Lethal renal cell carcinoma sub-clones: Defining mechanisms of tumour evolution, treatment resistance and immune escape.
Lead Research Organisation:
The Francis Crick Institute
Department Name: Grants Administration
Abstract
Kidney cancers have doubled in the UK over last 40 years, with >11,000 new cases annually and >4,200 deaths. Despite increased early detection the 5-year survival rates remain poor at 56%, with average survival of only ~18 months for advanced disease. Death is typically caused by disease spread to distal organs in a process called metastasis. While new drugs have been introduced to treat advanced metastatic disease, they are mainly used as palliative treatment options to delay rather than prevent mortality. This is due to drug resistance, which occurs in almost all patients, on average within 9 months. A major factor contributing to drug resistance is the extraordinary diversity found within tumours, caused by a pattern of continuous genetic mutation as the tumour grows. This means a tumour can actually be made up of many sub-tumours (called "subclones"), each of which is different. Treatment typically fails when some but not all of these "subclones" can be destroyed, and the ones left then grow back stronger causing terminal disease (called "lethal subclones").
This research will study how "lethal subclones" grow, how they spread across the body and how they resist drugs. The study will involve 320 kidney cancer patients, starting before drug treatment and will analyse DNA from their primary kidney tumour, which will be physically cut into a series of separate subregions (on average 7 per patient). This allows the different "subclones" to be looked at individually. As disease progresses and/or becomes treatment resistant, additional DNA will be analysed from tumours in other organs (metastases), from blood/urine samples as well as from autopsy tissue. This will allow the "lethal subclones" to be pinpointed, both before and after disease progression/drug resistance. By pinpointing the "lethal sub-clones" and tracking them through the disease course, it is anticipated that their strengths and weaknesses can be identified, generating fundamental biological knowledge to support the development of new treatment options. Another aim of this project is to develop a new cost effective diagnostic test to detect "lethal subclones", meaning high risk patients can be identified upfront and more aggressive treatment plans considered.
In the future a new generation of treatments called "immunotherapies" hold significant clinical promise to tackle "lethal subclones" and increase survival rates for kidney cancer. In other tumour types, such as skin, lung and blood cancers, breakthrough results have already been achieved in the last 5 years. The immune system plays an active role in kidney tumours, with white blood cells (lymphocytes) able to penetrate into the tumour and kill cancer cells. This process can be exploited therapeutically, either by raising the activity level of white blood cells or introducing more of them to attack the tumour. The great benefit of this approach, as compared to traditional drugs, is that the white blood cells are a living treatment that can adapt and keep up with the changing cancer cells. Immunotherapies have been previously tested in advanced kidney cancer patients with mixed results. A modest fraction of patients showed remarkable results (10+ years cancer free) however the majority failed to derive any benefit. The reasons for this are unclear, due to our limited biological understanding of how the immune system operates inside kidney tumours.
The second half of this project will conduct a detailed study of the immune system within kidney tumours. The DNA analysis from above will be complimented by RNA analysis and a technique called "multiplex immunohistochemistry", to map the location and activity of different types of white blood cell. This will be the biggest study of its kind in kidney cancer patients to date and aims to reveal how the immune system behaves in response to kidney cancer, providing insights to support the development of new immunotherapies.
This research will study how "lethal subclones" grow, how they spread across the body and how they resist drugs. The study will involve 320 kidney cancer patients, starting before drug treatment and will analyse DNA from their primary kidney tumour, which will be physically cut into a series of separate subregions (on average 7 per patient). This allows the different "subclones" to be looked at individually. As disease progresses and/or becomes treatment resistant, additional DNA will be analysed from tumours in other organs (metastases), from blood/urine samples as well as from autopsy tissue. This will allow the "lethal subclones" to be pinpointed, both before and after disease progression/drug resistance. By pinpointing the "lethal sub-clones" and tracking them through the disease course, it is anticipated that their strengths and weaknesses can be identified, generating fundamental biological knowledge to support the development of new treatment options. Another aim of this project is to develop a new cost effective diagnostic test to detect "lethal subclones", meaning high risk patients can be identified upfront and more aggressive treatment plans considered.
