Designing Novel Vectors for Targeted In Vivo Transduction of Monocytes to Deliver Cancer Therapeutics into the Tumour Microenvironment
Primary Supervisor: Dr Ahmet Hazini
Second Supervisors: Professor David Withers, Dr Keaton Jones
Project Overview
T cell-based immunotherapies have demonstrated significant success in treating haematological cancers. However, their efficacy in solid tumours remains limited. Recently, engineering macrophages to deliver cytokines or express chimeric antigen receptors (CARs) targeting cancer cells has emerged as a promising alternative approach for treating solid tumours. Macrophages possess distinct advantages over T cells due to their natural ability to infiltrate the tumour microenvironment, regulate other immune cells through cytokine secretion, and, critically, cross-present tumour antigens.
As professional antigen-presenting cells (APCs), macrophages can cross-present tumour antigens to T cells, thereby activating them to target cancer cells. This capability is crucial for initiating new T cell responses against cancer and is fundamental for the development of a cancer vaccine that can adapt alongside tumour escape mechanisms.
One of the primary challenges in developing macrophage- or monocyte-based therapeutics is the effective delivery of therapeutic cargo into these cells, as their innate defence mechanisms often hinder the uptake of foreign particles, genes, and vectors.
In this project, we aim to overcome these challenges by utilizing AAV and adenoviral libraries to identify monocyte-specific vectors capable of efficiently transducing monocytes. We will characterize these vectors and generate plasmids optimized for engineering purposes. Our ultimate goal is to “arm” monocytes with CARs and bispecific engagers using these novel vectors, paving the way for innovative and effective macrophage-based immunotherapies for solid tumours.
Training Opportunities
This DPhil project offers extensive training in advanced techniques at the intersection of cancer immunology, cell engineering, and virology. The candidate will gain hands-on experience with antigen cross-presentation assays using cancer cells, macrophages, dendritic cells, and T cells. This will provide insights into the mechanisms underlying adaptive immune responses in the tumour microenvironment. A key focus of the project is engineering primary immune cells, particularly macrophages and monocytes, using cutting-edge viral vector technologies. The student will acquire comprehensive expertise in the design, production, and functional evaluation of adeno-associated viruses (AAVs) and adenoviral vectors, including their optimization for efficient gene delivery to immune cells.
Additionally, the project includes training in molecular and cellular techniques such as flow cytometry, ELISA, and qPCR to analyse cytokine profiles, immune activation states, and vector performance. The student will develop interdisciplinary research skills through collaborative efforts in immunology, virology, and oncology.