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Study investigating targeted drug delivery by focused ultrasound for pancreatic cancer opens

University of Oxford researchers have begun recruitment to a study looking at whether chemotherapy medication can reach pancreatic tumours more effectively if encapsulated within a heat-sensitive shell and triggered with focused ultrasound.

The Phase I PanDox study, which is supported by the NIHR Oxford Biomedical Research Centre (BRC), aims to learn if using thermosensitive liposomal doxorubicin and focused ultrasound (FUS) results in enhanced uptake of doxorubicin in pancreatic tumours, compared to doxorubicin alone.

PanDox is being carried out as a multi-disciplinary collaboration between the Oxford University Institute of Biomedical Engineering, the Oncology Clinical Trials Office (OCTO),  Oxford University Hospitals (OUH) NHS Foundation Trust and Celsion corporation, the manufacturer of the proprietary heat-activated liposomal encapsulation of doxorubicin ThermoDox used in the study.

The Oxford BRC’s Co-theme Lead for Cancer, Prof Mark Middleton, Head of the university’s Department of Oncology at is the chief clinical investigator on the trial. Prof Constantin Coussios, Director of the Institute of Biomedical Engineering, is the lead scientific investigator.

The trial will recruit 18 patients; ThermoDox will be administered intravenously in 12 patients with a pancreatic ductal adenocarcinoma tumour that cannot be removed with surgery; the drug will then be released by gentle heating produced by focused ultrasound outside the body. This will be compared to conventional systemic delivery of doxorubicin without FUS in the other six patients.

As well as assessing whether uptake of doxorubicin is improved with FUS, the team will compare how the tumour responds to the treatment, examine the impact on patient symptoms and assess the safety of the treatment.

The study, which is expected to be completed by December 2022, is similar in design to Oxford’s 10-patient TARDOX study, which demonstrated that ThermoDox plus focused ultrasound increased doxorubicin tumour concentrations by up to 10-fold and enhanced nuclear drug uptake in patients with liver tumours. The findings were published in Lancet Oncology.

The lead oncology clinical research fellow on the PanDox study, Dr Laura Spiers of OUH, said: “Pancreatic cancer has a low five-year survival rate of approximately 10% and drug-based treatments remain less effective than in other cancers, in part due to the unique challenges presented by the stroma surrounding pancreatic tumours.

“Therefore, finding innovative and effective means of delivering high concentrations of anti-cancer agents such as doxorubicin may lead to a breakthrough for this difficult-to- treat cancer.”

Dr Michael Gray, lead biomedical engineering research fellow, said: “Based on the patient-specific treatment planning approaches developed and validated during the TARDOX trial, PanDox will deliver focused ultrasound mild hyperthermia without either MR-based or invasive thermometry. The ultimate goal is to develop a cost-effective and scalable approach that can be rapidly deployed for the benefit of pancreatic patients.”

Potential for radiotherapy and VTP multimodality therapy for prostate cancer

Each year in the UK around 48,500 men are diagnosed with prostate cancer, and 11,900 die from this malignancy. The most common radical treatments for prostate cancer are surgical removal of the prostate gland (prostatectomy), or radiotherapy (usually combined with hormone treatment).

However, there is a need to improve the overall patient outcomes from radical treatment, as many cases of high-risk prostate cancer recur. Moreover, there is an unmet clinical need to reduce radical treatment side effects.

Vascular targeted photodynamic therapy (VTP) is a novel minimally invasive precision surgery technique that has been developed to focally treat prostate cancer. VTP destroys the vasculature supply of blood to the tumour, thereby providing tumour control.

To date, VTP has been investigated in clinical trials as a monotherapy for low-volume, low-risk prostate cancer. Whilst VTP has been combined with other treatments such as hormone therapy in pre-clinical models, to date it has not been investigated alongside external beam radiotherapy to assess the effects of combined treatment on prostate cancer tumour control.

A recent study from Richard Bryant and Freddie Hamdy of the Nuffield Department of Surgical Sciences, alongside collaborators in the Institute of Biomedical Engineering & Department of Oncology, and collaborators from the Weizmann Institute of Science (Israel) and the National Cancer Institute (National Institutes of Health, USA), has investigated the impact of combining VTP with external beam radiotherapy treatment, and the potential improvement to treatment outcomes.