In the future a new generation of treatments called "immunotherapies" hold significant clinical promise to tackle "lethal subclones" and increase survival rates for kidney cancer. In other tumour types, such as skin, lung and blood cancers, breakthrough results have already been achieved in the last 5 years. The immune system plays an active role in kidney tumours, with white blood cells (lymphocytes) able to penetrate into the tumour and kill cancer cells. This process can be exploited therapeutically, either by raising the activity level of white blood cells or introducing more of them to attack the tumour. The great benefit of this approach, as compared to traditional drugs, is that the white blood cells are a living treatment that can adapt and keep up with the changing cancer cells. Immunotherapies have been previously tested in advanced kidney cancer patients with mixed results. A modest fraction of patients showed remarkable results (10+ years cancer free) however the majority failed to derive any benefit. The reasons for this are unclear, due to our limited biological understanding of how the immune system operates inside kidney tumours.
The second half of this project will conduct a detailed study of the immune system within kidney tumours. The DNA analysis from above will be complimented by RNA analysis and a technique called "multiplex immunohistochemistry", to map the location and activity of different types of white blood cell. This will be the biggest study of its kind in kidney cancer patients to date and aims to reveal how the immune system behaves in response to kidney cancer, providing insights to support the development of new immunotherapies.
Technical Summary
Aim: To study the evolutionary dynamics of clear cell renal cell carcinoma (ccRCC), focusing on the subpopulations of tumour cells (subclones) that evolve to become metastatic, resistant to immune response, treatment resistant and ultimately "lethal".
Objectives:
1) To determine the features of lethal ccRCC sub-clones.
2) To develop novel scalable methods to detect lethal sub-clones.
3) To characterise the immune landscape of ccRCC and the mechanisms of lethal sub-clone immune escape.
4) To investigate the heterogeneity of immune gene expression in ccRCC sub-clones.
Methodology: Patients (n=320) will be recruited through the renal TRACERx study (PI=Prof. C. Swanton) with primary, metastatic & autopsy tumour tissue, together with circulating cfDNA, collected. High-throughput DNA sequencing will be conducted on a multi-region basis, combined with computational image analysis of tumour slides and statistical methods, to identify recurrent features unique to lethal sub-clones. Immunogenic profiling will be conducted using multiplex immunohistochemistry to phenotype tumour-infiltrating lymphocyte sub-types, RNA-seq for expression analysis and bioinformatics techniques combined with experimental validation (tetramer assay) to identify tumour-specific neoantigens. The functional mechanisms of immune gene expression will be investigated using methylation profiling and Capture Hi-C.
Scientific Impact: It is anticipated novel biological mechanisms of ccRCC tumour progression and treatment resistance will be identified. In addition new cost-effective methods, providing detail on tumour clonal architecture, will be piloted. Finally an increased understanding of ccRCC anti-tumour immunity, and how this is impacted by intratumour heterogeneity, is expected.
Medical Impact: i) biomarkers to guide ccRCC treatment, ii) novel diagnostic to identify patients with high tumour diversity, iii) immunogenic insights to support ccRCC immunotherapy development.
Objectives:
1) To determine the features of lethal ccRCC sub-clones.
2) To develop novel scalable methods to detect lethal sub-clones.
3) To characterise the immune landscape of ccRCC and the mechanisms of lethal sub-clone immune escape.
4) To investigate the heterogeneity of immune gene expression in ccRCC sub-clones.
Methodology: Patients (n=320) will be recruited through the renal TRACERx study (PI=Prof. C. Swanton) with primary, metastatic & autopsy tumour tissue, together with circulating cfDNA, collected. High-throughput DNA sequencing will be conducted on a multi-region basis, combined with computational image analysis of tumour slides and statistical methods, to identify recurrent features unique to lethal sub-clones. Immunogenic profiling will be conducted using multiplex immunohistochemistry to phenotype tumour-infiltrating lymphocyte sub-types, RNA-seq for expression analysis and bioinformatics techniques combined with experimental validation (tetramer assay) to identify tumour-specific neoantigens. The functional mechanisms of immune gene expression will be investigated using methylation profiling and Capture Hi-C.
Scientific Impact: It is anticipated novel biological mechanisms of ccRCC tumour progression and treatment resistance will be identified. In addition new cost-effective methods, providing detail on tumour clonal architecture, will be piloted. Finally an increased understanding of ccRCC anti-tumour immunity, and how this is impacted by intratumour heterogeneity, is expected.
Medical Impact: i) biomarkers to guide ccRCC treatment, ii) novel diagnostic to identify patients with high tumour diversity, iii) immunogenic insights to support ccRCC immunotherapy development.
