Francis Crick Institute Crick Cancer Clinical Research Fellow Programme Three-Year Clinical Research Training Fellowships 2016
Names of project supervisors Crick supervisor: Charles Swanton CRUK Centre/University supervisor: Sergio Quezada (UCL)
Title of research project
Elucidating and Manipulation of Immune modulatory checkpoints in T Cells Recognising Tumour Neoantigens
Description of the research project: Tumour heterogeneity results in a challenge to precision cancer medicine. Intratumour heterogeneity contributes to drug resistance and therapeutic failure. Targeting clonally dominant somatic events present in every tumour cell holds promise to maximize therapeutic response and minimize risks of therapeutic failure. Modulation of the immune system through antibody-mediated blockade of immune checkpoints such as cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1), or programmed cell death ligand-1 (PD-L1), results in significant clinical benefit in a variety of cancers, including NSCLC (1-3). Moreover, T-cell responses elicited towards neoantigens have been demonstrated (2, 4-5), and a relationship between tumor neoantigens, immune activation and improved prognosis has been documented. However, the impact of tumour genetic heterogeneity, resulting in clonal and subclonal tumour neoantigens, on tumour immunosurveillance and response to cancer immunotherapies has not been explored.
The Swanton and Quezada laboratories have recently found evidence for the presence of CD8+ T cells recognising clonal tumour neo-antigens present in every tumour cell in non- small cell lung cancer (McGranahan, Furness, Rosenthal, Quezada and Swanton submitted to Science). We have demonstrated that the clonal architecture of the tumor affects the response to immunotherapeutic modulation and survival outcome in non-small cell lung cancer. Through single cell based phenotyping and parallel informatics approaches, we have confirmed that T cells recognising clonal neoantigens in NSCLC patients express a unique repertoire of immune checkpoint inhibitory proteins. In this project the clinical fellow will work on TRACERx samples in renal, melanoma and non-small cell lung cancer to 1) Define the breath of T cell reactivity against clonal and subclonal tumour neoantigens. 2) Characterise the expression of immunomodulatory receptors (co-inhibitory and co- activatory) on neo-antigen reactive T cells. 3) Use patient derived xenografts (PDX) and autologous TILs from TRACERx patients to compare the in vivo anti-tumour activity of neoantigen reactive T cells targeting clonal and non-clonal mutations. 4) Use the same model described in (3) and genome editing technologies (CRISPR and RNA interference technologies) to define the most relevant immune-modulatory checkpoints restricting the anti-tumour activity of neoantigen reactive T cells in vivo.
Through these techniques the candidate will develop broad insight into how such potent cytotoxic T cells, recognising tumour neo-antigens, are regulated in vivo and how this detailed genomic and phenotypic information can be used to leverage the next generation of cellular therapies for patients suffering from advanced metastatic disease.
References:
1. P. Sharma, J. P. Allison, The future of immune checkpoint therapy. Science (New York, N.Y 348, 56-61 (2015). 2. N. A. Rizvi et al., Cancer immunology. Mutational landscape determines sensitivity to PD- 1 blockade in non-small cell lung cancer. Science (New York, N.Y 348, 124-128 (2015). 3. S. L. Topalian et al., Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of medicine 366, 2443-2454 (2012). 4. J. C. Castle et al., Exploiting the mutanome for tumor vaccination. Cancer research 72, 1081-1091 (2012). 5. E. Tran et al., Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science (New York, N.Y 344, 641-645 (2014).
Summarise the medical/clinical component of the research, as well as the relevance to the Crick Cancer CRF programme:
Adoptive cellular therapies, tumour immunology and cancer heterogeneity are currently the most important and relevant research areas in the medical oncology curriculum. Despite this, formal training in these emerging areas of basic scientific research with direct patient impact remains lacking. This translational PhD will provide the successful candidate with in depth experience working in a multidisciplinary team within the cancer evolution laboratory at the Translational Cancer Therapeutics Laboratory at the Francis Crick Institute and more widely in the TRACERx program within the United Kingdom, collaborating closely with basic laboratory scientists, clinical trialists and bioinformaticians. The Quezada laboratory provides in depth knowledge and experience in immune regulation, cancer immunology and interrogation of the tumour microenvironment. In addition they provide state-of-the art access to immunophenotyping, single cell analytical techniques together with animal models to decipher the host immune response to cancer neoantigens. Both Quezada and Swanton are lead PI’s on the recent £5 million CRUK UCL Cancer Immunotherapy Accelerator award which will provide access to longitudinal immunophenotyping technologies for the TRACERx program. The PhD will focus on the basic mechanisms of T cell activation and inhibition within the context of tumour genetic heterogeneity and ultimately use this knowledge to translate these findings for clinical benefit.
Project supervisors’ contact details:
Crick supervisor: Name: Charles Swanton MBPhD FRCP Telephone: 07956 445302 Email: [email protected]
CRUK Centre / University supervisor: Name: Sergio Quezada Telephone: 020 7679 0743 Email: [email protected]