In a recent publication in the British Journal of Cancer, the team used a multi-modality treatment approach to test the sequential combination of fractionated radiotherapy and VTP – which have previously not been used together.

They found that, whilst fractionated radiotherapy or VTP alone can help delay tumour growth, combination therapy using fractionated radiotherapy followed by VTP suppressed tumour growth to a greater extent than either treatment alone. Radiotherapy induced changes to the blood vessels within the tumour, which may be a contributing factor to the increased effectiveness of subsequent VTP as part of combination therapy. Ongoing studies are now investigating the immunological effects of the combined treatment.

This is the first time that VTP has been evaluated in combination with external beam radiotherapy treatment, either for prostate cancer or any other solid-organ tumour. This pre-clinical study provides the proof-of-concept necessary to go on and test this multi-modality approach in first-in-man early phase clinical trials. Following future testing of safety and efficacy in patients, this combined radiotherapy and VTP approach could help to redefine best practice for treating certain prostate cancer patients in a more effective way.

About the study

This study was a collaboration between Richard Bryant (Nuffield Department of Surgical Sciences), Freddie Hamdy (Nuffield Department of Surgical Sciences), Ruth Muschel (Department of Oncology) and Avigdor Scherz (The Weizmann Institute of Science, Israel). It was funded by a Cancer Research UK & Royal College of Surgeons of England Clinician Scientist Fellowship (reference C39297/A22748) and by a research grant from The Urology Foundation.

Groundbreaking FOCUS4 clinical trials report their findings at ASCO

As FOCUS4 prepares to report findings at the ASCO (American Society of Clinical Oncology) Annual Meeting on 4-8 June 2021, the NIHR have taken a historical look at how this groundbreaking trial has helped shape the future of clinical trial delivery in the UK. Professor Tim Maughan of the Department of Oncology at the University of Oxford and co-Principal Investigator of the FOCUS4 studies, explores how experience gained from delivering FOCUS4 has helped the UK to rapidly answer questions of global importance about the treatment of COVID-19.

FOCUS4, one of the UK’s flagship precision medicine cancer trials, opened back in 2014. It is a randomised trial investigating treatments for colorectal cancer using a complex adaptive methodology which is known as Multi-Arm, Multi-Stage (MAMS) design. Such trials, also called umbrella or platform trials, allow for multiple treatments to be tested simultaneously against the standard of care (the control). However, FOCUS4 has the added complexity of stratified medicine, which requires that all eligible patients undergo genome sequencing to identify genetic biomarkers relating to their cancer. Patients are then matched to the trial arm/treatment to which they are most likely to respond.

This new way of working emerged following a rapid increase in the number of new cancer treatments being developed by life science companies which needed a systematic approach to quickly understand which treatments worked against which cancers. Professor Maughan explains:

“The adaptive, multi-arm, multi-stage approach was pioneered by the MRC Clinical Trials Unit at UCL and it provides a more efficient way of working compared to traditional back-to-back randomised clinical trials which only test one treatment at a time. Not only does it avoid the delays and costs of setting up a new trial for each new drug candidate, it also makes the screening process more efficient. Patients are screened for a match to all the drugs being trialled and have a higher probability of being able to join the trial and access a cutting-edge treatment. But more importantly – and this is where the adaptive bit comes in – new arms can be added to the trial platform as new drugs become available. Equally, where drugs are showing no benefit, that arm of the trial can be closed and another trial can be opened in the part of the trial.”

The FOCUS4 trial design was considered groundbreaking when it opened in 2014 as it was one of the first large-scale, molecularly stratified, MAMS cancer trials in the UK. It successfully enrolled 1,434 patients from 88 hospitals. Prior to this the FOCUS3 study, opening in February 2010, sought to establish the feasibility of this approach, recruiting 240 patients at 24 centres.

However, the UK’s experience of MAMS trials can be tracked back further to the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) Trial which opened in the UK in 2005. This trial is ongoing, has recruited almost 12,000 participants, and has produced practice-changing results in the treatment of prostate cancer. Although STAMPEDE commenced much earlier than FOCUS3 or FOCUS4, Professor Maughan says it is important to note:

“Although very challenging in other ways, STAMPEDE does not currently involve molecular stratification and this is a significant difference in the complexity of the trial delivery and why trials like FOCUS4 and the National Lung Matrix are world-renowned, despite opening a number of years after STAMPEDE.”