Planned Impact
This project aims to advance our understanding of clear cell renal cell carcinoma (ccRCC) evolution, in particular the mechanisms of tumour progression, metastasis and treatment resistance. The project will go on to profile the immune landscape of ccRCC and its level of intra-tumour heterogeneity. The outputs from this work will impact the following groups:
1) Patients - Greater understanding of the causes of disease progression and treatment resistance offers direct benefit to ccRCC patients, through the discovery of biomarkers to better optimise treatment choice. In terms of new therapies to treat metastatic disease, clinical evidence suggests immunotherapeutic approaches have the most promising potential. Indeed, pre-existing evidence supports this with durable (>10 years) responses to cytokine therapy observed in a modest fraction of treated patients. The majority of ccRCC patients fail to derive benefit however, and the mechanisms underlying this are poorly understood. This project aims to complete the largest immunogenic study of ccRCC patient samples to date, and the biological insights from this could inform the design of future novel treatments. In particular, this dataset is unique, collecting information across multiple tumour regions and time-points, allowing therapies to be designed that can work in all possible tumour conditions. This fellowship will be completed in close collaboration with medical oncologists who actively treat ccRCC patients, meaning results will be translated as rapidly as possible. Clinically useful biomarkers, that can better inform therapeutic choice, may conceivably impact patients in a short-to-medium term timescale. Biological insights to support therapeutic development will impact patients on a medium-to-long term horizon.
2) Private Sector - The data generated in this project will impact the private sector by providing a rich resource to support ccRCC therapeutic development. The benefits realised include an ability to better prioritise therapeutic candidates, which can improve clinical outcomes and/or reduce wasted investment. Several small scale biotechnology companies, together with multi-national Pharmaceuticals, are engaged in ccRCC drug development. The results will be available to all private sector stakeholders through open access journal publications, and will benefit private sector in both the short and long term.
3) Scientists - Novel biological insights generated from this project will be published in open access scientific journals. This will benefit research groups working in a broad range of areas, providing knowledge to help inform future work. New methodologies generated from this project may enable other scientists to achieve more accurate or more efficient results than they can with existing methods. The data generated from this project will be made available as a resource for the scientific community, allowing further research questions to be addressed at no additional cost. The impact of these benefits will be realised within a short-time frame, with results being published and methods/data released as quickly as possible throughout the course of the fellowship.
4) Training - The applicant will benefit from Bioinformatics skills development, which will positively impact them throughout their career. The demand for well-trained informatics experts in cancer research remains strong, and so this training helps address a short supply in these skills.
1) Patients - Greater understanding of the causes of disease progression and treatment resistance offers direct benefit to ccRCC patients, through the discovery of biomarkers to better optimise treatment choice. In terms of new therapies to treat metastatic disease, clinical evidence suggests immunotherapeutic approaches have the most promising potential. Indeed, pre-existing evidence supports this with durable (>10 years) responses to cytokine therapy observed in a modest fraction of treated patients. The majority of ccRCC patients fail to derive benefit however, and the mechanisms underlying this are poorly understood. This project aims to complete the largest immunogenic study of ccRCC patient samples to date, and the biological insights from this could inform the design of future novel treatments. In particular, this dataset is unique, collecting information across multiple tumour regions and time-points, allowing therapies to be designed that can work in all possible tumour conditions. This fellowship will be completed in close collaboration with medical oncologists who actively treat ccRCC patients, meaning results will be translated as rapidly as possible. Clinically useful biomarkers, that can better inform therapeutic choice, may conceivably impact patients in a short-to-medium term timescale. Biological insights to support therapeutic development will impact patients on a medium-to-long term horizon.
2) Private Sector - The data generated in this project will impact the private sector by providing a rich resource to support ccRCC therapeutic development. The benefits realised include an ability to better prioritise therapeutic candidates, which can improve clinical outcomes and/or reduce wasted investment. Several small scale biotechnology companies, together with multi-national Pharmaceuticals, are engaged in ccRCC drug development. The results will be available to all private sector stakeholders through open access journal publications, and will benefit private sector in both the short and long term.
3) Scientists - Novel biological insights generated from this project will be published in open access scientific journals. This will benefit research groups working in a broad range of areas, providing knowledge to help inform future work. New methodologies generated from this project may enable other scientists to achieve more accurate or more efficient results than they can with existing methods. The data generated from this project will be made available as a resource for the scientific community, allowing further research questions to be addressed at no additional cost. The impact of these benefits will be realised within a short-time frame, with results being published and methods/data released as quickly as possible throughout the course of the fellowship.
