Proof of Principle study in Diffuse Cutaneous Systemic Sclerosis

Difuse cutaneous systemic sclerosis (dcSSc) is a rare systemic autoimmune disease characterized by widespread microvascular damage and cellular inflammation followed by progressive fibrosis (scar formation) in skin and internal organs. DcSSc has the highest morbidity and mortality of any rheumatologic disease.

Autoreactive T cells and NK cells have been identified as key players in the disease process, especially in the early phase of the disease. An autologous hematopoietic stem cell transplantation (HSCT) is the only disease modifying treatment currently available that can improve symptoms and prolong survival by eliminating autoreactive immune cells. However, HSCT is associated with significant toxicity and high costs.

T-Guard, a therapeutic tool designed for resetting the body’s immune system, consists of a unique combination of two toxin-conjugated monoclonal antibodies that target the CD3 and CD7 molecules on T cells and NK cells. After intravenous administration, T-Guard specifically identifies and eliminates adult T cells (CD3+, CD7+), with a strong preference for the activated cells, and NK cells (CD7+). Previous work has shown that following a one-week therapy, T-Guard is swiftly washed out of the body, and the T cell compartment is rapidly restored with newly formed T cells that have normal function and a diverse T cell receptor repertoire.

The therapeutic window for T-Guard was identified in patients with severe steroid-refractory acute Graft-versus-Host Disease (SR-aGVHD). Over 40% of patients with severe SR-aGVHD Grade III-IV had durable complete responses. However, development in SR-aGVHD has been paused because of the heterogeneity and vulnerability of the patient population that resulted in the occurrence of early deaths on study, which fatal events led to the precautionary and early termination of the T-Guard registration studies in this critically ill population.

Investigators of the Rheumatology Department of the Radboudumc demonstrated in a set of preclinical experiments that SSc-affected skin contains proliferating, cytotoxic T and NK cells. These cells selectively express the costimulatory molecule CD7 in association with cytotoxic, pro-inflammatory and pro-fibrotic genes, especially in recent-onset and severe disease. In addition, they have shown that CD7 regulates the cytolytic activity of T and NK cells and that selective depletion of CD7+ and CD3+ cells prevents cytotoxic cell-induced fibroblast contraction. Finally, a case report showed that treatment of a severely affected SSc patient with T-Guard resulted in depletion of CD7+ skin cells associated with stabilized disease manifestations.

Proof of Principle (POP) study at the Radboud University Medical Center (Radboudumc)

Based on above, Philikos and their partner the Radboudumc have started preparations for a proof-of-principle (POP) study to explore T-Guard’s potential to serve as safe and effective alternative for HSCT. This PoP study is named ‘T-Guard against Autoreactive T cells in Systemic sclerosis: Erasion and Resolution (TASER)’ and is planned to start around the end of 2024 at the Rheumatology Department of the Radboudumc. The TASER study will be performed in a small well-selected cohort of patients with dcSSc with adverse prognosis. T-Guard will be administered as a one-week treatment course, after which patients will be followed for safety and efficacy for a minimum period of 12 months.

Ideally, TASER will demonstrate that T-Guard forms a safe and effective alternative for HSCT, that is able to stop the disease and prevents the occurrence of debilitating symptoms associated with the later phase of the disease, thereby setting the stage for a randomized active-controlled follow-on study.