New Biomarkers for Diagnosis and Follow-up of Patients With LRBA or CTLA4 Deficiencies

CTLA4 Haploinsufficiency Clinical Trial

Official title:

Identification of New Immunopathogenic Mechanisms Associated With LRBA or CTLA4 Deficiencies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04377867
• Other study ID #: 09.2018.624
• Status: Recruiting
• Start date: January 15, 2020
• Est. completion date: January 15, 2023

Study information

• Verified date: May 2020
• Source: Marmara University
• Contact: Safa Baris, M.D.
• Phone: +905052614986
• Email: safabaris[@]hotmail.com
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: January 15, 2023
• Est. primary completion date: July 15, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Year to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• CTLA4 Haploinsufficiency
• LRBA Deficiency

Intervention

Drug:
• Abatacept Injection [Orencia]
Patients on abatacept to control disease symptoms

Locations

Country	Name	City	State
Turkey	Marmara University	Istanbul	Pendik

Sponsors (2)

Lead Sponsor	Collaborator
Marmara University	The Scientific and Technological Research Council of Turkey

Country where clinical trial is conducted

Turkey, 

References & Publications (4)

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. — View Citation

Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A, Charbonnier LM, Bakir M, Boztug K, Chatila TA, Barlan IB. Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1. J Clin Immunol. 2016 Oct;36(7):641-8. doi: 10.1007/s10875-016-0312-3. Epub 2016 Jul 5. — View 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. — View Citation

Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Rivière JG, Garcia-Prat M, Moes N, Haerynck F, Gonzales-Granado LI, Santos Pérez JL, Mukhina A, Shcherbina A, Aghamohammadi A, Hammarström L, Dogu F, Haskologlu S, Ikinciogullari AI, Köstel Bal S, Baris S, Kilic SS, Karaca NE, Kutukculer N, Girschick H, Kolios A, Keles S, Uygun V, Stepensky P, Worth A, van Montfrans JM, Peters AMJ, Meyts I, Adeli M, Marzollo A, Padem N, Khojah AM, Chavoshzadeh Z, Avbelj Stefanija M, Bakhtiar S, Florkin B, Meeths M, Gamez L, Grimbacher B, Seppänen MRJ, Lankester A, Gennery AR, Seidel MG; Inborn Errors, Clinical, and Registry Working Parties of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. J Allergy Clin Immunol. 2019 Dec 27. pii: S0091-6749(19)32603-X. doi: 10.1016/j.jaci.2019.12.896. [Epub ahead of print] — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical Efficacy of abatacept in normalizing symptoms of disease	The symptoms including lymphoproliferation, autoimmunity and chronic diarrhea should be controlled.	3-9 months
Primary	Clinical tolerability of abatacept in patients	Drug related side effects should not be observed (Severe viral or bacterial infections)	1-24 months
Secondary	Discontinuation of other immunosuppressants	Drug used before and after abatacept should be minimized	3-12 months