Background/Purpose: Background/Purpose:  Immune checkpoint inhibitors have demonstrated durable benefit in some cancer patients.  However, checkpoint inhibitors are also associated with new onset autoimmune adverse events.  The link between checkpoints and autoimmune disease suggests that activating immune checkpoint receptors might be useful in treating autoimmune diseases like SLE.  As the role of B cells and T cells are implicated in SLE, we became interested in modulating BTLA (B- and T-lymphocyte attenuator) as potential therapeutic target for SLE.  The endogenous ligand for BTLA is HVEM (Herpes virus entry mediator), and BTLA attenuates lymphocytes by recruiting phosphatases SHP-1 and SHP-2 to the B cell receptor and T cell receptor signaling complexes, respectively.   The current study examined the BTLA/HVEM signaling pathway in two large phase 3 trials in SLE to determine if there was a therapeutic rationale for activating BTLA in SLE.

Methods: Methods:  Whole blood gene expression data from 1760 SLE patients was obtained from the phase 3 ILLUMINATE-1 and ILLUMINATE-2 studies in patients with SLE and active disease activity defined as SLEDAI-2K ≥ 6 (NCT01205438, NCT01196091).  Control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52. RNA was analyzed using Affymetrix Human Transcriptome Array 2.0. 

Results: Results:  High levels of BTLA mRNA were observed on B cells, CD4+ T cells, CD8+ T cells and plasmacytoid dendritic cells.   HVEM mRNA levels were lower in SLE patients compared to healthy controls, while BTLA levels were similar between SLE and control.  Low levels of HVEM mRNA were associated with increased disease activity at baseline, including proportion of patients with SLEDAI ≥ 10, and frequency of patients with anti-dsDNA antibodies, low complement (C3 and C4), and elevated interferon gene signature.   

Conclusion: Conclusions:  The analysis confirmed that BTLA is present on key immune cells linked to the pathogenesis of SLE.  The reduced levels of HVEM in SLE patients compared to control suggests that ligand deficiency in the BTLA system may play a role in SLE.  Importantly, low HVEM was associated with increased disease activity across multiple disease characteristics, including measures of high disease activity, serology and gene expression.  These data provide clinical rationale for evaluating a BTLA agonist in SLE.  A phase 1 trial with a BTLA agonist antibody in healthy volunteers is in progress.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-evidence-supporting-therapeutic-potential-of-activating-the-immune-checkpoint-receptor-btla-in-sle/