Scientists at UCL have discovered new biomarkers, which may identify those people with Type 1 diabetes who would benefit from the immunotherapy drug Abatacept, a finding which could eventually help thousands manage the disease more effectively.
Type 1 diabetes is an autoimmune disease, which means it is caused by the body’s own immune system attacking healthy body tissues.
People with the condition are unable to produce the hormone insulin, which is essential to control and use glucose as energy.
Abatacept is an immunosuppressive drug that subdues the aberrant immune response in people with autoimmune diseases, and identifying a biomarker will enable clinicians to give the drug to those who would positively respond.
The research group, led by Professor Lucy Walker (UCL Institute of Immunity & Transplantation), built on their discovery in 2014, which found that certain immune cells, known as ‘follicular helper T cells’ (Tfh), can cause Type 1 diabetes by triggering the destruction of insulin-producing cells in the pancreas.
In this latest study, published in Nature Immunology, researchers at UCL in collaboration with scientists from King’s College London and AstraZeneca, wanted to find out why some people with Type 1 diabetes responded well to Abatacept, while others did not.
Explaining the study’s focus, Professor Walker said: “Abatacept is already widely used to treat other autoimmune conditions, including rheumatoid arthritis.
“Early tests in people with Type 1 diabetes have found the drug is not suitable for routine use because the response is very variable – some people benefit a lot, while others not at all.
“Being able to tell in advance who is likely to respond may reignite interest in this therapy for those with diabetes.”
For the study, blood samples from people with Type 1 diabetes, who had taken part in a clinical trial of Abatacept were studied.
The team discovered that the numbers of Tfh cells were reduced by Abatacept treatment and the cells’ phenotype (biochemical characteristics) had been changed.
Machine learning was then used to compare blood samples from people who showed a good response to Abatacept with those who showed a poor response.
To the team’s surprise, the machine learning algorithm was able to detect differences in the profile of the Tfh cells, even before treatment, which could be used as biomarkers to establish whether someone was likely to respond to Abatacept.
Professor Walker said: “Our new work suggests that by analyzing these T cells, and looking at the markers they express, we can make predictions about how well people will respond to Abatacept.
“The next step will be to test this in more people and explore whether it works for other therapies and other autoimmune diseases. “New improved versions of Abatacept have now been developed and it will be particularly exciting to see if the biomarker approach is applicable to these.”
In the UK, there are around 400,000 people with the Type 1 diabetes, including 29,000 children. As those with the condition cannot produce insulin, glucose builds up in the bloodstream, and over time can cause serious kidney, heart and eye damage.
In 1999, Professor Walker identified signals that controlled ‘follicular helper T cell’ behavior, and later found that these cells appear in high numbers in those people with Type 1 diabetes.
She added: “The project has been years in the making and has relied heavily on collaboration between researchers, clinicians, bioinformaticians and industry partners.”
Professor Walker’s research team are part of the UCL Institute of Immunity & Transplantation, based at the Royal Free hospital, London. The project received funding from Diabetes UK, AstraZeneca, the Medical Research Council and the Rosetrees Trust.
Sarcoidosis is a granulomatous systemic disease that becomes chronic in approximately one third of affected patients resulting in quality of life and functional impairment. Immunosuppressive drugs other than steroids represent alternative therapeutic options, but side effects like liver and bone marrow toxicity or increased susceptibility to infections limit their use. Pathophysiological studies in sarcoidosis patients demonstrate altered regulatory T-cell functions with a reduced expression of CTLA-4 (CD152) and prolonged inflammation. Therefore, interfering with CTLA-4 using abatacept might be a therapeutic option in sarcoidosis similar to rheumatoid arthritis therapy.
Methods/design
This is a multicenter prospective open-labeled single arm phase II study addressing the safety of abatacept in sarcoidosis patients. 30 patients with chronic sarcoidosis requiring immunosuppressive therapy beyond 5 mg prednisolone equivalent will be treated with abatacept in combination with corticosteroids for one year in two centers.
The primary endpoint is the number and characterization of severe infectious complications under treatment with abatacept.
Secondary endpoints are the rate of all infections, patient-related outcomes (assessed by questionnaires), lung function and immunological parameters including alveolar inflammation assessed by bronchoaveolar lavage.
Discussion
This is the first trial of abatacept in patients with sarcoidosis. It is hypothesized that administration of abatacept is safe in patients with chronic sarcoidosis and can limit ongoing inflammation. Patients’ wellbeing is assessed by established questionnaires. Immunological work-up will highlight the effect of abatacept on inflammatory pathways in sarcoidosis.
Trial registration
The trial has been registered at the German Clinical Trial Registry (Deutsches Register Klinischer Studien, DRKS) with the identity number DRKS00011660.
Discussion
The ABASARC trial described herein focusses on three aims, which are (i) assessing the safety and efficacy of abatacept in sarcoidosis patients, (ii) exploring different endpoints that might prove suitable for further trials and (iii) characterization of the patient collective.
Even though there are several different drugs used to treat corticosteroid-dependent sarcoidosis [2,46,47], abatacept may represent a novel and unique therapeutic option for two main reasons: First, as outlined before, there are several hints that CTLA-4 expression [15,32,33,35,[48], [49], [50]] and function are dysregulated in sarcoidosis and therefore abatacept restore this defect as a target therapy. Second, its side effects differ substantially from drugs like methotrexate, azathioprine or mycophenolate mofetile especially concerning bone marrow and liver toxicity.
