Identification of early and late transformation events in adult T-cell leukaemia/lymphoma

Adult T-cell leukaemia/lymphoma (ATL) is a highly aggressive type of blood cancer that only occurs in individuals who are infected with the human T-lymphotropic virus type 1 (HTLV-1). Despite many advances in cancer treatment the survival of patients with this blood cancer remains poor. Patients typically surviving just 6-9 months following diagnosis. However, the majority of individuals with this viral infection are completely well and do not develop ATL. As yet we do not have ways to identify the people with the virus who are at most risk of developing the disease. In this project we aim to understand the process from infection of a cell to a blood cancer. The aim is then to develop the tools to identify individuals at highest risk of disease. This will allow us to offer early treatment of ATL and ideally to take steps to prevent this leukaemia. This is particularly important because current treatments rarely cure this disease.

The research will be undertaken at Imperial College London, supervised by a group of scientists who are internationally regarded as experts in this field. I will be using state of the art technology to identify the damage that the virus is causing to the cell before cancer develops. The research will be carried out using stored blood samples donated by patients infected with HTLV-1 who attend the National Centre for Human Retrovirology at Imperial College Healthcare NHS Trust, London.

Adult T cell leukaemia/lymphoma (ATL) occurs in ~20% of high proviral (PVL) load carriers of human T-cell lymphotropic virus type-1 (HTLV-1). In the 35 years since ATL was first described, the median overall survival of these subtypes remains unchanged at 6-10 months. The best chance of long term survival is with allogeneic transplantation, but only ~10% of patients reach this point. There are thus several urgent unmet needs: (1) to develop markers that identify HTLV-1 carriers at highest risk of ATL - in order to offer earlier interventions, (2) to allow a lead-time to identify suitably matched allogeneic stem cell donors and (3) to identify novel therapeutic targets. This is also a unique opportunity to study the evolution from infection (HTLV-1 infected cells can be identified through distinct surface expression) through clonal expansion to malignant transformation in readily available primary cells.

I plan to flow-sort the non-malignant and the 'ATL-like' populations of infected CD4+ cells from the peripheral blood of HTLV-1 carriers who have been followed up for >5 years, followed by mRNA-sequencing, germline exome sequencing and viral integration site analysis to study clonal evolution from asymptomatic infection through asymptomatic clonal expansion to malignant transformation in readily available primary cells. I will select specific subgroups of individuals for this study (high risk carriers with no malignancy within 5 years of follow up, high risk carriers who develop malignancy within 1 year of follow up, and fully transformed ATL cases). The objectives of this study are to (1)identify the RNA expression signatures unique to each step of clonal evolution and expansion, (2) to identify the somatic mutations that arise at each step of disease progression which suggest putative driver events, (3) quantify HTLV clonal evolution at each step.

In addition to the academic impact of understanding of the process of transformation in leukaemia/lymphoma and training a highly skilled clinician/academic, this study will have measurable societal and economic impact for the following stakeholders:

High risk HTLV-1 carriers: This study will directly benefit high risk HTLV-1 carriers by identifying better predictors of ourcome. (1) By allowing clinicians to offer more accurate prognostic outlook for each individual justifying enrollment of high risk individuals into intervention clinical trials in the National Centre for Human Retrovirology (NCHR); and (2) earlier detection of ATL/premalignancy will fast-track access to treatment potentially improving survival by expanding the therapeutic window for ATL.
How: These predictors will be validated through further translational research in the HTLV molecular diagnostic unit, with the ultimate aim of offering an improved diagnostic testing/risk stratification service both nationally and internationally. This will build on a history of successful translation of basic research to clinical provision. Improved risk stratification will provide reassurance to a subset of patients that they are lower risk for developing disease - there is a significant psychological burden associated with not knowing if HTLV-1 infection will remain asymptomatic.

ATL patients: This study has the potential to identify novel drug targets for ATL patients, paving the way for development of new therapies, and identifying existing drugs which could have previously unrecognised clinical benefit (e.g. specific kinase inhibitors).
How: Clinical trials of novel therapeutic strategies involving of existing drugs or novel therapeutic agents will be conducted in partnership with pharamaceutical companies. This will be done by directly engaging appropriate pharmaceutical companies, with the support of the clinical trials unit at Hammersmith hospital (http://www.imperialclinicaltrialsunit.org/trials/), with the aim of conducting trials at multiple centres, to improve access for patients. This follows a history of clinical trial provision at the NCHR.

HTLV-1 infected individuals:
HTLV-1 carriers and their families will benefit from the continued contact and involvement with research at the NCHR. This will aid awareness and understanding of the virus and research conducted at the NCHR, and will encourage patient recruitment into future studies.

NHS/ the taxpayer:
How: Disease prevention (through intervention trials) and more effective, well tolerated treatments will improve survival and quality of life, thus reducing the economic burden of ATL.

Imperial College and industrial partners:
How: Intellectual property translated into clinical investigations and therapies may have economic value: we aim to investigate potential in partnership with industry, facilitated by Imperial Innovations (https://www.imperialinnovations.co.uk/) - the technology commercialisation partner for Imperial College London.