MSCTRAIL for lung cancer
Lead Research Organisation:
University College London
Department Name: Medicine
Abstract
Worldwide, cancer remains one of the leading causes of mortality and morbidity. The mainstay of cancer therapy includes treatment with surgery, chemotherapy and radiotherapy; however, despite improvements in these treatments, many tumours do not respond. Importantly, once a cancer has spread to more than one site (metastasised) it is, in all but the rarest cases, incurable. Of the common cancers lung cancers are a particular problem to treat.
Lung cancer accounts for 34,000 deaths in the UK alone and is the biggest cancer killer of both men and women. In 85% of cases, patients with lung cancer present to their doctor with disease that has already spread. These patients have an average survival of 8 months. Current therapies used to treat lung cancers that have spread include chemotherapy, a treatment delivered into a vein. Chemotherapy is not targeted to the cancer in any way and therefore treats the whole body, not just the cancer, resulting in widespread toxicity from the treatment. Disappointingly only around 40% of patients will show any sign of their cancer responding to these therapies, and life expectancy, even in the lucky ones, is improved by a handful of months only. More recent discoveries have led to targeting of genetic defects in tumours. These defects unfortunately occur in less than 10% of a single subgroup of lung cancers (adenocarcinomas) and even these patients stop responding to treatment after around 9 months.
One of the many challenges of cancer treatment relates to the delivery of the anti-cancer therapy to the cancer site. We, and others, have recently shown that bone marrow-derived stem cells (BMSCs) are able to migrate specifically to and incorporate within tumours after being delivered into a vein, and this property can be used to deliver 'targeted' anticancer therapies. Using these cells to deliver various anti-cancer molecules, intravenously delivered MSCs have been shown preferentially to move towards and survive in cancer tissue in breast, lung, and melanoma lung metastases, Kaposi's sarcoma (KS), colorectal cancer and gliomas.
In this research, a novel treatment for metastatic lung cancer will be investigated by giving a new treatment (called MSCTRAIL), which consists of cells (MSCs) carrying an anti-cancer gene (TRAIL), injected into lung cancer patients a day after they have chemotherapy. The first part of the research will be a phase I clinical trial aiming to find the safest dose which will benefit a lung cancer patient. The second part of the research will be a phase II clinical trial which will compare what effect MSCTRAIL has when given with chemotherapy compared to chemotherapy alone. We will do this by measuring how much the tumour has become smaller and also whether patients live longer. If successful, this novel cell and gene therapy treatment will then be tested in a larger (phase III) clinical trial.
Lung cancer accounts for 34,000 deaths in the UK alone and is the biggest cancer killer of both men and women. In 85% of cases, patients with lung cancer present to their doctor with disease that has already spread. These patients have an average survival of 8 months. Current therapies used to treat lung cancers that have spread include chemotherapy, a treatment delivered into a vein. Chemotherapy is not targeted to the cancer in any way and therefore treats the whole body, not just the cancer, resulting in widespread toxicity from the treatment. Disappointingly only around 40% of patients will show any sign of their cancer responding to these therapies, and life expectancy, even in the lucky ones, is improved by a handful of months only. More recent discoveries have led to targeting of genetic defects in tumours. These defects unfortunately occur in less than 10% of a single subgroup of lung cancers (adenocarcinomas) and even these patients stop responding to treatment after around 9 months.
One of the many challenges of cancer treatment relates to the delivery of the anti-cancer therapy to the cancer site. We, and others, have recently shown that bone marrow-derived stem cells (BMSCs) are able to migrate specifically to and incorporate within tumours after being delivered into a vein, and this property can be used to deliver 'targeted' anticancer therapies. Using these cells to deliver various anti-cancer molecules, intravenously delivered MSCs have been shown preferentially to move towards and survive in cancer tissue in breast, lung, and melanoma lung metastases, Kaposi's sarcoma (KS), colorectal cancer and gliomas.