Fast forward to 2020 and the COVID-19 pandemic. The emergency situation necessitated a systematic approach to quickly understand which treatments worked against the novel coronavirus. Sound familiar?

Collaborative research culture

Speed and agility are imperative in a pandemic situation. This caused a seismic shift in attitudes towards developing new ways of working in areas such as streamlining the trial approval process.

Rapid trial set-up and delivery are also crucial. Thankfully, as we’ve established, the UK already had experience and understanding of implementing large scale, adaptive multi-arm, multi-stage clinical trials. This existing knowledge and ability to collaborate on a national scale certainly seems to have underpinned our rapid COVID-19 research response seen in trials like RECOVERY (Randomised Evaluation of COVID-19 Therapy). Professor Maughan said:

“FOCUS4 lies in this historic development of complex innovative designs. It builds first of all on the establishment of the research infrastructure through the Clinical Research Network, which is integral to the support of all these major UK national trials. Secondly, it builds on the adaptive statistical methodology, which was first developed in STAMPEDE – the multi-arm, multi-stage design approach.

“The RECOVERY trial is built on the same adaptive statistical model and also the fact that there was this fantastic research delivery infrastructure in the UK, which enabled it to move very fast and recruit these huge numbers of patients in a very short period of time. The success of RECOVERY and other MAMS trials in recent years is testament to the 20 years of investment in clinical research delivery culture in the NHS and the collaborative working across the industry in the UK.”

The world-leading RECOVERY trial does, indeed, use the MAMS trial design to test emerging treatments for the novel coronavirus and was established during the early stage of the pandemic when there were no proven treatments available. Within three months, it generated clinical evidence resulting in dexamethasone becoming the world’s first proven drug to reduce mortality for the most seriously ill patients. It also showed that hydroxychloroquine, once considered a promising therapeutic candidate for COVID-19, has no clinical benefit for hospitalised patients and this arm of the trial ceased immediately.

The PRINCIPLE (Platform Randomised trial of INterventions against Covid-19 In older peoPLE) and REMAP-CAP (A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia) trials also utilise an adaptive platform approach. These flagship trials, building on the foundations of STAMPEDE, FOCUS4 and Lung Matrix, are likely to accelerate uptake and acceptance of the adaptive platform approach in clinical trial delivery in future years as the global drive for faster and more efficient clinical trials intensifies.

Forthcoming findings

It seems quite pertinent then for FOCUS4 to be on the cusp of publishing new findings in the wake of the pandemic. Professor Maughan looks back at some of the previously published results of the trial:

“Our first molecular cohort showed comprehensive negative results, and we were able to close it after only 32 patients had been accrued to FOCUS4-D – one arm of the FOCUS4 trial. That was published back in 2017 and you’ll see in many platform designs that a number of negative results come out. That’s important because we’re showing that things don’t work as well as the things that do work.

“The trial has now closed to recruitment in October 2020, after conducting three molecularly targeted sub-trials and one non-molecularly stratified trial in six years, and has generated some interesting results. Prof Richard Adams will be presenting some of these at the ASCO (American Society of Clinical Oncology) Annual Meeting on 4-8 June 2021 and we are in conversation with journals about publications.

“When we embarked on FOCUS4 we knew it would be a challenge, and we have learnt a huge amount along the way. It’s really important now that we share this learning and continue to improve the way we do clinical trials in the future.”

Professor Maughan also recognises that complex trials like FOCUS4 require the right ingredients to enable successful delivery. He emphasises the importance of the UK’s unique clinical research landscape:

“The whole complex research ecosystem of the UK presents an unparalleled opportunity for complex and innovative trials. We have the NHS as a single health care provider, the NIHR Clinical Research Network as a coordinated research delivery organisation, collaborative laboratory scientists delivering the sequencing, the collective work of the funders, forward-thinking regulators, and the National Cancer Research Institute. All this facilitates a really collaborative clinical research culture within the UK where organisations don’t have to compete with each other for patients, for example. Not a lot of countries in the world that can replicate that same environment.

“We have also shown that our research infrastructure can be adapted to an emergency situation and this is thanks to the NIHR Clinical Research Network and the trained research workforce who are based in every hospital and primary care setting in the UK. I think the real challenge now is ensuring that we learn from the COVID-19 crisis to improve the way we do things normally, in the clinical research setting, outside of the pandemic.”

