Enhancing Immunotherapy Using Oxygen Microbubbles

Immunotherapy is a highly promising emergent strategy for treating a plethora of malignant cancer forms. In contrast to the use of widespread chemotherapeutic and radiological methods to halt tumour progression, immunotherapy instead augments the host's immune system to induce a localised cytotoxic response to cancerous cells. As a result, immunotherapy affords the potential for patient treatment specificity and continual immune surveillance.
Hypoxia, defined as localised deprivation of tissue oxygen supply, is a property of the tumour microenvironment (TME) as a result of abnormal angiogenesis giving rise to highly irregular vascularisation. Hypoxic regions arise where local respiratory demand outweighs oxygen supply, a consequence of the TME perfusion imbalance. The resulting hypoxic stress disables the host's immune response through enhancing immune--suppressive stromal cell proliferation and forming a metabolically--hostile immune environment. Consequently, hypoxic regions of solid tumours have poorer prognosis in all forms of oncological treatment.
As a result of the above factors it has been theorized that overcoming the hypoxic barrier, through the application of oxygen microbubbles, will result in substantial increases in immunotherapeutic efficacy. Existing studies in the BUBBL group have demonstrated the significant clinical potential of O2 microbubbles for use in hypoxic tumours, and it is hoped that the results from these immunotherapeutic studies will be even more successful.
Ultrasound--mediated drug delivery has been significantly enhanced by recent advances in drug--loaded microbubble engineering enabling the development of targeted release strategies. Upon exposure to the high--intensity ultrasound the acoustic energy deposition bursts the microbubble shell; this releases the therapeutic payload in an extremely short timescale. For this study, oxygen molecules will be the therapeutic agent held in the microbubble core. Various delivery methodologies will be trialled as part of this study: Loading the shell with immunotherapeutic molecules to deliver both the oxygen and drug concurrently would be one approach. Another would be co-injection.
Proposed Experimental Methodology
Development of a robust and effective therapeutic regime to deliver O2 to hypoxic TME regions requires a multifaceted analysis of the fluid-mechanical, biochemical and thermodynamic influences governing microbubble physics and the subsequent immunotherapeutic response in the host. Listed below are a selection of primary project areas
Hypoxic regions are often situated a significant distance (50--250 micrometres) from the nearest blood vessel and so interstitium penetration studies are imperative to determine the ability of O2--carrying microbubbles to induce local increases in oxygen saturation. These (initially in--silico only) studies will involve the formulation of a physiologically--derived computational model (in MATLAB and COMSOL Multiphysics) simulating the abnormal TME vasculature and interstitial space. The model will be used to study and optimise ultrasound--mediated penetration and delivery capabilities of microbubble variants within the context of different tumor variants and ultrasound protocols.
Real--time imaging of Oxygen transport within the TME represents a substantial challenge (and is imperative for efficacy, dosing and safety studies). NMR/MRI using O2 represents an area of significant clinical potential, but further work is needed to ascertain the feasibility of this method, and the viability of using exotic species (such as Oxygen--17) in the chosen imaging modality.
In--vitro studies using various pancreatic cancer (a particularly hypoxic solid tumour with poor prognosis) cell lines will be conducted to validate the results from the in--silico work, and hopefully will pave the way for in--vivo research.
This project falls within the Cancer section of the Molecular and Cellular Medicine research area.