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Take a look at a selection of our recent media coverage:
25th November 2022
Tumour infiltrating lymphocyte (TIL) scoring based on a machine-learning model has superior classification accuracy for an immune checkpoint inhibitor (ICI) response in patients with advanced non-small cell lung cancer (NSCLC) according to a retrospective analysis by an international research group.
Immunotherapy with immune-checkpoint inhibitors (ICI) has revolutionised the field of oncology for many patients. Nevertheless, not all patients with non-small cell lung cancer benefit from these agents with studies suggesting that in advanced disease, at 1 year, the overall survival rate with, for example, nivolumab, was only 51%. A more favourable response to ICI therapy occurs in those with high programmed cell death ligand-1 expression and a high tumour mutation burden (TMB). A further prognostic factor associated with an improved prognosis in NSCLC patients is high tumour-infiltrating lymphocyte (TIL) levels and which are visually assessed on routine haematoxylin and eosin-stained slides. However, with the increasing use of machine-based learning algorithms in healthcare, some preliminary data highlights the potential for such assessment of haematoxylin and eosin-stained slide sections.
Given the prognostic value of TIL levels, for the present study, researchers developed a machine-learning TIL scoring model to evaluate its association with clinical outcomes in patients with advanced NSCLC. The researchers undertook a retrospective analysis of patient cohorts prescribed PD-(L)1 inhibitors initially for a discovery cohort within a French hospital, followed by an independent validation cohort from hospitals in the UK and the Netherlands. The machine learning model counted tumour, stroma and tumour infiltrating lymphocyte cells whereas values for TMB and PD-L1 expression were determined separately.
Tumour infiltrating lymphocyte cells and ICI response
A total of 685 patients with advanced-stage NSCLCL treated with first or second-line ICI monotherapy were included within the two independent cohorts. The median age in both groups was 66.
Among patients in the discovery cohort, those with a higher TIL cell count had a significantly longer median progression-free survival (Hazard ratio, HR = 0.74, 95% CI 0.61 – 0.90, p = 0.003) and a significantly longer overall survival (HR = 0.76, p = 0.02). Moreover, similar findings of an association between higher tumour infiltrating lymphocyte cell count and both progression-free and overall survival were also observed in the validation cohort.
When using PD-L1 levels as a biomarker, the area under the curve (AUC) was 0.68 and for tumour infiltrating lymphocyte cell levels, only 0.55 and 0.59 for TMB. But when combined, both the PD-L1/TIL and TMB/PD-L1 had higher AUC values (0.68 and 0.70 respectively).
The authors concluded that TIL levels were robustly and independently associated with the response to ICI treatment and could be easily incorporated into the workflow of pathology laboratories at minimal additional cost and might even enhance precision therapy.
Rakaee M et al. Association of Machine Learning-Based Assessment of Tumor-Infiltrating Lymphocytes on Standard Histologic Images With Outcomes of Immunotherapy in Patients With NSCLC. JAMA Oncol 2022
8th August 2022
Racial disparities in access to immunotherapy as a first-line option for advanced hepatocellular carcinoma (HCC) have been revealed in a retrospective analysis of the US National Cancer Database by US researchers.
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and data for 2018 indicate that globally, there were an estimated 661,000 cases. Moreover, in recent years, treatment for HCC has been revolutionised by the introduction of checkpoint inhibitors and data has shown how the combination of the anti-PDL1 antibody atezolizumab and the anti-VEGF antibody bevacizumab was superior to sorafenib in a phase 3, randomised controlled trial. Whilst such treatments have proven to be effective, a problem for the wider generalisability of these findings is that in major cancer trials, there is under enrolment of racial and ethnic minorities. For the present study, the US team sought to explore the demographic breakdown of immunotherapy for advanced HCC to examine if there was any evidence of racial disparity in the uptake of therapy.
Turning to the National Cancer Database, the team retrospectively looked at patients with tumour node metastasis stage 3 or 4 HCC between 2017 and 2018 and who underwent either chemotherapy or immunotherapy. They also collected a range of additional information such as co-morbidities, demographics and specific clinical parameters e.g., tumour size, alpha-fetoprotein category etc as well as socioeconomic status, insurance status and reported levels of income and educational achievement.
Racial disparities and immunotherapy
A total of 3990 patients with a mean age of 64.2 (81.3% male) were included in the analysis of whom, 81.4% received chemotherapy.
Among those treated with immunotherapy, there was a much higher proportion of White individuals (66.6%) compared to Hispanic (9.1%) or Black (14%).
