In spite of the relatively low tumour mutational burden (TMB), a significant proportion of ovarian cancers has been shown to harbour tumour infiltrating lymphocytes (TILs) with prognostic significance. However, rejuvenation of TILs in ovarian cancer using checkpoint inhibitors has not been successful in contrast to the success that has been achieved in other tumours, such as in melanomas. This highlights the need for a better understanding of ovarian-cancer-specific mechanisms that are involved in T cell activation and exhaustion. Furthermore, a correlation exists between TMB and the success of checkpoint-blocking antibodies. Therefore, the known low TMB in ovarian cancer underscores the unmet need for development of complimentary immunotherapeutic strategies.
Successful adoptive T cell therapy has shown promise in ovarian cancer, but specificity and efficacy are still lacking. Recent novel technologies for robust neo-epitope selection and isolation and expansion of neo-epitope-specific T cells offer exciting prospects for successful adoptive T cell therapy as recently demonstrated in breast cancer with low TMB. Moreover, the use of human organoid model systems makes it possible to test the efficacy and specificity of therapeutic T cells in powerful and relevant models of cancer, opening new opportunities for further optimization of patient-specific protocols for immunotherapy.
This proposal aims to establish a translation-ready therapeutic platform for treating ovarian cancer patients using adoptive T cell therapy. In addition to detailed hypothesis-testing, we will work with a leading industry collaborator (Miltenyi) to ensure that our process is ready for implementation in clinical research trials. Specifically, our proposal has two main research aims:
1- We will test the hypothesis that the subcellular localization of neo-epitopes is critical in modulating their immunogenicity.
2- We will test the hypothesis that tissue resident memory CD8+ T lymphocytes (TRMs) in the fallopian tubes (FT) contribute to the ovarian cancer-immune equilibrium and that they are important therapeutic targets in ovarian cancer.
Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.
Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.
All WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.
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