 

Adrian Hill elected to Royal Society

Professor Adrian Hill, Director of the Jenner Institute (Nuffield Department of Medicine), has become a Fellow of the Royal Society for his leading role in the design and development of new vaccines for globally important infectious diseases over the course of over 25 years.

One of his most important developments has been the spin out of Vaccitech, which he co-founded in 2016, to capitalise on the discovery of ChAdOx. The chimp cold virus, ChAdOx, became a weapon of choice against what the World Health Organization called “Disease X” – a hypothetical future pathogen with epidemic or pandemic potential.

ChAdOx is a viral vector which safely mimics viral infection in human cells and elicit antibody and T cell responses to pathogens and tumours. Thus far, ChAdOx has already been applied in cancers (prostate), malaria, and most recently, the AstraZeneca-Oxford vaccine for Sars-Cov-2.

Through his work, Professor Hill has demonstrated the applications of adenoviruses in immunisation regimes supporting new vaccination approaches for a variety of disease, many of which have previously not had treatment options available.

Professor Hill becomes one of 6 new Oxford researchers to join the Royal Society. Read about them here.

Using Herpesvirus to fight cancer

The Seymour lab at the Department of Oncology, University of Oxford, has published a new paper investigating the use of oncolytic herpes virus-1 as a vector to augment immunotherapy in cancer

Further funding secured to hunt out cancer using innovative radiotherapy techniques

Professor Bart Cornelissen and Dr Tiffany Chan, from the Department of Oncology, have received an additional £408,338 award from the charity Prostate Cancer Research (PCR) to continue their innovative work to help a new type of radiotherapy, designed to hunt out cancer even after it has spread, to benefit even more men with prostate cancer. Prostate cancer is now the most commonly diagnosed cancer in the UK and their work could lead to more personalised treatment for those with prostate cancer.

Bart and Tiffany are working with a type of radionuclide therapy called 177Lu-PSMA. PSMA seeks out a protein found almost exclusively on prostate cancer cells, and by linking it to radioactive Lutetium (Lu), it can guide the radiotherapy directly inside tumour cells. ‘An advantage of 177Lu-PSMA is that we don’t need to know where all the cancer cells are before treatment, unlike in external beam radiotherapy’ explains Tiffany. ‘In theory, even if we just have a single cell that has split away from the main tumour, if it expresses PSMA, we should still be able to target it.’

Some Lu-PSMA treatments are already used in the UK, but on a private basis only and at the moment they are primarily used for pain relief. The Oxford researchers aim to combine Lu-PSMA with other therapies, and their initial results, from testing nearly 2,000 drugs, have led to the discovery of a group of drugs that may be able to help 177Lu-PSMA hunt out prostate cancer better and make it more effective for more patients. This discovery, which led to further funding from PCR for them to continue this exciting work, comes at an important time for radionuclide therapies. ‘There’s a very large Phase 3 clinical trial with Lu-PSMA and that seems to suggest that you actually get benefits in overall survival from this treatment’ explains Bart. ‘Rather than just being pain relief, we can now start to think of these as cures as well.’

“Speaking as a patient whose prostate cancer has been previously treated with radiotherapy and is likely to be so again in the future, I find this work to be a very welcome addition to the treatments available for the disease,’ said prostate cancer patient David Matheson. ‘It is heartening to see such progress with this treatment, and I look forward to it becoming more widespread in the future.’

During lockdown, the closure of their lab meant they had to find alternative ways to reach their goal. They found an innovative solution – reversing their original plans and developing new and efficient ways to analyse results in lockdown first, and then conducting the experiments when they could return to the lab. Tiffany developed a network analysis tool to enable them to predict which combinations might work. ‘I’m a Londoner, so I like to think of it like a tube map, where have all of our different tube stops, connected by different tube lines, with some lines being more efficient than others. The idea behind mapping the system in this way is that we can hopefully find the best line, or in this case, the best biological pathway, that is most likely to lead to synergism with Lu-PSMA,’ she said. PCR initially awarded £100,000 to Bart and Tiffany in 2019 to test up to 1,000 drugs in combination with 177Lu-PSMA. Despite the challenges brought on by the Covid-19 pandemic, the team surpassed their target and managed to test an incredible number of drugs.