4) Training - The applicant will benefit from Bioinformatics skills development, which will positively impact them throughout their career. The demand for well-trained informatics experts in cancer research remains strong, and so this training helps address a short supply in these skills.
Organisations
- The Francis Crick Institute (Lead Research Organisation)
- University College London (Collaboration)
- Roche Pharmaceuticals (Collaboration)
- Royal Marsden Hospital (Collaboration)
- Weizmann Institute of Science (Collaboration)
- Institute of Cancer Research (Project Partner)
- University College London (Fellow, Project Partner)
- Royal Marsden NHS Foundation Trust (Project Partner)
People |
ORCID iD |
Kevin Litchfield (Principal Investigator / Fellow) |
Publications
Abbosh C
(2018)
Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.
in Nature
Abbosh C
(2018)
Circulating tumour DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer.
in Annals of oncology : official journal of the European Society for Medical Oncology
Abbosh C
(2020)
Abstract CT023: Phylogenetic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx study
in Cancer Research
AbdulJabbar K
(2020)
Geospatial immune variability illuminates differential evolution of lung adenocarcinoma.
in Nature medicine
Arce Vargas F
(2018)
Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
in Cancer cell
Bailey C
(2021)
Tracking Cancer Evolution through the Disease Course.
in Cancer discovery
Bakhoum S
(2018)
Chromosomal instability drives metastasis through a cytosolic DNA response
in Nature
Barrett JE
(2017)
Quantification of tumour evolution and heterogeneity via Bayesian epiallele detection.
in BMC bioinformatics
Bentham R
(2021)
Using DNA sequencing data to quantify T cell fraction and therapy response.
in Nature
Berenjeno IM
(2017)
Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling.
in Nature communications
Description | The first findings from this award relate to the discovery that one particular type of tumour mutation, called a "frameshift indel", was found to be especially important in relation to how well patients respond to a new class of drugs called immunotherapy. Immunotherapies have led to complete disease regression and improved survival in a subset of cancer patients, notably in those with tumours of the kidney, lung or skin. A challenge that remains is working out which patients will benefit from these drugs. I studied the genetic mutations in detail across 200 melanoma patients, and found that 88% of patients with a high number of "frameshift indels" responded to immunotherapy, compared to only 43% of patients with a low number. The importance of "frameshift indels" is believed to stem from the fact they can cause long strings of altered DNA. Other mutation types (e.g. single nucleotide variation) typically change only a single letter of DNA code - this small scale change can be missed by the patient's immune system. However in the face of tens or hundreds of mutated letters it is the patients' immune system is much more likely to spot these errors and mount a potent immune response, leading to cancer cell destruction. An additional finding in my study was that unexpectedly kidney cancers had the largest number of "frameshift indels", more than either lung or skin cancers, which are typically among the most highly mutated tumours due to tobacco/UV exposure. This may be one of the contributing factors which explains why some kidney cancer patients respond exceptionally well to immunotherapy. |
Exploitation Route | In future research it is hoped "frameshift indels" can be used as part of a predictive diagnostic test, to better select which patients will benefit from immunotherapy. Work is already underway to test the feasibility of this approach. In addition the authors plan to explore whether frameshift indels can used therapeutically, as potent immune targets in tumour cell vacinations or adoptive immune cell-based therapies. |
Sectors | Pharmaceuticals and Medical Biotechnology |
URL | http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30516-8/abstract |
Description | Crick Idea to Innovation (i2i) Fund |
Amount | £70,000 (GBP) |
Funding ID | Project - 10646 |
Organisation | Francis Crick Institute |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2017 |
End | 08/2018 |
Description | Exploring cancer mutations as a preventative vaccination target, in individuals with high cancer risk from environmental exposure |
Amount | £237,000 (GBP) |
Funding ID | A2347 |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 02/2023 |
Description | Immune dysfunction as a biomarker for the early detection of lung cancer development and relapse |
Amount | £100,000 (GBP) |
Funding ID | C69256/A30194 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2021 |
Description | Investigating melanoma metastases |
Amount | £680,357 (GBP) |
Funding ID | Unknown |
Organisation | Melanoma Research Alliance |
Sector | Charity/Non Profit |
Country | United States |
Start | 01/2021 |
End | 12/2023 |
Description | Next generation IO targets |
Amount | £260,628 (GBP) |
Organisation | Cancer Research Technology (CRT) |
