Immune-checkpoint therapy in non-small cell lung carcinoma:molecular characterisation of tumour microenvironment to improve anti-PD1/PD-L1 drug class.
Lead Research Organisation:
University of Liverpool
Department Name: Institute of Translational Medicine
Abstract
Lung cancer kills more people worldwide than any other cancer and has already spread in most patients at diagnosis, for whom chemotherapy of limited effectiveness has been the only treatment available. Fortunately, a new class of 'immune modulating drugs' has been recently developed. These work by removing the defences the tumour develops to protect it from the body's normal immune system, exposing it to attack by the body's immune cells.
The only means currently to predict whether these drugs will work is to assess the amount of a protein called PD-L1 on the tumour cells. Unfortunately, this particular 'biomarker' lacks accuracy; some patients who should respond do not and some patients who have little/no PD-L1 would probably respond but are missing out on this treatment.
Our study will examine why PD-L1 lacks precision by looking at how it varies between different parts of the tumour and areas of tumour spread, how it relates to inflammation and genetic mutations, and how all of these inter-relate. Ultimately, we wish to improve the accuracy of determining whether an individual patient with lung cancer will respond to these drugs, so that the most beneficial treatment can be given in an efficient and cost-effective manner.
The only means currently to predict whether these drugs will work is to assess the amount of a protein called PD-L1 on the tumour cells. Unfortunately, this particular 'biomarker' lacks accuracy; some patients who should respond do not and some patients who have little/no PD-L1 would probably respond but are missing out on this treatment.
Our study will examine why PD-L1 lacks precision by looking at how it varies between different parts of the tumour and areas of tumour spread, how it relates to inflammation and genetic mutations, and how all of these inter-relate. Ultimately, we wish to improve the accuracy of determining whether an individual patient with lung cancer will respond to these drugs, so that the most beneficial treatment can be given in an efficient and cost-effective manner.
Technical Summary
PLAN OF INVESTIGATION
Phase 1
Archived, formalin-fixed, paraffin wax-embedded (FFPE) tissue blocks are available from 651 resected specimens of NSCLC and are consented for research purposes. Of these, 156 have accompanying, involved, regional (intrathoracic) lymph nodes. Standard immunohistochemical analysis will determine the expression levels and heterogeneity of PD-L1 in tumour and immune cells and the nature of the immune cell populations within the tumour. The presence of EGFR gene mutations and ALK gene rearrangement will be determined where not known.
Phase 2
There are various options locally available for analysis of extracted genetic material. This field is constantly updating in techniques and panels of genes to be targeted. However the use of cutting-edge technology such as NGS-panels, Nanostring and MassArray has been ascertained as feasible with this tissue by discussing with the respective teams and companies. The specific panels may update to reflect the changing environment, but these can be used to assess TMB, immune profiling, actionable mutations and so on. Validation of techniques, including the minimum amount of genetic material required for sufficient analysis, will be performed and can be combined with approaches for minimal sampling, including laser-capture microscopy (LCM) and needle core biopsy.
Phase 3
This phase will mostly concentrate on working with Eli Lilly (see part B3b) and local oncologists for access to tissue samples after immune checkpoint therapy. Patients who fail immune checkpoint therapy are the primary group of interest and both post-therapy and archival tissue can be assessed for inherent and de novo resistance.
Phase 1
Archived, formalin-fixed, paraffin wax-embedded (FFPE) tissue blocks are available from 651 resected specimens of NSCLC and are consented for research purposes. Of these, 156 have accompanying, involved, regional (intrathoracic) lymph nodes. Standard immunohistochemical analysis will determine the expression levels and heterogeneity of PD-L1 in tumour and immune cells and the nature of the immune cell populations within the tumour. The presence of EGFR gene mutations and ALK gene rearrangement will be determined where not known.
Phase 2
There are various options locally available for analysis of extracted genetic material. This field is constantly updating in techniques and panels of genes to be targeted. However the use of cutting-edge technology such as NGS-panels, Nanostring and MassArray has been ascertained as feasible with this tissue by discussing with the respective teams and companies. The specific panels may update to reflect the changing environment, but these can be used to assess TMB, immune profiling, actionable mutations and so on. Validation of techniques, including the minimum amount of genetic material required for sufficient analysis, will be performed and can be combined with approaches for minimal sampling, including laser-capture microscopy (LCM) and needle core biopsy.
