Outline

This project will explore successful cancer vaccines from successful cancer immunotherapy. 

Recent immunotherapeutic approaches using adoptive cell therapy, or checkpoint blockade, have demonstrated the powerful anti-cancer potential of CD8 cytotoxic T-lymphocytes (CTL). While these approaches have shown great promise, they are only effective in some patients with some cancers.

The potential power, and relative ease, of therapeutic vaccination against tumour associated antigens (TAA) that can be present in many different cancers has been a long sought-after approach for harnessing the discriminating sensitivity of CTL to treat cancer that has seen recent renewed interest following cancer vaccination successes using unique tumour neoantigens.

Results with TAA-targeted ‘universal’ cancer vaccines (UCV) have been largely disappointing. Infectious disease models have demonstrated that T-cell clonotypes that recognise the same antigen should not be viewed as being equally effective. Extrapolation of this notion to UCV would suggest that the quality of response in terms of the T-cell receptor (TCR) clonotypes induced might be more important than the quantity of the response.

Unfortunately, there is little opportunity to assess the effectiveness of individual T-cell clonotypes in vivo. We have identified effective, persistent T-cell clonotypes in HLA A*0201+ patients following successful tumour infiltrating lymphocyte (TIL) therapy. Many of these clonotypes can kill other HLA A*0201+ tumour types through novel HLA A*0201-restricted epitopes.

Thus far, one such T-cell clone has been used to generate super-agonist altered peptide ligands (APLs) by our current Tenovus funded student, Sarah Galloway. Further refinement has produced an APL that was capable of inducing T-cells in greater magnitude, and with improved effectiveness, from the blood of all 12 healthy donors tested. Importantly, this APL also induced T-cells from melanoma patient blood that exhibited superior recognition of the patient’s own tumour compared to those induced by the natural antigen sequence.

We already have similar results with renal cell carcinoma, ovarian cancer and chronic lymphocytic leukaemia. These results suggest that use of APL to skew the clonotypic quality of T-cells induced by cancer vaccination could provide a promising avenue in the hunt for the UCV ‘magic bullet’.

What is funded

For more information on what is funded in this studentship please visit: https://www.cardiff.ac.uk/study/postgraduate/funding/view/phd-in-cancer-immunotherapy-successful-cancer-vaccines-from-successful-cancer-immunotherapy

Duration

4 years

Eligibility

For more information on the eligibility for this studentship please visit: https://www.cardiff.ac.uk/study/postgraduate/funding/view/phd-in-cancer-immunotherapy-successful-cancer-vaccines-from-successful-cancer-immunotherapy