Using multivariable regression, use of immunotherapy was independently associated with improved overall survival (adjusted hazard ratio, aHR = 0.76, 95% CI 0.65 – 0.88) compared to chemotherapy and there was no evidence of racial disparities with respect to overall survival. However, when the researchers considered the factors associated with use of immunotherapy as a first-line treatment for advanced HCC, Black patients were significantly less likely to receive immunotherapy compared to White patients (odds ratio, OR = 0.71, 95% CI 0.54 – 9.89, p = 0.006) as were Hispanics (OR = 0.63, 95% CI 0.46 – 0.83, p = 0.002). Despite this there was no evidence that first-line use of immunotherapy was influenced by socioeconomic or educational factors.
The authors concluded that a comprehensive approach is urgently required to both monitor and eliminate racial disparities observed in the management of advanced HCC.
Ahn JC et al. Racial and ethnic disparities in early treatment with immunotherapy for advanced HCC in the United States Hepatology 2022
29th March 2022
Matching cancer patients to treatment based on their levels of a key immune protein may allow clinicians to select those who would benefit most from the combination of immunotherapy and chemotherapy, according to research among patients with head and neck cancer. The study found patients benefited from different treatments depending on the results of a test measuring levels of the protein PD-L1 in tumours and on surrounding cells. The researchers hope use of the test will be adopted in guidelines as a way to personalise patients’ treatment by selecting immunotherapy, chemotherapy or the combination of the two depending on PD-L1 levels.
Immunotherapy has transformed treatment of head and neck cancer and several other cancer types – but there are still major difficulties in predicting who will respond best and so personalising treatment effectively.
A team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust analysed data from the major KEYNOTE-048 trial to assess whether they should be treated with a combination of the immunotherapy pembrolizumab and chemotherapy.
Out of the 882 people involved in the trial, 373 had a moderate PD-L1 score between 1 and 19. Among people in this group, pembrolizumab on its own or with chemotherapy was able to stop tumour growth in many patients.
However, it was the pembrolizumab-chemotherapy combination that led to a longer overall survival – 12.7 months, compared with 9.9 months for the comparator of cetuximab plus chemotherapy. The latest results, together with previous findings from the trial, suggest that three different approaches to treatment should be considered, depending on PD-L1 levels. Patients with low levels of PD-L1 are highly unlikely to benefit from pembrolizumab alone, and should receive chemotherapy alone or chemotherapy plus cetuximab. Patients with moderate levels of PD-L1 may benefit most from a pembrolizumab and chemotherapy combination, and those with high levels of PD-L1 may benefit most from pembrolizumab alone.
This led to differing regulatory approvals of pembrolizumab across the globe as a first-line treatment for patients with relapsed head and neck cancer, based on a PD-L1 scoring system. In England, NICE recommended pembrolizumab alone for patients with moderate or high levels of PD-L1.
But the new findings suggest patients with moderate levels of PD-L1 may have better outcomes if they also receive chemotherapy. Overall, they support use of the PD-L1 test, which is cheap and reliable, to target pembrolizumab’s use more precisely than before in relapsed head and neck cancer.
Researchers cautioned that some of the results should be interpreted carefully, given the small number of participants with a PD-L1 score of less than 1, and that additional biomarkers are needed to further select patients who could benefit from pembrolizumab.
Study leader Professor Kevin Harrington, Professor of Biological Cancer Therapies at The Institute of Cancer Research, London, and Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust, said:
“We have found that patients with head and neck cancer benefit from different approaches to treatment depending on the levels of a key immune protein in the tumour and among the surrounding cells. This new, more refined interpretation of the PD-L1 test should give clinicians a much clearer indication of which patients are most likely to benefit from immunotherapy alone and who should be considered for immunotherapy in combination with chemotherapy.
“Our new findings suggest people with a moderate PD-L1 score would benefit more from a combination of pembrolizumab plus chemotherapy. Currently, NICE has only recommended pembrolizumab on its own for this group of people, so I hope our new evidence will be taken into account and potentially change care for people in England and Wales.”
Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:
“Smarter tests to identify patients who are most likely to respond to treatment are a key aspect of precision medicine and are urgently needed for immunotherapies. Tests like these can help improve outcomes for patients and make sure we don’t subject people who are unlikely to respond to treatments that won’t benefit them. I hope our new study can improve care for patients with head and neck cancer by helping to optimise treatment depending on test results.”
