Every individual harbours a vast and unique repertoire of immune receptors (T-cell receptors and B-cell receptors) which discriminate, at the molecular level, self from non-self. The structural diversity of the T-cell receptor (TCR) that is necessary for recognizing diverse antigens is generated mainly by stochastic shuffling of the large number of short DNA segments that comprise TCR genes. Although the central importance of T cells in adaptive immunity has been well established for decades, the actual number and diversity of T cells that exist in an individual (i.e. the T-cell repertoire), how this changes in response to immune challenge, and how it varies from one individual to the next has remained unknown, and subject to much speculation. We applied deep sequencing to T-cell repertoire analysis to obtain a first glimpse of repertoire diversity at the ultimate resolution of individual clonotypes (Freeman et al., Genome Research 2009). Currently, we are using these methods to explore the role of T cells in cancer, and how to enhance the anti-cancer immune response. We are particularly focussed on developing new sequence based approaches to T cell antigen discovery and characterization.
Cancer immunotherapies using engineered autologous T-cells have shown remarkable efficacy against some cancer. We are engineering T cells to selectively deliver modified cytotoxic payloads and pro-drug activators, for the purpose of enhanced tumor cell killing and overcoming immune resistance.
A substantial proportion (at least 15%) of the global cancer burden is attributable to known infectious agents, such as HPV, HBV and H.pylori. It is possible that infectious agents may have a still greater role in cancer etiology, but traditional methods for finding them have limited sensitivity. We find pathogens by their sequence signatures in human tissues, using genomic methods. Our application of these methods to colorectal carcinoma identified a strong link to the emerging pathogen Fusobacterium nucleatum (Castellarin et al., Genome Research 2011). Cancer-associated infectious agents are of potential utility as targets for vaccination, treatment and prevention.
We are using deep sequencing and novel computational methods to identify the spectrum of somatic mutations in various cancers, with a particular focus on tumor evolution and the identification of antigens for cancer vaccines.
While most tumor mutations are sporadic, some hotspot mutations at seen in certain cancers at high frequency. We are systematically assessing the most highly recurrent cancer mutations for their immunogenicity using a combination of mass spectrometry, flow cytometry and cellular immunoassays. We are optimizing procedures of isolating, expanding, activating, and redelivering these mutation-reactive T cells as targeted immunotherapies.