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Enhancing tumour specific immune responses for the treatment of ovarian cancer


Project Description

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.

Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2020 entry, the application deadline is 10th January 2020 at 12 noon (midday).
Please visit our website for more information on how to apply.

References

1. Napolitani G, Kurupati P, Wei Weng Teng K, Gibani MM, Rei M, Aulicino A, Preciado-Llanes L, Wong MT, Bect E, Howson L, de Haas P, Salio M, Blohmke CJ, Olsen LR, Susano Pinto DM, Scifo L, Jones C, Dobinson H, Campbell D, Juel HB, Thomaides Brears H, Pickard D, Bumann D, Baker S, Dougan G, Simmons A, Gordon MA, Newell E, Pollard AJ, Cerundolo V. Clonal analysis of Typhoidal Salmonella specific effector CD4+ T cells in challenged human volunteers reveals immunodominant Serovar specific and cross-reactive T cell responses. Nat Immunol. 2018 Jun 20.
2. Howson LJ, Napolitani G, Shepherd D, Ghadbane H, Kurupati P, Preciado-Llanes L, Rei M, Dobinson HC, Gibani MM, Teng KWW, Newell EW, Veerapen N, Besra GS, Pollard AJ, Cerundolo V. MAIT cell clonal expansion and TCR repertoire shaping in human volunteers challenged with Salmonella Paratyphi A. Nat Commun. 2018 Jan 17;9(1):253.
3. Salio M, Gasser O, Gonzalez-Lopez C, Martens A, Veerapen N, Gileadi U, Verter JG, Napolitani G, Anderson R, Painter G, Besra GF, Hermans IF, Cerundolo V. Activation of human mucosal-associated invariant T cells induces CD-40L-dependent maturation of monocyte-derived and primary dendritic cells. J Immunol. Sept 2, 2017
4. Timosenko E, Ghadbane H, Silk JD, Shepherd D, Gileadi U, Howson LJ, Laynes R, Zhao Q, Strausberg RL, Olsen LR, Taylor S, Buffa FM, Boyd R, Cerundolo V. Nutritional stress induced by tryptophan-degrading enzymes results in ATF4-dependent reprogramming of the amino acid transporter profile in tumor cells. Cancer Res. Sept. 20, 2016.
5. Yang H, Mao W, Rodriguez-Aguayo C, Mangala LS, Bartholomeusz G, Iles LR, Jennings NB, Ahmed AA, Sood AK, Lopez-Berestein G, Lu Z, Bast Jr. RC. Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability. Clin Cancer Res, 24, 5072-5084. October 2018
6. Zheng Y, Sethi R, Mangala LS, Taylor C, Goldsmith J, Wang M, Masuda K, Karaminejadranjbar M, Mannion D, Miranda F, Herrero-Gonzalez S, Hellner K, Chen F, Alsaadi A, Albukhari A, Fotso DC, Yau C, Jiang D, Pradeep S, Rodriguez-Aguayo C, Lopez-Berestein G, Knapp S, Gray NS, Campo L, Myers KA, Dhar S, Ferguson D, Bast RC Jr, Sood AK, von Delft F, Ahmed AA.Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation. Nat Commun. 2018 Feb 2;9(1):476.

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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