Mr Richard John, a head and neck cancer patient at The Royal Marsden with high levels of PD-L1, said:
“My PD-L1 test was over 20, which meant I was treated with pembrolizumab, a form of immunotherapy, on its own. I am now in complete remission and so grateful to have benefitted from this study at The Royal Marsden and the ICR. It is such a relief that I didn’t have to undergo any additional treatments, such as chemotherapy, which wouldn’t have done any more for me than having immunotherapy on its own. The understanding about what treatments are best suited to each individual is transformative for patients like me, meaning we do not have to spend any more time in hospital or dealing with side effects of treatment than is necessary.”
The research which is published in the Journal of Clinical Oncology was funded by the drug’s manufacturer, Merck & Co., Inc., known as MSD outside the US and Canada.
20th August 2021
Allergic rhinitis is characterised by several symptoms including sneezing, itching, nasal congestion and rhinorrhoea. It can be categorised as either seasonal allergic rhinitis, in which symptoms are evoked in response to season triggers such as pollen or perennial allergic rhinitis, where symptoms are continually present. Seasonal allergic rhinitis is a global health problem and has been reported to affect 15 to 25% of adults and children. Moreover, while localised symptoms are problematic for patients, the condition also has a more generalised effect upon sufferers leading to fatigue, mood changes and reduced cognitive function which can affect work and overall quality of life. Treatment involves the use of oral and intranasal antihistamines as well as intranasal corticosteroids. However, when such treatments fail to provide symptomatic relief, subcutaneous or sublingual allergen immunotherapy can be used with subcutaneous therapy appearing to be more effective. In fact, a recent review found that the benefits of allergen immunotherapy were sustained for at least 2 – 3 years after cessation of treatment.
The role of interleukins (IL) in the pathophysiology of seasonal allergic rhinitis is uncertain although some evidence observed a trend towards higher levels of both IL-4 and IL-13. The monoclonal antibody dupilumab targets the IL-4 and IL-13 receptor and been recently shown to improve asthma and perennial allergic rhinitis symptoms. This led a team from the Department of Medicine and Paediatrics, David Geffen School of Medicine, California, US, to examine whether addition of dupilumab to subcutaneous immunotherapy would provide an additional benefit to patients with seasonal allergic rhinitis. They undertook a phase 2a, randomised trial with four arms, comparing subcutaneous immunotherapy (SCIT) either alone or combined with dupilumab verses placebo in patients with seasonal allergic rhinitis. The study involved a 12-week screening period, a 16-week treatment phase and an 8-week post-treatment follow-up in adult patients (aged 18 years and over but less than 55 years) with seasonal grass pollen allergy. The four treatment arms were: SCIT + placebo; SCIT + dupilumab 300mg every 2 weeks; Dupilumab alone; SCIT alone. The primary outcome as the percentage change from pre-baseline in the area under the curve for peak total nasal symptom score (TNSS), a composite of rhinorrhoea, nasal congestion, nasal itching, and sneezing and measured 0 – 1 hour following a nasal allergen challenge.
A total of 103 patients were enrolled and randomised to one of the four arms. The mean age of participants assigned to SCIT and dupilumab was 33 years (30.8% male) and the mean age across the study ranged from 33 to 40.3 years. At week 17 and following a nasal allergen challenge, there was no difference between SCIT and SCIT + dupilumab (least squares mean – 56.76% vs 52.03%). Similarly, there was no significant difference in the absolute change in TNSS scores. There was however, a slight, but significant improvement in the peak TNSS scores when dupilumab was added to SCIT (p = 0.026), suggesting that addition of the drug may help improve SCIT tolerability. The authors concluded that there was no benefit from adding dupilumab to SCIT in terms of reducing the response to an allergen challenge.
Corren J et al. Short-term subcutaneous allergy immunotherapy and dupilumab are well tolerated in allergic rhinitis: a randomised trial. J Asthma Allergy 2021
18th August 2021
The treatment of cancer has traditionally involved surgery, chemotherapy or radiotherapy although in recent years, there has been increased interest in immunotherapy which makes use of the patient’s immune system to fight cancer. One form of immunotherapy is Chimeric Antigen Receptor (CAR) T-cell therapy which involves genetic modification of a patient’s T cells to express a specific tumour antigen. After modification, these modified T cells are infused back into a patient, attacking and destroying chemotherapy-resistant cancer. However, a major limitation to the use of CAR-T cells is that the tumour antigen can also be expressed by normal, healthy tissue and the modified T cells are unable to differentiate between malignant and benign cells. It is therefore not always easy to identify a specific antigen that is preferentially expressed on tumour cells. This led a team from the Department of Bioengineering, University of California, US, to create inducible cells that were engineered to express the surface protein but only in response to short-pulsed, focused ultrasound stimulation.