Bart and Tiffany are hopeful that Lu-PSMA could become more widespread in the clinic but believe more research needs to be done. ‘Lu-PSMA is the new kid on the block, it’s a very new technology. I think there’s still a lack of understanding about how Lu-PSMA itself works, and there’s a lot of biology we can learn to improve its efficacy’ says Tiffany. ‘So that’s what we’re trying to achieve, particularly with our network analysis approach to map out the biology behind it.’

‘Bart and Tiffany’s project is already showing promising results on the route to improving radiotherapy for men with prostate cancer. We look forward to continuing to support their project on a larger and long-term basis and hope it will mean that more people can benefit from enhanced radiotherapy, without the side effects’

– Dr Naomi Elster, Head of Research and Communications, PCR

‘There are Lu-PSMA treatments that are already given in the UK but on a private basis’ Bart explains. ‘Whether that will hit the NHS depends on approval by NICE but given the fantastically positive data out there, the upcoming results of the VISION Phase 3 clinical trials that are very positive, and given the improvement in actual survival of patients, I think there is good hope there that that will be approved.’

– Professor Bart Cornelissen

“Perhaps, what is most exciting is that, by targeting PSMA, this therapy delivers the radiotherapy directly to the sites of the cancer, wherever they are located. It is heartening to see such progress with this treatment, and I look forward to it becoming more widespread in the future.”

– David Matheson, prostate cancer patient

For more information, please visit: www.pcr.org.uk. Full story on the Department of Oncology website.

Novel imaging device enters first round of development funding programme

Proton-beam-therapy (PBT) is becoming increasingly important for treating cancer, with projected increases of up to 50% more patients per year being treated with the technology in the UK and worldwide by 2025.

Although the precision of PBT has many advantages over traditional radiotherapy, there some uncertainty over the range of delivery the beam provides. There is risk of potential overdose to normal tissues or underdose to tumour, resulting in reduced tumour-control and long-term side-effects due to treatment of healthy tissue. This can be detrimental to patients and a burden on healthcare systems if side-effects become apparent later in a patient’s life.

Therefore, a method to verify the range of treatment beams when using PBT on patients is crucial to increase the treatment accuracy. Dr Anna Vella, Postdoctoral with the Radiation Therapy Medical Physics Group, led by Prof. Frank Van Den Heuvel, at the University of Oxford’s Department of Oncology, is investigating the efficacy of a device with this purpose.

Anna is leading CAPULET (Coded Aperture Prompt-gamma Ultra-Light imaging detector), an imaging device for quality assurance assessment of radiotherapy plan efficacy, designed for daily use in clinical practice. CAPULET could be installed onto a variety of PBT devices, and used to verify and fine-tune the dose between fractions in particle-beam radiotherapy. It does this through collecting 3D images of the particle beam penetrating soft-tissue, with the ultimate goal to fine-tune planning doses and improving the efficacy of the overall radiotherapy treatment.

This novel and unique technology is faster & more compact than current devices, increases the field-of-view, and improves the signal-to-noise ratio. The impact on patients will be to improve cancer-control, fewer complications, and improved quality-of-life following treatment.

CAPULET has recently been selected as one of 35 projects in the Pre-Development Phase of the Alderley Park Oncology Development Programme – a national programme designed to develop and progress start-up oncology projects. Funded by Innovate UK and Cancer Research UK. It will now be work-shopped, and potentially be chosen to join the full development programme with grant funding.

Proof-of-concept experiments will be performed in collaboration with the CRUK-funded ART-NET. The long-term plan of CAPULET is to develop a large-area detector to fully image the beam delivery range within lungs, liver, H&N and other large sites in the human body to overcome limited field-of-view found in other existing devices on the market.

New partnership enables access to state-of-the-art radiotherapy machine

The first NHS patient has received treatment on the cutting-edge ViewRay MRIdian technology, thanks to a new partnership between the University of Oxford, Oxford University Hospitals (OUH) NHS Foundation Trust and GenesisCare.

The partners, with the support of the John Black Charitable Foundation, have collaborated to establish a ten-year programme of clinical treatment for NHS patients, with further research into improving cancer treatment using the Viewray MRIdian.

Due to the natural, unavoidable movement of soft tissue inside the body, normal tissue around the cancer can be exposed to radiotherapy treatment, particularly when targeting soft-tissue tumours deep within the body. It can be challenging to visualise these organs during radiotherapy with routine radiotherapy delivery.

