneous collection ofnormal non-cancerous cells which get recruited into the tumour microenvironment and facilitate cancer progression. Macrophagesget hijacked by the tumour to help support angiogenesis, immune and chemotherapeutic suppression, and tumour cell migration.Our laboratory has characterised a subpopulation of TAMs which have potent immune suppressive functions in the tumourmicroenvironment through their expression of the enzyme heme oxygenase-1 (HO-1). Arnold lab published a paper in ClinicalCancer Research (2018) that demonstrated using a small molecule inhibitor for HO-1 called tin mesoporphyrin (SnMP) to targetthe HO-1 activity in these macrophages could be used to improve the efficacy of a chemotherapy-elicited immune response tocontrol tumour growth. As such, the combination of an immune-stimulating chemotherapy and SnMP represented a novelimmunotherapy combination. Chemotherapy has been utilised for the treatment of cancer for nearly 70 years. These moleculeswere first administered to patients with cancer for their ability to target the cell cycle. However, chemotherapy can also act as animmunotherapy, stimulating immune surveillance through both priming anti-tumour CD8+ T cells and eliciting their infiltration intothe tumour microenvironment. As cytotoxic chemotherapies are widely used in the clinic, they represent an appropriate pairingfor SnMP, or other Ho-1 inhibitor, to take into a phase I trial. However, SnMP does have drawbacks that could hinder its long-termprogress through later phase trials as SnMP cannot be delivered orally to the patient, inhibits both HO-1 and HO-2 and has noopportunity for intellectual property as it is a generic compound. As such, the current project aims to develop the next generation of HO-1 inhibitors for clinical translation as novel immunotherapeutics.

The Aim of this project is to redesign an orally available selective HO-1 inhibitor which we will validate for preclinical efficacy andgenerate a data-package for clinical translation as well as a tool to further investigating the role of HO-1 in cancer progression. We also hypothesise that some drugs already used in the clinic may actually have off-target effects on modulating HO-1 activityand these will be explored and predicted using in silico screening approaches and validated using the assays that will establishedfor the primary project goal.