Sector | Private |
Country | United Kingdom |
Start | 11/2020 |
End | 12/2021 |
Title | Representative-Sequencing dataset |
Description | While thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g. 6mm-biopsy), which becomes grossly under-powered as tumor volume scales. Here we demonstrate Representative-Sequencing (Rep-Seq), as a new method to achieve unbiased tumor tissue sampling. Rep-Seq utilizes fixed residual tumor material, which is homogenized and subject to next generation sequencing. Analysis of intra-tumor tumor mutation burden (TMB) variability shows a high level of misclassification with current single biopsy methods, with 20% of lung, and 52% of bladder tumors, having =1 biopsy with high-TMB, but low clonal-TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | This data offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility. |
URL | https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3404257 |
Title | TRACERx Renal 100 Sequencing Dataset |
Description | Tumour sequencing data from 1209 primary tumour regions, from 101 patients, was generated as part of this grant, and this data has been deposited to the European Genome phenome Archive (EGAS00001002793) |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | The results from this research were published in Cell. |
URL | https://ega-archive.org/studies/EGAS00001002793 |
Description | Early detection collaboration with Dr Richard Lee |
Organisation | Royal Marsden Hospital |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | Myself and Dr Lee have recently jointly been awarded a CRUK Early Detection Primer Award, to investigate immune dysfunction as a biomarker for tumour development and progression. |
Collaborator Contribution | Dr Richard Lee - Consultant physician in respiratory medicine and champion for early cancer diagnosis at the Royal Marsden Hospital. Dr Lee is an expert clinician in respiratory medicine and early diagnosis of lung cancer. Dr Lee leads on the early diagnosis strategy at the Royal Marsden Hospital, and is developing an innovative range of clinical services and trials to support increased rates of lung cancer early detection including his role as joint clinical lead for the NHS England national lung cancer screening pilot. Within this project Dr Lee will lead the set-up and recruitment efforts to develop a new cohort of pre/non-malignant samples from patients undergoing longitudinal management for pulmonary nodules. |
Impact | Myself and Dr Lee have recently jointly been awarded a CRUK Early Detection Primer Award, to investigate immune dysfunction as a biomarker for tumour development and progression. |
Start Year | 2019 |
Description | Immunology collaboration with Dr Sergio Quezada |
Organisation | University College London |
Department | UCL Cancer Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is an academic collaboration with Dr Sergio Quezada, world expert in anti-tumour immunology. I have conducted bioinformatic analysis, related to Fc-gamma receptor (FCGR) function, and the influence of human germline FCGR polymorphisms in melanoma patient response to immunotherapy. |
Collaborator Contribution | Laboratory work related to Fc-gamma receptor (FCGR) function, and other tumor immunology projects. |
Impact | Paper accepted with Cancer Cell, titled: "Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies". |
Start Year | 2017 |
Description | Immunopeptidomics collaboration with Prof. Yardena Samuels |
Organisation | Weizmann Institute of Science |
Department | Laboratory of Body and Mind Immunology Weizmann |
Country | Israel |
Sector | Academic/University |
PI Contribution | A collaboration has been initiated with Prof. Yardena Samuels at the Weizmann Institute in Israel. Through this collaboration I will be trained in a new technique called immunopeptidomics, a state of the art method for neoantigen identification. I will be spending a month in Israel in May-2019 training in the method. I am contributing tumour tissue samples from the TRACERx study. |
Collaborator Contribution | A collaboration has been initiated with Prof. Yardena Samuels at the Weizmann Institute in Israel. Through this collaboration I will be trained in a new technique called immunopeptidomics, a state of the art method for neoantigen identification. I will be spending a month in Israel in May-2019 training in the method. Weizmann is contributing methodological knowledge and expertise. |
Impact | Training skills will be the output, delivered in 2019 |
Start Year | 2018 |
Description | Representative Sequencing Project |
Organisation | Roche Pharmaceuticals |
Country | Global |
Sector | Private |
PI Contribution | I have worked collaboratively with Roche/Ventana to develop a novel tumour sequencing approach called "Representative Sequencing". My contribution has been to perform bioinformatic analysis, and importantly give scientific input/direction to the project. |
Collaborator Contribution | Roche/Ventana have performed the laboratory experiments, and sequencing work. |
Impact | I presented an oral conference presentation at the annual 2018 Tucson Symposium related to this project. |