In this research, a novel treatment for metastatic lung cancer will be investigated by giving a new treatment (called MSCTRAIL), which consists of cells (MSCs) carrying an anti-cancer gene (TRAIL), injected into lung cancer patients a day after they have chemotherapy. The first part of the research will be a phase I clinical trial aiming to find the safest dose which will benefit a lung cancer patient. The second part of the research will be a phase II clinical trial which will compare what effect MSCTRAIL has when given with chemotherapy compared to chemotherapy alone. We will do this by measuring how much the tumour has become smaller and also whether patients live longer. If successful, this novel cell and gene therapy treatment will then be tested in a larger (phase III) clinical trial.
Technical Summary
Lung cancer is the leading cause of cancer death worldwide with a 5 year survival of only 10%. The majority of patients present with advanced, incurable disease and existing therapies have significant systemic toxicities with only a modest improvement in life expectancy. Other cancer types frequently spread to the lungs at which stage they too become incurable. Our pre-clinical data shows human bone marrow derived mesenchymal stem cells (MSCs) can be successfully modified to carry an anti-cancer therapy using a lentiviral vector. The anti-cancer therapy is TNF-related apoptosis inducing ligand (TRAIL) which induces death in only cancer cells, leaving healthy cells unaffected. The MSCs engineered to express TRAIL (MSCTRAIL) have been shown to home to the sites of tumours, induce tumour cell death and eliminate or reduce lung metastases in mouse models.
We have robust processes for production of MSCs, lentiviral vectors and cell transduction within our fully Good Manufacturing Practice (GMP) licensed facilities. UCLH is a large cancer centre with highly skilled clinical staff. UCL is one of the national Experimental Cancer Medicine Centres with a dedicated Clinical Research Facility for early phase trials and is one of the 9 accredited clinical trials units of the National Cancer Research Institute (NCRI) and one of the UKCRC registered Clinical Trials Units.
We propose a 60 month (m) project encompassing final testing of a clinical grade product, followed by a phase I/II trial of MSCTRAIL in 28 patients with metastatic lung cancer predominantly affecting the lungs with one year follow-up.
Milestones will be:
1. Complete GMP viral manufacture (13m)
2. Trial approvals obtained and cell manufacture process validated (25m)
3. Complete phase I trial identifying Maximum Tolerable dose (MTD) and safety of dose delivery (36m)
4. Completion of phase II, follow-up, reporting to MRC and MHRA and publication (60m)
We have robust processes for production of MSCs, lentiviral vectors and cell transduction within our fully Good Manufacturing Practice (GMP) licensed facilities. UCLH is a large cancer centre with highly skilled clinical staff. UCL is one of the national Experimental Cancer Medicine Centres with a dedicated Clinical Research Facility for early phase trials and is one of the 9 accredited clinical trials units of the National Cancer Research Institute (NCRI) and one of the UKCRC registered Clinical Trials Units.
We propose a 60 month (m) project encompassing final testing of a clinical grade product, followed by a phase I/II trial of MSCTRAIL in 28 patients with metastatic lung cancer predominantly affecting the lungs with one year follow-up.
Milestones will be:
1. Complete GMP viral manufacture (13m)
2. Trial approvals obtained and cell manufacture process validated (25m)
3. Complete phase I trial identifying Maximum Tolerable dose (MTD) and safety of dose delivery (36m)
4. Completion of phase II, follow-up, reporting to MRC and MHRA and publication (60m)
Planned Impact
Academic Impact
Enhancing Knowledge
It is crucial the UK positions itself to deliver state of art manufacturing, as cellular therapeutic trials and eventually products for routine clinical use move forwards. Our manufacture of a transduced cellular product will see a step-change in mass production of transduced cells. This know-how will position us at the international forefront in manufacturing. This knowledge will be developed by UCLB and close working with the Cell Therapy Catapult. Several discussions have already taken place to this end and we have received interest from third party companies including 'Apceth' and 'Athersys'.