Phase 3
This phase will mostly concentrate on working with Eli Lilly (see part B3b) and local oncologists for access to tissue samples after immune checkpoint therapy. Patients who fail immune checkpoint therapy are the primary group of interest and both post-therapy and archival tissue can be assessed for inherent and de novo resistance.
Publications
Elwin F
(2020)
PD-L1 expression in non-small cell lung cancer according to specimen type; a retrospective study of over 2,000 cases
in Lung Cancer
Gosney J
(2018)
Problem solving in Cancer immunotherapy
Gosney J
(2018)
ESMO handbook of Immuno-Oncology
Gosney J.
(2018)
PD-L1 Expression in EBUS-Guided Cytology Specimens of Non-Small Cell Lung Cancer is Not Affected by Type of Fixation: A Study of Matched Pairs
in JOURNAL OF THORACIC ONCOLOGY
Gosney JR
(2020)
Programmed death ligand 1 expression in EBUS aspirates of non-small cell lung cancer: Is interpretation affected by type of fixation?
in Cancer cytopathology
Haragan A
(2019)
Heterogeneity of PD-L1 expression in non-small cell lung cancer: Implications for specimen sampling in predicting treatment response.
in Lung cancer (Amsterdam, Netherlands)
Haragan A
(2019)
PD-L1 expression in resected non-small cell lung cancer: variation between primary tumour and nodal metastases
in Lung Cancer
Haragan A
(2019)
Biomarkers in NSCLC: a pathologist's insight into PD-L1 and TMB
Haragan A
(2020)
High expression of PD-L1 by pulmonary adenocarcinoma metastatic to body cavities; artefact or biology?
in Lung Cancer
Haragan A
(2018)
P1.04-24 Digital Core Needle-Biopsy to Assess PD-L1 Expression in Non-Small Cell Lung Cancer: Optimal Sampling and Need for Re-Biopsy
in Journal of Thoracic Oncology
Haragan A
(2020)
Accelerated instability testing reveals quantitative mass spectrometry overcomes specimen storage limitations associated with PD-L1 immunohistochemistry.
in Laboratory investigation; a journal of technical methods and pathology
Haragan A
(2019)
DLL3, a new biomarker for neuroendocrine tumors of the lung
Haragan A.
(2018)
Digital Core Needle-Biopsy to Assess PD-L1 Expression in Non-Small Cell Lung Cancer: Optimal Sampling and Need for Re-Biopsy
in JOURNAL OF THORACIC ONCOLOGY
Haragan A.
(2018)
Utilising Heterogeneity: Using a Digital Database of Lung Cancers and Immune Profile to Complement Subjective Assessment
in JOURNAL OF THORACIC ONCOLOGY
Haragan A.
(2019)
PD-L1 expression in resected non-small cell lung cancer: variation between primary tumour and nodal metastases
in LUNG CANCER
Haragan A.
(2021)
High Concordance in Scoring PD-L1 in NSCLC Using the Roche Digital Pathology uPath system and PD-L1 Assessment Algorithm
in JOURNAL OF THORACIC ONCOLOGY
Haragan A.
(2021)
Deep Learning Based Analysis of Multiplex IHC Accurately Interprets PD-L1 and Provides Prognostic Information in NSCLC
in JOURNAL OF THORACIC ONCOLOGY
Haragan A. K.