Start Year | 2017 |
Title | Frameshift indels as a therapeutic target |
Description | The technology is based on recent research findings arising from my fellowship, centred on the role of frameshift-insertion/deletion mutations (fs-indels) in tumour immunogenicity (1). The technology represents a therapeutic method that targets fs-indel derived neoantigens, as a cancer immunotherapy treatment. This technology is based contained in (1), which imply targeting fs-indel neoantigens specifically as opposed to single-nucleotide variant (SNV) derived neoantigens will give rise to superior efficacy. 1) Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, Wong YNS, Rowan A, Kanu N, Al Bakir M, Chambers T, Salgado R, Savas P, Loi S, Birkbak NJ, Sansregret L, Gore M, Larkin J, Quezada SA, Swanton C. Lancet Oncol. 2017 Aug;18(8):1009-1021. doi: 10.1016/S1470-2045(17)30516-8. Epub 2017 Jul 7. |
IP Reference | P112425GB |
Protection | Patent granted |
Year Protection Granted | 2017 |
Licensed | No |
Impact | A company called Achilles Therapeutics has requested a license to the patent - negotiations with the Francis Crick Institute commercial team are underway. |
Title | Frameshift indels as a treatment biomarker |
Description | The technology is based on recent research findings arising from my fellowship, centred on the role of frameshift-insertion/deletion mutations (fs-indels) in tumour immunogenicity and checkpoint inhibitor (CPI) response (1). The technology represents a predictive test/biomarker that uses the number (or fraction) of fs-indels within a tumour to predict response rates to CPIs such as ipilimumab, nivolumab and pembrolizumab, wherein a high number fs-indels compared to a reference sample indicates increased chance of drug response. 1) Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, Wong YNS, Rowan A, Kanu N, Al Bakir M, Chambers T, Salgado R, Savas P, Loi S, Birkbak NJ, Sansregret L, Gore M, Larkin J, Quezada SA, Swanton C. Lancet Oncol. 2017 Aug;18(8):1009-1021. doi: 10.1016/S1470-2045(17)30516-8. Epub 2017 Jul 7. |
IP Reference | P112332GB |
Protection | Patent granted |
Year Protection Granted | 2017 |
Licensed | No |
Impact | The Crick translation team are exploring licensing opportunities, in discussion with pharmaceutical/diagnostic companies. |
Title | Molecular profiling as a clinical decision aid for patients with clear cell Renal Cell Carcinoma (ccRCC) |
Description | A new method to stratify patients for surgery or drug treatment, based on an evolutionary classification system using tumour sequencing data. |
IP Reference | P113326GB |
Protection | Patent granted |
Year Protection Granted | 2018 |
Licensed | No |
Impact | This invention has potential to help optimise patient treatment, leading to improved clinical outcome. |
Title | Representative diagnostics |
Description | The disclosure generally relates to the preparation of representative samples from clinical samples, e.g., tumors (whole or in part), lymph nodes, metastases, cysts, polyps, or a combination or portion thereof, using mechanical and/or biochemical dissociation methods to homogenize intact samples or large portions thereof. The resulting homogenate provides the ability to obtain a correct representative sample despite spatial heterogeneity within the sample, increasing detection likelihood of low prevalence subclones, and is suitable for use in various diagnostic assays as well as the production of therapeutics, especially "personalized" anti-tumor vaccines or immune cell based therapies. |
IP Reference | AU2016349644 |
Protection | Patent granted |
Year Protection Granted | 2018 |
Licensed | Yes |
Impact | The method has potential to make a more sensitive tracking panel, to identify at an earlier time point when a patient's tumour has returned. This time benefit may allow additional treatment options to be available. |
Description | CRUK Research Fundraisers Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | I gave a lay talk to ~100 CRUK fundraising staff, who lead CRUK's work engaging with individual high profile donors. I presented an overview of the principles of tumour evolution, and an update on work from the TRACERx study. |
Year(s) Of Engagement Activity | 2017 |
Description | Lay fundraising talk for CRUK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | I was the keynote speaker at an annual CRUK fundraising luncheon event |
Year(s) Of Engagement Activity | 2022 |
Description | Talk at University College London Hospital Clinical Trials Unit team building day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | ~150 clinical trial unit team members attended my talk, and were highly engaged and interested in the content. Several members followed up to find out more information. |
Year(s) Of Engagement Activity | 2019 |
Description | Talk to national team of research nurses |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | I gave a 30 minute lay talk to a national team of CRUK Nurses, explaining principles of kidney cancer evolution and the transnational benefits from this research. |
Year(s) Of Engagement Activity | 2019 |