The team subcutaneously injected the specific CAR-T cells at the site of a tumour in mice, followed by three 5-minute pulses of focused ultrasound at 43 degrees centigrade. This resulted in a significant reduction in tumour size. To ensure that it was specifically the combination of the CAR-T cells and focused ultrasound that were shrinking the tumour, the team used two control groups of mice with tumours. In one group, the pulsed ultrasound was used in the absence of the specific CAR-T cells injected and this had no impact on tumour growth. The second group of mice also received the ultrasound but this time, but this time in the presence of naïve T cells, as opposed to the CAR-T cells and again, there was no effect on tumour growth. Finally, the researchers examined whether localised, pulsed ultrasound was effective using mice with both a local and distal tumour. Injection of standard CAR-T cells reduced the size of both the local and distal tumour. However, after injection of the CAR-T cells and directing the ultrasound only at the local tumour, there was a dramatic reduction in size of the local, but not distal tumour.
Discussing their findings, the authors noted the use of the targeted pulsed ultrasound was a potentially effective approach to the treatment of localised tumours. They added the local administration of the CAR-T cells has already been tested in animals and patients and a further advantage of their technique was the potential for a reduction in off-target activity, i.e., where the CAR-T cells affected healthy tissue.
While this novel approach appeared to be effective, further work is required to ensure that the method represents a much safer form of cell therapy.
Wu Y et al. Control of the activity of CAR-T cells within tumours via focused ultrasound. Nat Biomed Eng 2021
28th June 2021
The European Alliance of Associations for Rheumatology (EULAR) is the organisation that represents the people with arthritis/rheumatism, health professions in rheumatology and scientific societies of rheumatology of all the European nations. With immune mechanisms clearly involved in the evolution of more severe COVID-19, there is a potentially important role for immunotherapy in those infected with the virus. As a result, EULAR convened a task force to develop overarching principles (OPs) and points to consider (PtC) on the pathophysiology of COVID-19 from a rheumatological perspective through a systematic review of the available evidence. The task force included 24 members from 8 different countries and comprised rheumatologists, translational immunologists, haematologists, paediatric rheumatologists and a patient representative. Based on the evidence from the literature, a series of statements were prepared and circulated to members, discussed and voted on. Initially EULAR sought at least 75% agreement on statement wording from members but where this did not occur, refinements were made and the revised statement re-circulated and the accepted level of acceptance was set at 67% for this second round.
The task force defined two overarching principles. The first was that the phenotype of COVID-19 infection is heterogenous and ranged from asymptomatic to lethal disease as a result of multi-organ failure. The second highlighted the need for different treatment approaches to manage an infection and that these were required at different stages of the disease.
The task force also approved 14 PtC, with a view to offering guidance on the management COVID-19 with immunotherapy. Six of the PtC covered aspects of the pathophysiology of COVID-19 with the remainder discussing the use of immunotherapy. For example, it was recognised that while cellular and humoral immune responses to COVID-19 were highly variable in patients, there was insufficient evidence to associate these differing responses directly with patient outcomes. The first PtC for immunotherapy noted the absence of evidence supporting a role for this treatment modality among non-hospitalised patients, or for the value of initiating such treatment. In contrast, given the evidence on oral corticosteroids, there was a recommendation to use these drugs (in particular dexamethasone and which has the strongest evidence), in patients receiving supplemental oxygen, non-invasive or mechanical ventilation. While the evidence base continued to change rapidly, another PtC was that it was still inappropriate to offer a formal recommendation for the routine use of tocilizumab in hospitalised COVID-19 patients requiring either supplemental oxygen, non-invasive or mechanical ventilation. The final PtC was that there was a lack of evidence to recommend the use of immunomodulators including convalescent plasma, interferon kappa, interferon beta, lenzilumab, cyclosporin or canakinumab.
An important caveat with the EULAR document is that it is not intended to undermine or override local regulations or guidelines produced by bodies such as the World Health Organization. Rather the purpose is to provide recommendations of good practice to help clinicians analyse their own therapeutic strategy and inspire change were appropriate. The authors concluded that given how knowledge around COVID-19 changes quickly, these PtCs will be updated as and when appropriate.
Aluno A et al. EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19. Ann Rheum Dis 2021; 80(6): 698-706