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Development of immune therapy combinations in urology cancers

This project focuses on the window of opportunity studies in renal and bladder cancer. It will be performed within the immune oncology group at Barts Cancer Institute (BCI).

Applications are now closed for the 2019 postgraduate training programme.

  • Primary Supervisor: Prof Thomas Powles, Centre for Experimental Cancer Medicine, Barts Cancer Institute, QMUL
  • Secondary Supervisor: Dr Axel Bex, UCL

Funding note: Non-EU candidates are not eligible to apply 

Project

Clinical work will include time at the Renal Cancer Center at the Royal Free Hospital. The immune oncology groups at BCI have a successful track record in these window of opportunity studies over the years (NCT02662309, NCT01512186) as well as an excellent track record of developing immune therapies and biomarkers with publications in leading high impact journals. The group currently consists of three clinical fellows, 4 research nurses as well as data-managers. The group has internal and external collaborations (Histogenex, NKI and Genentech). It also has dedicated training and education program. The Renal Cancer Centre at the Royal Free Hospital has a dedicated research team and is the highest volume renal cancer center in the EU. 

Patients with potentially operable tumors will have a period of immune therapy prior to surgery. The studies have clinical and translational endpoints. Clinical endpoints focus on response which translational endpoints have focused on analysis for protein, DNA and RNA analysis. 

The most recent example of this format of trial is the ABACUS trial (atezolizumab prior to cystectomy in operable bladder cancer). Clinical results were impressive, also data showed increased stromal and fibroblast signatures associated with resistance and changes to T effector signatures associated with response (IHC and RNAseq). This work has been submitted to a high impact factor journal. Ongoing work, which will from part of this project includes analysis of circulating tumor free DNA and analysis of mutational analysis on the sequential tissue (Foundation One analysis).  The molecular analysis of this existing tissue will make up the first part of this clinical fellowship.  

Window of opportunity studies are a good platform for drug development. The plan for this project is to have a prominent role in the development of a 2nd generation of drugs in this setting.

Bladder cancer studies:
Patients: T2a-T4b N0 M0 TCC due for cystectomy. Drug combination: Durvalumab and tremilimumab. This combination will be explored in 50 patients. Initial analysis will occur after the first 20 patients. This will include the molecular analysis (RNAseq and DNA whole exome sequencing).

Upper tract Transitional Cell Carcinoma:  
Patients: T2a-T4b N0 M0 TCC due for nephrectomy. Drug: single agent atezolizumab. Sequential tissue has not yet been collected in this population before and after immune checkpoint inhibitors. This study will start in Mar 2019 and tissue will be ready for analysis in Q3 2019. RNAseq, IHC (CD8,CD4,CD39, GZMB, FAP, TGFb will be explored).

Renal cancer:
Patients: T2a-T4b N0 M0 TCC due for cystectomy. Drug combination: Durvalumab and tremilimumab. This combination will be explored in 50 patients. Initial analysis will occur after the first 20 patients. This will include the molecular analysis. The clinical fellow will also participate in other clinical aspects of the research program including prospective and retrospective data analysis within the immune oncology group. The fellowship is designed to give the successful candidate detailed training in translational science with a focus on the latest immune therapies. 

Potential research placements

  1. Good clinical practice
  2. Bioinformatics
  3. computational biopsy

References

  1. McDermott DF et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018; Jun;24(6):749-757.
  2. Mariathasan S, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; Feb 22;554(7693):544-548.
  3. Powles T et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018; Feb 24;391(10122):748-757.
  4. Rini B et al. Pembrolizumab plus Axitinib vs. Sunitinib for Advanced Renal-Cell Carcinoma. NEJM (in press Jan 2019).