Cancer PhD: Optimising vaccine response through cytokine modulation in urothelial cancer

Urothelial cancer is a common cancer and was the first tumour to be treated with an approved immunotherapeutic agent – BCG. BCG is a live attenuated form of tuberculosis that non-specifically stimulates the immune system and promotes cancer cell death. Subsequently, targeted immunotherapy has shown promise in urothelial cancer in the form of checkpoint inhibition, antibody drug conjugates, and most recently cytokine therapy(1). An IL-15 fusion protein that mimics antigen presentation by dendritic cells, in combination with BCG, led to durable responses in around 25% patients(2).

Following the COVID-19 outbreak, and the widespread use of vaccines, there is renewed interest in cancer vaccines. The UCL sponsored DURANCE study is investigating the role of a tumour associated antigen peptide vaccine in non-muscle invasive bladder cancer. Patients who have progressed though BCG are treated with a combination of vaccine and checkpoint inhibitor but only a minority of patients are likely to respond. Treatment capable of high rates of durable response remains an unmet clinical need.

The aim of this work is to develop a novel cytokine based immunotherapy to enhance the activity of a vaccine in urothelial cancer as part of the immunotherapy engineering program at UCL(3). 

Aims:

1. Characterisation of tumour autologous targets through evolution. The student will identify potential antigenic targets using single cell transciptomics in patients from the DURANCE study (pre-and post treatment) and from patients undergoing cystectomy from muscle invasive bladder cancer. Immune landscapes, particularly the CD8, NK-Cells and dendritic cell compartments will be evaluated.
2. Development of a urothelial co-culture explant model The student will optimise an explant model of urothelial cancer with autologous PBMCs in order to be able to study the immune response to therapy through multi-spectral flow cytometry and cytokine arrays.
3. Develop a cytokine based drug to enhance vaccine response As part of the novel immunotherapeutic team, top drug candidates will be validated with co-culture patient-derived organoids and patient-derived explants to test 1) tissue penetration within the solid tumour; 2) Tumour killing; 3) Changes in the tumour immune microenvironment.

About the Department

The University College London Cancer Institute (UCL CI) (https://www.ucl.ac.uk/cancer/welcome-ucl-cancer-institute) is the hub for cancer research at UCL, one of the World’s leading universities. The Institute draws together over 400 talented scientists and 150 PhD students who are working together to translate research discoveries into developing kinder, more effective therapies for cancer patients. The Urological Cancer Biology Group is aimed at translating high quality basic science into clinical care for patients with Prostate or Bladder Cancer. 

Formal supervisory meetings will be once weekly with primary and secondary supervisors. The student will participate in the UCL CI CIRPS seminars, departmental seminars and the weekly lab meetings in addition to the UCL teaching and training meetings. Students are also supported by a Thesis Committee. All students take part in a compulsory first year Cancer programme and are part of the UCL Doctoral School’s Development Training Programme.     

Entry Requirements

Enthusiastic about cancer immunology and keen to develop and validate novel immunotherapeutics in the setting of urothelial cancer. The ideal candidate must have previous experience in molecular biology and primary cell culturing.

A UK master’s degree, or a minimum of a first or an upper second-class UK Bachelor’s degree, in a relevant discipline, or an overseas qualification of an equivalent standard. Candidates will need to demonstrate a strong research component. We welcome applicants from disadvantaged backgrounds, or via an unconventional career path.

If you’re unclear as to whether you are eligible or would like to discuss the project, we encourage you contact the project supervisor, Dr. Mark Linch ([email protected])

English Language Requirements

If your education has not been conducted in the English language, you will be expected to demonstrate evidence of a good level of English proficiency. The English language level for this programme is: level 3

Deadline and Application Process 

The deadline for submission is: 17:00 on July 21st 2024. Interviews will be around the 29th July.

To apply please send your selection materials to [email protected]:

1.  An academic CV

2.  Two academic/ professional references: two scientists/ academics who are familiar with your academic work and/ or research experience and who can judge your potential as a PhD student. One should be your current or most recent employer/supervisor, at least one must be able to comment on your university academic record, and at least one must be able to comment on your previous research experience.

3.  Transcript/s of the marks you achieved in your qualifications.

4.  A 1 page statement. Please expand on

• a. why you want to do a PhD and why this one,
• b.  what are your career aspirations and previous experience.
• c.  details on your research experience in molecular biology and primary cell culturing.

5.  If you are not a UK candidate, please explain how you will cover the difference in fees. Please note that we will only be able to offer studentships to candidates that have home tuition fee status or provide evidence that they can fund the international portion of the tuition fee from external sources (i.e. not self-funded).

Shortlisting will be immediately after so please make sure all your documents and your referees have provided their references before so your application can be processed. Shortlisted candidates only will be asked to apply formally through UCL.

We wish you every success in your application.

References

1.         Jones RJ, Crabb SJ, Linch M, Birtle AJ, McGrane J, Enting D, et al. Systemic anticancer therapy for urothelial carcinoma: UK oncologists’ perspective. British journal of cancer. 2024;130(6):897-907.

2.         Chamie K, Chang SS, Kramolowsky E, Gonzalgo ML, Agarwal PK, Bassett JC, et al. IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer. NEJM Evid. 2023;2(1):EVIDoa2200167.

3.         Galvez-Cancino F, Simpson AP, Costoya C, Matos I, Qian D, Peggs KS, et al. Fcgamma receptors and immunomodulatory antibodies in cancer. Nat Rev Cancer. 2024;24(1):51-71.