About the Project
This 4-year PhD studentship is offered by the Cancer Research UK City of London Centre
Despite recent advances in therapy for primary breast cancer, relapse remains a significant concern, particularly for the triple-negative subset. Immunotherapy is opening up new therapeutic options for treatment of triple-negative breast cancer (TNBC). However, current clinical trials report only rare durable responses to immune checkpoint blockade strategies. Thus, new strategies are required to improve clinical outcome for these patients. This project specifically focuses on combining personalised vaccines and viro-immunotherapy to develop an effective approach for the treatment of TNBC.
The PhD student will develop of a therapeutic platform that combines a personalised neo-epitope-based vaccine and oncolytic virotherapy (OV) to treat TNBC. This platform will induce robust and effective anti-tumour immunity through: i) identification and validation of patient-specific, immunogenic neo-epitopes, ii) generation of strong neo-epitope-specific CD8+ T cell responses, iii) induction of efficient T cell homing to tumour cells and iv) reversal of the immunosuppressive tumour micro-environment to successfully promote T cell-mediated tumour clearance. These will be achieved through completion of the following objectives:
1. Identification and in vitro validation of immunogenic neo-epitopes discovered from TNBC patients and murine tumour cell lines.
2. Development of an effective vaccination strategy for the induction of cellular immunity against a panel of patient specific neo-antigens and common tumour-associated antigens (TAS). The vaccination strategy will be optimised by combining multiple complementary TLR agonists, helper functions (stimulatory anti-CD40) and IFN-g, plus a panel of synthetic peptides, derived from neo-antigens and TAS, as well as replicating oncolytic viruses.
3. Enhancement of the clinical efficacy of vaccination with the aid of an oncolytic vaccinia virus (VV) to help modulate and suppress the tumour microenvironment by expression of VV encoded immune stimulating molecules, such as inhibitors of immune check points (antibody mediated blockade of PDL1/PD1 interaction) and expression of factors/chemokines for better effector T cell penetration of the tumour mass.
Genomic, transcriptomic and proteomic analysis of in-house TNBC patients has allowed us to find some potential neo-antigens that are displayed specifically in TNBC cancer cells. We now intend to analyse each of these molecules in terms of their ability to promote the immune system to attack the cancer cells. Then we plan to use all the validated molecules to create a library of molecules such that treatment of patients can be individually tailored after analysis of the patients’ cancer samples (in order to verify which corresponding molecules are present in the patients’ cancer cells). This project is designed to provide optimised combination regimes both for prevention of TNBC recurrence after surgery and for the treatment of advanced TNBC. The potential candidate should have a good knowledge of cancer cell biology, immunology and virology, in addition to proven skills in basic cell and molecular biology techniques. Having lab experience in immunology, computational techniques (bioinformatics) and animal experiments will be of great advantage. We anticipate that the outlined PhD studies will provide proof of concept data for the translation of this personalised cancer vaccine regimen into clinical studies towards the end of the PhD studentship. The outlined programme of research is expected to provide the candidate with extensive training in the cutting-edge technologies in immune therapy of cancer, including detailed experience on bioinformatics and computational biology from some of the internationally leading centres of excellence in this area.
Potential research placements
1. Discovery of cancer neo-epitope for personalised cancer vaccine. Prof Claude Chelala, Barts Cancer Institute, QMUL.
2. Training in viral vector production. Prof Farzaneh, King’s College London.
3. Construction and validation of tumour-targeted replicating oncolytic virus. Prof Wang, Barts Cancer Institute, QMUL.
Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the CRUK CoL Centre PhD Programme in September 2019 and will register for their PhD at their primary supervisor’s university.
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.
APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 19 MARCH 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
References
1. Collignon J et al., Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer (Dove Med Press), 2016; 8: p. 93-107.
2. Nanda R et al., Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol, 2016; 34(21): p. 2460-7.
3. Zhang X et al., Breast Cancer Neoantigens Can Induce CD8(+) T-Cell Responses and Antitumor Immunity. Cancer Immunol Res, 2017; 5(7): p. 516-523.
4. Wang P et al., Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent. Nat Commun, 2017; 8(1): p. 1395.
5. Tysome JR et al., A novel therapeutic regimen to eradicate established solid tumors with an effective induction of tumor-specific immunity. Clin Cancer Res, 2012; 18(24): p. 6679-89.
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