Injectable chitosan hydrogel as a delivery system for cancer immunotherapy

Adoptive cell therapy (ACT) is a cancer immunotherapy where high quantities of T cells that specifically target cancer cells are administered intravenously to patients, where the delivered cytotoxic CD8+ T cells can directly eliminate cancer cells. In various forms, it has shown success against previously treatment-resistant cancers such as metastatic melanoma and certain blood cancers, though its use is often limited in solid cancers. Despite its success, limitations persist including the difficulty of cultivating the high number of cells required, their dispersal to non-tumour sites and side effects resulting from the drugs necessary in clinical ACT. Localised delivery of T cells, for example via a scaffold, could address these limitations by concentrating cells at the tumour site, reducing both the initial number of cells and the dosage of associated drugs required for successful treatment. An ideal scaffold for this application should be easily administered and mixed with cells, biodegradable and biocompatible with encapsulated cells, allowing them to perform their anti-cancer function. The hypothesis of this PhD is that localised delivery will allow treatment with fewer cells and greater efficacy than systemic treatment. The thermosensitive chitosan hydrogel that we have developed was shown to be biocompatible and biodegradable in vivo, and supported the survival, escape and anti-cancer functionality of encapsulated T cells. In the MC38-OVA murine tumour model, gel-encapsulated OT-I limited tumour growth compared to untreated and mice treated with PBS-suspended OT-I, though IVdelivered OT-I were more effective than the gel in limiting tumour growth. This showed the feasibility and potential of the chitosan gel for localised OT-I delivery as a cancer immunotherapy. Microbeads were successfully produced as an alternative gel format to potentially improve oxygen and nutrient access to encapsulated cells, although their fabrication must be optimized due to the currently elevated mortality in microbead-encapsulated cells. Further development of the microbeads, as well as the addition of growth factors and binding motifs, could further improve gel efficacy and continue progress towards eventual clinical translation.