Monogenically driven therapies: the new first line

In this issue of Blood, Dhunputh et al describe the efficacy of off-label use of abatacept, a CTLA-4 immunoglobulin protein, in a cohort of patients with pediatric immune-mediated cytopenia related to CTLA-4–related pathway defects (CTLA-4 deficiency, lipopolysaccharide responsive and beige-like anchor protein [LRBA] deficiency, and DEF6 deficiency).¹ 

Identification of the genetic etiology of inborn errors of immunity (IEIs)² has revolutionized the use of precision targeted therapy to treat complications of IEIs that are unrelated to infection. Immune-mediated pathologies, such as autoimmune cytopenia (AIC), are a prominent feature of IEIs as a result of CTLA-4–related pathway defects. Severe AIC is often refractory to initial immunosuppression, and flares of disease are common. The disrupted mechanisms driving AIC include T cell– and B cell–driven autoimmunity, pathologic inflammation, poorly controlled inflammatory responses, and impaired production. Dhunputh et al focused on autoimmunity-driven AIC caused by CTLA-4–opathies. CTLA-4 is an inhibitory receptor essential for T-cell regulation. CTLA-4 regulation is key to modulating inflammation and turning down the inflammatory response by inducing sequestration of costimulatory ligands on antigen-presenting cells. Interaction with LRBA prevents its degradation. Furthermore, Serwas et al³ discovered that interaction with DEF6 is important for CTLA-4 availability and trafficking. Defects involving CTLA-4,^4,LRBA,⁵ and DEF6³ result in immunodeficiency and autoimmunity (see figure).

Abatacept was first studied in tumor necrosis factor α–refractory rheumatoid arthritis⁶ and was US Food and Drug Administration approved in 2007. In the study by Dhunputh et al, the authors used the drug to mechanistically target the mutant genes. Patients with CTLA-4 defects are unable to suppress CD4⁺ proliferation compared with healthy controls, leading to a phenotype of humoral immunodeficiency and autoimmunity. A prior study showed that CD80/86 ligand–dependent proliferation was blocked by abatacept.⁴ Egg et al⁷ recently reported a cohort of patients treated with various immunomodulatory agents for the disease manifestations of CTLA-4 deficiency and found that a majority of patients with AIC responded to abatacept. Concurrently, a long-term study of 76 patients in Europe with LRBA deficiency treated with abatacept showed improvement in most organ systems affected.⁸ In this study, 9 patients with pediatric immune cytopenia were treated with abatacept for CTLA-4 deficiency (n = 5), LRBA deficiency (n = 3), and DEF6 deficiency (n = 1). At the start of treatment, 6 were in complete remission (CR) on other therapies, two had partial remission (PR), and one had not achieved remission. After starting therapy, an additional patient achieved CR, and the remaining 2 patients in this group reached sustained PR. Six patients were able to wean off all other therapies. No patient had a new flare of AIC on therapy. Abatacept response continued for up to 4.9 years after initiation of therapy and allowed for steroid-sparing therapy.

This concept of targeted therapy has shown some promise in monogenic gain-of-function diseases in the JAK/STAT signaling pathway.⁹ AIC caused by lymphoproliferation and abrogation in production has either completely or partially resolved with treatment using ruxolitinib, baracitinib, or tofacitinib in STAT1 and STAT3 gain-of-function disorders.¹⁰ More studies are needed to assess clinical efficacy in multiorgan immune dysregulation disorders allowing for 1 drug to target multiple defects. In addition, remission of AIC is a durable outcome measure to consider in future clinical trials. Currently, there is 1 safety and efficacy trial (Safety and Efficacy of Abatacept for Treating Chronic Cytopenia in Cytotoxic T-Lymphocyte Antigen 4 [CTLA4] Haploinsufficiency; registered at www.clinicaltrials.gov as #NCT03733067), which will be enrolling patients soon, and 1 observational study (New Biomarkers for Diagnosis and Follow-up of Patients With LRBA or CTLA-4 Deficiencies; registered at www.clinicaltrials.gov as #NCT04377867).

A significant number of IEIs present with immune-mediated pathology as a major feature in addition to infection. AIC is a common manifestation in these patients. Specific genetic disorders are teaching us about basic mechanisms of autoimmunity/inflammation in humans, which in turn has led to better targeted therapy. If the cellular mechanisms or genetics are known, therapy can be personalized. The use of targeted therapies to enhance efficacy warrants close study and expansion of clinical trials in IEIs.