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Optimising CAR-T cells for enhanced activity in the tumour microenvironment


Institute of Immunology and Immunotherapy

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Dr Francis Mussai , Dr C De Santo No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

Research interests/description of main research theme:

Background: Although for some cancers, like retinoblastoma or Acute Lymphoblastic Leukaemia over 90% of patients will be cured, for many solid cancers or those that relapse, the mortality remains unacceptably high. Chimeric Antigen Receptor (CAR)-T cells (CAR-T) are autologous patient-derived T cells which have been engineered with an antibody fragment (scFv) that specifically recognises the tumour surface antigens. Preclinical and clinical studies indicate these CAR T cells could represent a powerful new way of killing tumour cells. The proof-of-principle of using CAR-T cells to successfully treat paediatric cancers has been established in patients with chemo-resistant, relapsed paediatric B Acute Lymphoblastic Leukaemia who underwent rapid and sustained remissions using anti-CD19 CAR T cells. However in solid cancers, despite infusion of large numbers of these cells, CAR T cell numbers become low or undetectable within weeks, and that the majority of patients with active disease do not achieve a long-term, complete remission. These findings suggest that the local and systemic tumour microenvironment impairs the activity of CAR-T cells.
We have shown that multiple factors can have a negative impact on autologous and engineered T cell function – including amino acid availability, presence of myeloid-derived suppressor cells, and cytokine release from tumour cells.

Aim 1: To develop enhanced CAR T cells which are resistant to the immunosuppressive microenvironment created by tumours
Aim 2: To investigate the proliferation, persistence, and anti-tumour cytotoxicity of these resistant CAR-T cells in cancer models in vitro and in vivo

Training opportunities:

The candidate will gain important experience in the development of immunotherapies and cancer biology. Skills will include:
• Tissue culture
• CAR-T cell/ retroviral preparation of cells
• Cytotoxicity and proliferation assays
• Flow cytometry, PCR, Western Blotting
• Murine studies

The group holds lab meeting every 2 weeks in which the student will present their data. In addition the student will be able to attend seminars held weekly by the Institute. When appropriate the student will be encouraged to attend and present data and national and international meetings, and submit the data for publication alongside their thesis.

Candidate:
Development and testing of modified CAR-T cells is a complex endeavour. The candidate should have strong evidence of prior experience in tissue culture of human cells, and common in vitro techniques such as western blotting, qPCR, and cell based phenotyping assays. Prior experience with T cells and/or viral transduction of human cells is highly desirable. Candidates will likely have a MSc (or equivalent) in an area of laboratory science such as immunology or cell biology.

The candidate should be enthusiastic, very well organised, keen to learn and strong team-player.

Host laboratory:
The laboratory is co-headed by Dr Francis Mussai and Dr Carmela De Santo. The group is composed of post-doctoral and technical staff alongside students, in a supportive and ambitious team. The group’s research focuses on understanding how adult and paediatric cancers interact with the immune system, and developing novel therapeutic strategies. The laboratory is well equipped and based within the Institute of Immunology and Immunotherapy at the University of Birmingham.

How to apply
Applications should be directed to the UoB portal, https://sits.bham.ac.uk/lpages/MDS069.htm Please select PhD Immunology and Immunotherapy Full Time.
To apply, please upload:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.


Funding Notes

3 year studentship to cover stipend and tuition fees.


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