Addressing Questions
We will answer several questions that the cellular therapy field current does not know. For example of the 400 clinical trials involving MSC intravenous delivery no trial has yet defined where these cells go or how long they circulate. The radiolabelling of doses in Phase 1 of our study will answer some of these questions. Cell tracking will also give evidence for cell tumour tropism. The combined Phase 1/2 trial will also of course deliver efficacy data on the use of these cells in solid tumours. This will help investigators across the cell and gene therapy fields treating cancer and other diseases.
Developing Cross Disciplinary Approach to Manufacture and Clinical Delivery
The proposed project involves a group of established collaborators working together in the UK to advance the clinical translation in cell and gene therapy for cancer. We believe this is a unique group of experts as shown by the significant global interest from pharma and biotech in how we plan to develop infrastructure, know-how and delivery of the trial. This potential trial became a focus for discussion in the International Society for Cellular Therapies in Paris this year.
Delivering High Quality Training and Staff
Funding of this trial will ensure the development of a manufacturing process for high volume cell and gene therapy product and hence will result in improved academic and technical knowledge in this field in the UK. It will also develop a team of staff with high quality training.
Economic and Social Impact
Lung cancer is an important public health problem due to its high incidence, and poor survival. In the UK, the total annual cost of treating lung cancer in 2012 was £2.4 billion, much of which on ineffective therapies. The expected cost of MSCTRAIL in our study is likely to be £9,500 for a 3 cycle treatment. This would be expected to fall within improved manufacturing capability.
Enhancing quality of life, health and well-being
We believe this therapy has a significant chance of success, and if so this will have a major effect on health and well-being of patients with metastatic cancers. Moreover, we hypothesise that MSCTRAIL is unlikely to show significantly worse toxicity compared with standard chemotherapy. If clinical effects are demonstrated as anticipated, the duration of quality of life might be improved.
If successful in Phase 2 then the Cell Therapy Catapult group has committed to engage with an industrial partner to steer the therapy into a phase 3 clinical trial. This could have a significant impact in the generation of a new company or arm of an established company. Through the UK Cell Therapy Catapult group, the project will inform policy makers at the TSB and DH, able to influence the regulation of gene and cell therapies within the UK.
Success of the Phase 2 and subsequent Phase 3 trial will have a major international impact. It is likely other solid cancer trials would follow with the potential delivery of other agents known to affect particular tumour types. The UK would have a major competitive advantage in driving and shaping this area of research in the future since the knowledge and skills set already exist.
Enhancing Knowledge
It is crucial the UK positions itself to deliver state of art manufacturing, as cellular therapeutic trials and eventually products for routine clinical use move forwards. Our manufacture of a transduced cellular product will see a step-change in mass production of transduced cells. This know-how will position us at the international forefront in manufacturing. This knowledge will be developed by UCLB and close working with the Cell Therapy Catapult. Several discussions have already taken place to this end and we have received interest from third party companies including 'Apceth' and 'Athersys'.
Addressing Questions
We will answer several questions that the cellular therapy field current does not know. For example of the 400 clinical trials involving MSC intravenous delivery no trial has yet defined where these cells go or how long they circulate. The radiolabelling of doses in Phase 1 of our study will answer some of these questions. Cell tracking will also give evidence for cell tumour tropism. The combined Phase 1/2 trial will also of course deliver efficacy data on the use of these cells in solid tumours. This will help investigators across the cell and gene therapy fields treating cancer and other diseases.
Developing Cross Disciplinary Approach to Manufacture and Clinical Delivery
The proposed project involves a group of established collaborators working together in the UK to advance the clinical translation in cell and gene therapy for cancer. We believe this is a unique group of experts as shown by the significant global interest from pharma and biotech in how we plan to develop infrastructure, know-how and delivery of the trial. This potential trial became a focus for discussion in the International Society for Cellular Therapies in Paris this year.
Delivering High Quality Training and Staff
Funding of this trial will ensure the development of a manufacturing process for high volume cell and gene therapy product and hence will result in improved academic and technical knowledge in this field in the UK. It will also develop a team of staff with high quality training.
