Clinical trial NCT04377867: New Biomarkers for Diagnosis and Follow-up of Patients With LRBA or CTLA4 Deficiencies
Official title: Identification of New Immunopathogenic Mechanisms Associated With LRBA or CTLA4 Deficiencies
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: LRBA Deficiency
CTLA4 Haploinsufficiency
Lead sponsor: Marmara University
Sponsor class: OTHER
Collaborators: name: The Scientific and Technological Research Council of Turkey
First posted: 2020-05-06
Enrollment: 30
Sex: ALL
Minimum age (years): 1
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Primary immune deficiencies characterized by immunodyregulatory diseases (LRBA and CTLA4 deficiencies). Age matched healthy individuals.

Brief summary: Primary immune deficiencies (PID) are a group of chronic diseases characterized by recurrent infections. Apart from recurrent infections, in some of PIDs autoimmunity, allergy or malignancy could be accompanied to the diseases. Recently, the advanced sequencing technologies have led to the identification of a growing number of novel PIDs including the immune dysregulation syndromes caused by loss of function mutations in the LRBA (encoding lipopolysaccharide-responsive beige like anchor protein) and CTLA4 (encoding cytotoxic T lymphocyte antigen 4) genes, which are in common associated with autoimmunity in addition to a predisposition to recurrent infections. PIDs with autoimmune components usually tend to have a more protracted clinical course and poorer prognosis rendering early diagnosis and treatment more crucial. The accurate diagnosis largely relies on the molecular diagnosis due to the significant overlaps between the phenotypic expression of these various genetic defects. The project aims to provide better and early diagnosis for LRBA, CTLA4 deficiencies by using basic and advanced immunological, genetic and molecular assays and rendering an early targeting therapy for patients, discover disease related new pathways and biomarkers that can be helpful during diagnosis and monitoring abatacept targeted therapy responses.

Detailed description: Lipopolysaccharide-responsive beige-like anchor (LRBA) and cytotoxic T lymphocyte protein-4 (CTLA-4) deficiencies are primary immunodeficiency characterized by recurrent sinopulmonary infections with hypogammaglobulinemia, lymphoproliferation and immunodysregulation, which presents by enteropathy, cytopenias and autoimmune endocrinopathy. LRBA plays a pivotal role in the intracellular trafficking of by CTLA4 re-routing it away from lysosomal degradation and back to the cell surface. CTLA-4 is an key immune checkpoint protein that is constitutively expressed on fork-head box P3 (FOXP3)+ regulatory T (Treg) cells and is also induced upon activation of conventional T cells. LRBA deficiency results in very low CTLA4 expression, which explains the phenotypic overlap between LRBA and CTLA4 deficient subjects. Furthermore, reduced Treg cells number and function have been demonstrated in LRBA-deficient patients. Consequent upon this, LRBA deficiency may manifest as an IPEX like disease with early onset autoimmunity.

LRBA was originally described as a common variable immune deficiency (CVID)-like disease with autoimmunity. To date, different agents have been applied in the treatment of LRBA and CTLA4 deficiencies, including corticosteroids, intravenous immunoglobulin therapy (IVIG), sirolimus, infliximab, rituximab and azathioprine. Some patients also benefit from hematopoietic stem cell transplantation (HSCT), which can be curative. More recently, studies have suggested the effectiveness of abatacept, a CTLA4-Ig fusion protein, in controlling disease-related immune dysregulatory phenotypes. In addition, some biomarkers like soluble CD25 and circulating T Follicular helper (cTFH) cells were described as useful to monitor patients' disease activity. Nevertheless, the long-term effectiveness of abatacept is not well documented. Also, there is no established consensus as to the dose and frequency of abatacept therapy for the treatment of those diseases and which biomarker is most reliable for follow up of patients.

Aims of this current study include:

1. Provide better and early diagnosis for LRBA, CTLA4 deficiencies by using basic and advanced immunological, genetic and molecular assays and rendering an early targeting therapy for patients.
2. Discover disease related new pathways and biomarkers that can be helpful during diagnosis and monitoring abatacept targeted therapy responses.

Eligibility criteria: Inclusion Criteria:

* Patients diagnosed with LRBA and CTLA4 deficiencies and eligible for the study
* Patients accept consent to participate in this study and followed prospectively on abatacept treatment.

Exclusion Criteria:

* History of hypersensitivity to abatacept
* History of acquired immunodeficiency diseases like HIV
* EBV viremia during the study screening
* Documented malignancy
* Current active infectious disease (bacterial or fungal) like tuberculosis
* Chronic hepatitis B or hepatitis C infections

Primary outcomes:
measure: Clinical Efficacy of abatacept in normalizing symptoms of disease
timeFrame: 3-9 months
measure: Clinical tolerability of abatacept in patients
timeFrame: 1-24 months
Secondary outcomes:
measure: Discontinuation of other immunosuppressants
timeFrame: 3-12 months
Other outcomes:
Locations:
city: Istanbul
country: Turkey
facility: Marmara University
state: Pendik
Study officials:
affiliation: Marmara University
name: Safa Baris, M.D.
role: STUDY_DIRECTOR
References:
citation: Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, Dogruel D, Karaca NE, Cogurlu MT, Bilir OA, Cansever M, Kapakli H, Baser D, Kasap N, Kutlug S, Altintas DU, Al-Shaibi A, Agrebi N, Kara M, Guven A, Somer A, Aydogmus C, Ayaz NA, Metin A, Aydogan M, Uncuoglu A, Patiroglu T, Yildiran A, Guner SN, Keles S, Reisli I, Aksu G, Kutukculer N, Kilic SS, Yilmaz M, Karakoc-Aydiner E, Lo B, Ozen A, Chatila TA, Baris S. Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2790-2800.e15. doi: 10.1016/j.jaip.2019.06.011. Epub 2019 Jun 22.
citation: Alroqi FJ, Charbonnier LM, Baris S, Kiykim A, Chou J, Platt CD, Algassim A, Keles S, Al Saud BK, Alkuraya FS, Jordan M, Geha RS, Chatila TA. Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018 Mar;141(3):1050-1059.e10. doi: 10.1016/j.jaci.2017.05.022. Epub 2017 Jun 7.
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