(2019)
PD-L1 Expression Heterogeneity in NSCLC: Accuracy and Reliability of Using Primary Lung Tumour Versus Metastatic Lymph Node Deposits
in JOURNAL OF PATHOLOGY
Kapil A
(2021)
Domain Adaptation-Based Deep Learning for Automated Tumor Cell (TC) Scoring and Survival Analysis on PD-L1 Stained Tissue Images.
in IEEE transactions on medical imaging
Liebler DC
(2020)
Analysis of Immune Checkpoint Drug Targets and Tumor Proteotypes in Non-Small Cell Lung Cancer.
in Scientific reports
Rognoni Lorenz
(2019)
Combining the best of two worlds: Transfer of multiplex immunofluorescence images from non-small cell lung carcinoma patients into pseudo multiplex chromogenic immunohistochemistry images
in JOURNAL FOR IMMUNOTHERAPY OF CANCER
Sastre Ana Hidalgo
(2019)
Looking beyond the assay: Comparison of multiplex chromogenic and fluorescent immunohistochemistry for standardized immune oncology profiling in non-small cell lung carcinoma patients
in JOURNAL FOR IMMUNOTHERAPY OF CANCER
| Description | Expert Panel Meeting for UK NEQAS PD-L1 Scheme |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | UK NEQAS is a national voluntary scheme that pathology departments and laboratories across the UK sign up to for quality assurance matters. I have twice sat on the panel as an expert at interpretation of PD-L1 (programmed death-ligand 1) immunohistochemistry to assess the quality of laboratories staining, antibody retrieval for use as a clinically diagnostic tool, and their material as chosen to represent controls for the same. This information is fedback to each laboratory with advice as to how they might improve in an effort to standardise, as far as possible, the PD-L1 reporting quality across the UK, and ensure a minimum quality is reached by every involved diagnostic lab. |
| URL | https://ukneqas.org.uk |
| Description | Expert Panel Meeting for UK NEQAS PD-L1 Scheme |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | Ongoing member of Expert Panel for PD-L1 immunohistochemistry as part of UKNEQAS. |
| Description | Expert Panel Meeting for UK NEQAS PD-L1 Scheme |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | NEQAS (National external quality assurance scheme) is the national UK body in ensuring the highest standards of technical proficiency for various medical diagnostic and clinical tests. Participation in this scheme was for technical quality assurance of PD-L1 testing and feedback helps maintain consistency for testing across labs in the UK |
| URL | https://www.ukneqasiccish.org/pd-l1-pilot-methodology-data-entry/ |
| Description | Lecturing at Molecular Diagnostics School, Vienna, Austria 2019 |
| Geographic Reach | National |
| Policy Influence Type | Influenced training of practitioners or researchers |
| Impact | Lecturing to professional medical practitioners and pathologists for molecular diagnostics in immuno-oncology with practical guidance on how to perform adequate testing in the routine clinical setting. |
| URL | https://www.personalized-medicine.at/die-oeppm/news/detail/molecular-diagnostics-training-school-ima... |
| Description | Lecturing at Molecular Diagnostics Training School, Vienna, Austria, 2020. |
| Geographic Reach | National |
| Policy Influence Type | Influenced training of practitioners or researchers |
| Impact | Lecturing to professional medical practitioners and pathologists for molecular diagnostics in immuno-oncology with practical guidance on how to perform adequate testing in the routine clinical setting. |
| URL | https://www.meduniwien.ac.at/hp/pathologie/news/singleview/?tx_ttnews%5Btt_news%5D=5111&cHash=a3b9cd... |
| Description | Membership of Scientific Advisory Board (UKNEQAS) |
| Geographic Reach | Europe |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | The scientific advisory board (SAB) for UKNEQAS is a newly formed group with reviews the practices, findings and approaches for the international EQA scheme for immunohistochemistry. Outcomes are so far limited, but immediate impact and feedback on the way in which the UKNEQAS groups the panels of tests, and the increased drive for academic output has already been implemented. |
| Description | Presentation and Q&A session at Diagnostics Summit (AZ funded) |
| Geographic Reach | National |
| Policy Influence Type | Influenced training of practitioners or researchers |
| Impact | Talk and Q&A session with medical professionals (largely pathologists) on the practical considerations on how to use and manage bio-specimens for effective use in predictive immunohistochemistry immune-landscape profiling with PD-L1 expression. |
| Description | BTOG Scholarship Bursary |
| Amount | £300 (GBP) |
| Organisation | British Thoracic Oncology Group |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2019 |
| End | 01/2019 |
| Description | MRC Flexible Supplement Grant |
| Amount | £2,430 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2018 |
| End | 12/2018 |
| Description | Wellcome trust strategic support funds |
| Amount | £15,000 (GBP) |
| Funding ID | 163504 |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2020 |