Inclusion criteria for this trial (i.e. starting an immunosuppressive treatment with abatacept) are based on the daily clinical practice. Immunosuppressive therapy beyond corticosteroids in sarcoidosis is not well established and varies between different centers based on expected side effects and local experiences, also local recommendations to change immunosuppressive therapy may be handled differentially [51,52].
Generally, deterioration of organ function, reduced quality of life or side effects of established therapies (e.g. diabetes or weight gain induced by steroids) are considered indications for therapy adaptation [46].
Therefore, the physicians’ appraisal for starting or changing an immunosuppressive therapy in sarcoidosis patients represents a main inclusion criteria for patients who are affected by (i) an organ manifestation requiring immunosuppression, (ii) having sarcoidosis-associated complaints assessed by KSQ and (iii) inflammatory activity of sarcoidosis measured by sIL2R or neopterin.
The first aim of the study, assessing the safety of abatacept treatment is assessed addressed as primary endpoint as the number of severe infections during treatment with abatacept and as secondary endpoint addressing the rate of severe infections, non-severe infections and non-infectious complications of abatacept therapy.
Recent studies in other indications (especially rheumatoid arthritis) have shown that infections are the most important severe side effects of abatacept treatment even though infections and cardiac side effects are not increased compared to e.g. anti TNF antibodies [53,54]. Therefore, an open-labeled trial design was chosen which allows a better assessment of infectious complications occurring during treatment.
To closely assess safety, the first six patients included in the trial will be monitored closely in six week-intervals. Their safety data will be monitored by an independent data safety board.
As patients with an immunosuppressive therapy are at an increased risk of infections, the infectious complications occurring during the trial will be compared to infections retrospectively collected for the year prior to study participation. This will allow estimating whether abatacept markedly increases the risk of infections.
Second, secondary endpoints explore different surrogates of an effective treatment for sarcoidosis that cover markers of inflammation, lung function and patient-reported outcome parameters.
Therefore, three questionnaires assessing patients’ well-being were included as secondary endpoints. In particular, the King’s Sarcoidosis Questionnaire that covers different health domains affected by sarcoidosis, e.g. pulmonary health, general well-being (including fatigue) or concerns about medication.
This questionnaire has rarely been investigated in clinical drug studies and may prove a suitable endpoint because it has been specifically designed to capture sarcoidosis-associated symptoms and hence is clearly different from several other questionnaires typically used in sarcoidosis studies. Because KSQ has rarely been used in studies, we decided to additionally use SGRQ as an additional questionnaire.
Even though validated for COPD, but not for sarcoidosis, it has been used widely in different studies investigating different interstitial lung diseases [[55], [56], [57]]. Thereby the combination of a generally used questionnaire (SGRQ) with a very disease-specific questionnaire (KSQ) may cover a broad range of patient-related outcomes.
Therapeutic interventions in sarcoidosis have been undertaken basing on pathophysiological observations and analogies to other Th1-driven inflammatory diseases. Nevertheless, to date there are no randomized controlled trials demonstrating the efficacy of a single drug intervention in sarcoidosis patients.
Obstacles for a meaningful clinical study are due to the study design and the chosen endpoint on the one hand and to the heterogeneity of sarcoidosis patients and their unpredictable disease course on the other hand.
For example, infliximab failed to achieve a clinically meaningful gain in FVC in sarcoidosis patients [12]. However, in a subgroup of patients with a high TNF-level, lung function improvement was more pronounced by infliximab treatment [13].
Additionally, extrapulmonary manifestations improved in the treatment group [58]. These observations indicate that meaningful clinical trials in sarcoidosis will need a well-chosen endpoint and requires inclusion of well characterized patients.
Therefore, the third aim of the ABASARC trial focusses on the identification of patients, who benefit most of abatacept treatment.
Before starting and after terminating abatacept treatment, the study protocol requires an intense clinical and immunological assessment of the recruited patients including bronchoalveolar lavage.
The use of BAL in a clinical study and changes in alveolar cell composition as a secondary outcome parameter is uncommon in clinical sarcoidosis studies. On the one hand, BAL procedure may vary between different centers, therefore a similar protocol of BAL procedure and analysis is used that is established in both centers [59].
On the other hand, alveolar inflammation may also be monitored by use of 18FDG-PET-CT, which has been used in some trials [60]. The use of BAL and its immunological work-up offers the benefit to gain insight in the pathophysiology of sarcoidosis and changes induced by abatacept.
The interaction of T-cells, regulatory T-cells and antigen-presenting cells is influenced by abatacept enabling regulatory T-cell response to dampen the inflammatory response. Therefore, the immunological assessment will focus on these pathways by analyzing T-cell subpopulations in blood and BAL samples.
In summary, the immunological assessment of the alveolar and blood compartment and their changes induced by abatacept treatment together with clinical data may allow the identification of patients who experience the greatest benefit of abatacept therapy.
REFERENCE LINK : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292904/
More information: Edner, N.M., Heuts, F., Thomas, N. et al. Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes. Nat Immunol (2020). doi.org/10.1038/s41590-020-0744-z