The ViewRay MRIdian machine is the only one of its kind in the UK, with only 41 machines worldwide. It allows doctors to see the normal soft tissue and the tumour in real time by combining MRI scanning with targeted radiotherapy. Incorporating MRI scans will allow doctors to then tailor doses in real time to the specific internal anatomy of the patient on the day of treatment.

MRIdian technology also minimises the damage to surrounding healthy tissues by switching off when tumour tissue moves outside of the targeted beam. This could mean less side effects for patients and increased dosage of treatment delivered directly to the tumour.

GenesisCare, the University of Oxford and OUH will also partner in research collaborations to develop real-world evidence which will inform future utilisation of the MRIdian technology in hard-to-reach tumours, such as pancreatic cancers. The research partnership will assess the benefits of the MRIdian technology in terms of improved cancer outcomes and reduced toxicity.

Elizabeth Rapple, from South Oxfordshire, is the first patient to use the machine to treat her renal cancer, as part of the new partnership. She says:

“I feel very fortunate to be able to access this machine as part of a new Oxford-wide partnership. Any operation to remove my tumour would have been highly invasive, so it’s lucky that my cancer was suitable for MRIdian radiotherapy. I am so grateful that this unique machine has been made accessible through the NHS, and that I can be the first of many to benefit from this partnership going forward.”

Project leader Professor Tim Maughan, from the University of Oxford, said:

“Treating patients on the MRIdian is like a surgeon putting on their spectacles for an operation – for the first time we can see exactly what the cancer is doing during treatment and adapt to change accordingly.  This accuracy allows us to reduce side effects and we hope to improve cancer outcomes in hard-to-treat cancers.”

Dr James Good, Clinical Oncologist at GenesisCare, said:

“The MRIdian machine is at the cutting-edge of what is possible in radiotherapy technology. The ability to visualise the tumour more accurately, to follow it while it’s being treated and to adapt the plan every day means we can deliver the best possible outcomes.

“This collaboration with the University of Oxford and Oxford University Hospitals will be truly beneficial for cancer patients in the UK. Not only will it provide patients who otherwise would have limited, or sadly, no options with a really viable treatment option, but we can also help demonstrate the effectiveness of this treatment, with the ambition to make it available for all NHS patients in the future.”

Carol Scott, Lead Therapeutic Radiographer & Deputy Clinical Director at Oxford University Hospitals , said:

“OUH are excited to be part of this collaboration offering NHS patients the opportunity to take part in these clinical trials. The use of daily advanced imaging that clearly shows us the tumour and normal soft tissue around it will enable us to take the next step in making our treatments even more personalised and effective”

Prof Andi Roy receives new award for immune-cell research

Co-funded by Cancer Research UK and Children with Cancer UK, Andi is one of 5 to receive £1 million each to investigate children’s and young people’s cancers.

Improving immunotherapy through epigenetics

Immunotherapy has shown remarkable efficacy against a range of cancers. One approach, termed immune checkpoint blockade therapy, blocks an inhibitory immune receptor called PD-1 to take the brakes off the immune system and allow it to kill cancer cells. However, despite this success, anti-PD-1 therapy is ineffective in the majority of cancer patients.

Research is underway to discover strategies that can overcome tumour resistance to immunotherapy. A promising avenue for further investigation is the manipulation of epigenetic regulators. Epigenetic regulators influence the expression of genes without changing the underlying DNA sequence. They can dampen the response of the immune system and their inhibition has been shown to enhance the response to anti-PD-1 treatment. However, because epigenetic regulators are involved in several aspects of the anti-tumour immune response, inhibiting them can result in potentially opposing effects, with the result of little or no overall benefit.

In this paper published in the journal Cancer Discovery, Professor Yang Shi and his laboratory explore the opposing effects of inhibiting one such epigenetic regulator, LSD1. Using mouse and tumour cell models, they show that when LSD1 is repressed, there is a greater immune cell infiltration into the tumour but this is counteracted by the increased production of a cell regulatory protein called TGF-β that suppresses the ability of these infiltrating immune cells to kill cancer cells.

To tackle these conflicting effects, the team experimentally depleted both LSD1 and TGF-β during anti-PD-1 therapy and demonstrated a significant increase in immune cell infiltration, cytotoxicity and cancer cell killing. This combination treatment led to eradication of these previously resistant tumours and long-lasting protection from tumour re-challenge, making it a promising future strategy for increasing the efficacy of this important class of cancer treatment.