| End | 12/2020 |
| Description | Definiens |
| Organisation | Definiens AG |
| Country | Germany |
| Sector | Private |
| PI Contribution | Definiens are an image analysis (https://www.definiens.com/io-panel) company who offer a comprehensive immuno-oncology panel with automated machine learning digital analysis with online platform for access to results. My research has provided 100 images of cases of resected non-small cell lung carcinoma (NSCLC) primary sections of tumour stained with SP263 clone for PD-L1 allowing them to refine their automated processes of PD-L1 detection with "real" cases. In addition I have provided up to 5 sections of unstained tissue from each of these cases for use with their immuno-oncology panel and image analysis, the results of which are shared for both this research team and their industry. At least one publication and presentation of results is agreed within a year. |
| Collaborator Contribution | Definiens have provided a substantial discount of the cost of the multi-plex immunohistochemical staining for their propriety immuno-oncology panel and digital image analysis, as well as ongoing access to their portal for results. The outcomes and interpretation of the sections are included in the cost (upfront commercial cost of project would be in excess of 100k, we have agreed a price of 15k) |
| Impact | Collaboration is ongoing. Publication and presentation of findings at conferences is anticipated, at a minimum. |
| Start Year | 2018 |
| Description | Eli |
| Organisation | Protypia |
| Country | United States |
| Sector | Private |
| PI Contribution | Ongoing collaboration with Protypia in which we have devised a project that will look at the proteomic landscape of the tumour microenvironment in non-small cell lung cancer (NSCLC). Specifics are under a NDA at present. |
| Collaborator Contribution | Protypia provide the mass-spectrometry and analysis of the results. Specifics are under a NDA at present. |
| Impact | Work is in early phases, but a publication is expected at a minimum. |
| Start Year | 2019 |
| Description | MRC Festival of Science "Ask a Scientist"/"Im a Scientist, Get me Out of Here) |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | Throughout the month of June participated in an online series of questions and live chat sessions that allowed school children from around the country to ask a variety of questions to scientists and to discuss matters of varying topics. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://mrcfestival2018.imascientist.org.uk |
| Description | Manchester Science Spectacular |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | This science spectacular is a public engagement event (PE) that involved creating a stand aimed at school-age children to explain our area of work - with a focus on immunotherapies and cancer research. Our bright and interactive stand involved a variety of challenges and quizzes that engaged children and parents and informed them as to the relevance and impact of research in our area. Physicals tasks and challenges for the children inspired critical thinking and the parents and carers were also very active in asking questions and understanding the relevance of our work to the wider community and healthcare environment. |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.engagement.manchester.ac.uk/highlights/manchester_science_festival/science_spectacular/ |
| Description | NWCRC Seminar Series |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Other audiences |
| Results and Impact | A talk as part of the North West Cancer Research Centre (NWCRC) seminar series entitled ""Immunotherapy in cancer treatment - current successes and future perspectives" This reached local and regional students, academics, researchers and medical professionals. Much debate was generated./ |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.liverpool.ac.uk/nwcrc/events/ |
| Description | Pint of Science |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Pint of Science is a non-profit organisation that brings scientists to local pubs to discuss their latest research and findings with you. I was one of 3 speakers talking in the broader theme of "Our Body" and talked with an audience of varied and wide background of the specifics of my project and how immunotherapy changes and is changing medical and oncological care, and how my project and these related schemes are actively benefiting the wider public and improving this care. After my 25 minute presentation on the talk I took a Q&A session and over the rest of the evening fielded more questions from interested attendees. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://pintofscience.co.uk |
| Description | Pint of Science 2019 host |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | In addition to hosting the night for a Pint of Science 2019 event hosted in Liverpool, I was invited to attend a BBC Radio Merseyside interview to explain the reason for this event and to illustrate the benefits of the ongoing research. |
| Year(s) Of Engagement Activity | 2019 |