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Transcript
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 nonsmall 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 coactivatory) 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 PD1 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]