Economic and Social Impact
Lung cancer is an important public health problem due to its high incidence, and poor survival. In the UK, the total annual cost of treating lung cancer in 2012 was £2.4 billion, much of which on ineffective therapies. The expected cost of MSCTRAIL in our study is likely to be £9,500 for a 3 cycle treatment. This would be expected to fall within improved manufacturing capability.
Enhancing quality of life, health and well-being
We believe this therapy has a significant chance of success, and if so this will have a major effect on health and well-being of patients with metastatic cancers. Moreover, we hypothesise that MSCTRAIL is unlikely to show significantly worse toxicity compared with standard chemotherapy. If clinical effects are demonstrated as anticipated, the duration of quality of life might be improved.
If successful in Phase 2 then the Cell Therapy Catapult group has committed to engage with an industrial partner to steer the therapy into a phase 3 clinical trial. This could have a significant impact in the generation of a new company or arm of an established company. Through the UK Cell Therapy Catapult group, the project will inform policy makers at the TSB and DH, able to influence the regulation of gene and cell therapies within the UK.
Success of the Phase 2 and subsequent Phase 3 trial will have a major international impact. It is likely other solid cancer trials would follow with the potential delivery of other agents known to affect particular tumour types. The UK would have a major competitive advantage in driving and shaping this area of research in the future since the knowledge and skills set already exist.
Organisations
Publications
Yuan Z
(2016)
Cryopreservation of human mesenchymal stromal cells expressing TRAIL for human anti-cancer therapy.
in Cytotherapy
Yuan Z
(2017)
TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy.
in Journal of extracellular vesicles
Thakrar RM
(2016)
Combined cell-gene therapy for lung cancer: rationale, challenges and prospects.
in Expert opinion on biological therapy
Sage EK
(2016)
Genetically modified mesenchymal stromal cells in cancer therapy.
in Cytotherapy
Patrick PS
(2020)
Lung delivery of MSCs expressing anti-cancer protein TRAIL visualised with 89Zr-oxine PET-CT.
in Stem cell research & therapy
Pandey G
(2023)
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma
in Cell Reports Medicine
Lourenco S
(2015)
Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors.
in Journal of immunology (Baltimore, Md. : 1950)
Levy L
(2021)
TRAIL Coated Genetically Engineered Immunotherapeutic Nano-Ghosts Vesicles Target Human Melanoma-Avoiding the Need for High Effective Therapeutic Concentration of TRAIL
in Advanced Functional Materials
Lathrop MJ
(2015)
Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma.
in Cancer gene therapy
Kumar N
(2019)
Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma.
in Lung cancer (Amsterdam, Netherlands)
Kolluri KK
(2018)
Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.
in eLife
Kalber TL
(2016)
Hyperthermia treatment of tumors by mesenchymal stem cell-delivered superparamagnetic iron oxide nanoparticles.
in International journal of nanomedicine
Janes SM
(2021)
Perspectives on the Treatment of Malignant Pleural Mesothelioma.
in The New England journal of medicine
Ishii Y
(2021)
BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma.
in The Journal of biological chemistry
Greening NJ
(2015)
Review of the British Thoracic Society Winter Meeting 2014, 3-5 December, London, UK.
in Thorax
Busacca S
(2021)
BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma
in Molecular Cancer Therapeutics
Alrifai D
(2018)
Emerging resistance pathways in lung cancer: what has ROS-1 taught us?
in Translational lung cancer research
Description | Development of small molecule inhibitors of BRCA1 Associated Protein-1 (BAP1) for the treatment of malignant pleural mesothelioma. |
Amount | £89,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Department | MRC Confidence in Concept Scheme |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2020 |
Description | Gli as a novel therapeutic target in malignant mesothelioma |
Amount | £100,000 (GBP) |
Funding ID | MPHD16-8 |
Organisation | British Lung Foundation (BLF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2017 |
End | 10/2020 |
Description | MSC TRAIL for Mesothelioma |
Amount | £640,000 (GBP) |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 04/2019 |
End | 04/2021 |
Description | Training Fellowship |
Amount | £280,000 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Bloomsbury Centre |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2015 |
End | 12/2017 |