The immune system, which defends the body against a wide array of threats, is gaining a growing role in the fight against cancer. For an immunotherapy to be successful, it needs to overcome intrinsically weak tumour-specific immune responses. There are two broad approaches to achieving this goal: targeting the various arms of the immune system or targeting the cancer and its microenvironment. The experiments discussed in this thesis adopt the second approach. Tumours were transduced with a combination of costimulatory molecules: CD48, CD54, CD70 & CD86, the chemokine CX3CL1 and the cytokines: IFNγ, GM-CSF and IL-12. Transduction of costimulatory molecules enhances priming in-vitro and cause tumour rejection and delayed tumour growth in-vivo. This effect is demonstrated with single costimulatory molecules but is more pronounced when multiple costimulatory molecules are transduced. Addition of the cytokines and chemokine enhanced tumour rejection, and also resulted in partial rejection of contralateral parental tumours. Attempts to enhance anti-tumour memory by fusing IL-2 and IL-15 to their respective receptors are also discussed. Work in a human/mouse chimeric PD-1 mouse model shows that transduction of multiple costimulatory molecules is able to overcome intrinsic anti-PD-1 resistance. Radiation is known to result in upregulation of several costimulatory molecules within tumours or their infiltrating dendritic cells. The experiments presented here suggest that radiation therapy may be useful in overcoming anti-PD-1 therapy resistance. In human trials, approximately three quarters of cancers fail to respond to anti-PD-1 therapies. Understanding and potentially overcoming anti-PD-1 therapy resistance is therefore of great interest.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:711717 |
| Date | January 2015 |
| Creators | Ajzensztejn, Daniel |
| Contributors | Cerundolo, Vincenzo ; Muschel, Ruth J. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://ora.ox.ac.uk/objects/uuid:1aafa1f4-ee10-4081-b621-d81b9979d96a |
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