Daratumumab for Familial Cerebral Cavernous Malformations: A Single-Arm Safety and Efficacy Study

Overview

Cerebral cavernous malformation (CCM) is a common vascular abnormality of the brain, affecting 0.1%-0.5% of people. It often causes recurrent brain hemorrhages, epilepsy, and neurological impairments, with surgery being the main treatment. However, surgery carries high risks for patients with multiple lesions or lesions in critical areas, and no effective pharmacological treatment is available. CCM is linked to mutations in genes like CCM1, CCM2, CCM3, or MAP3K3, which activate the MEK5-ERK5-KLF2/4 pathway, disrupting endothelial function. Immune cell infiltration, particularly plasma cells with high CD38 expression, suggests a role for humoral immunity in CCM. Depleting B cells in mouse models reduced lesions and hemorrhages, but broad B cell depletion is risky. To find a safer treatment, researchers tested anti-CD38 monoclonal antibodies in mice, showing that targeting CD38 reduced CCM lesion formation. Given the success of CD38-targeted therapies like daratumumab in treating multiple myeloma, this study proposes evaluating daratumumab for CCM in a single-center trial with 10 adult patients to assess its safety and efficacy.

Cerebral cavernous malformation (CCM) is a vascular anomaly occurring within the brain, with a prevalence of approximately 0.1%-0.5% in the general population, representing the most common vascular malformation of the central nervous system. CCM is the leading cause of recurrent intracerebral hemorrhage in adolescents and can also induce epilepsy, neurological deficits, and other related symptoms. Currently, the mainstay of treatment for CCM is surgical resection via craniotomy. However, for patients with multiple lesions or lesions located within the brainstem or eloquent brain regions, surgical intervention carries a significant risk of severe functional impairment or even mortality. At present, no effective pharmacological treatments are available for CCM. Studies have demonstrated that endothelial cell mutations in genes CCM1, CCM2, CCM3, or MAP3K3 are key drivers of CCM pathogenesis. These pathogenic mutations activate the MEK5-ERK5-KLF2/4 signaling axis within endothelial cells, disrupting endothelial barrier function and coagulation regulation, thereby leading to lesion formation. Nevertheless, it has been recognized that, in addition to these genetic mutations, essential co-factors such as endothelial cell proliferation are also required for CCM initiation and progression. Our previous research revealed that the CCM lesion microenvironment is characterized by substantial infiltration of immune cells, including myeloid cells and lymphocytes. Further analysis of the enriched cell types and their functions indicated the presence of a large number of specific plasma cells within CCM lesions, suggesting a role for activated humoral immunity in CCM pathogenesis. Gene expression profiling of these plasma cells revealed a marked expression of CD38. To clarify the role of B cell-mediated humoral immunity in CCM development, we employed B cell-depleting antibodies in mouse models of CCM. Depletion of B cells resulted in a significant reduction in both lesion burden and associated hemorrhage. However, pan-B cell depletion is associated with broad immunosuppressive effects, potential adverse events, and lacks therapeutic precision, thereby limiting its clinical applicability. To identify a more precise therapeutic target, we tested the efficacy of anti-CD38 monoclonal antibodies in two distinct mouse models of CCM. Our results demonstrated that targeting CD38 effectively inhibited CCM lesion formation and progression. In recent years, CD38-targeted immunotherapies have been widely applied in the treatment of plasma cell malignancies and autoimmune diseases, exhibiting favorable safety profiles and sustained efficacy. Notably, in hematologic malignancies such as multiple myeloma (MM), CD38 monoclonal antibodies have become a cornerstone of first-line treatment. Daratumumab, an anti-CD38 monoclonal antibody, was the first CD38-targeted therapy approved for MM treatment and has significantly improved patient survival outcomes, demonstrating excellent safety and efficacy in clinical practice. Based on these findings, we propose to explore the therapeutic potential of daratumumab, an anti-CD38 monoclonal antibody, for the treatment of CCM.This study is an open-label, single-arm, single-center clinical trial aimed at evaluating the safety and efficacy of the CD38 monoclonal antibody daratumumab in the treatment of familial cerebral cavernous malformations (CCM). Adult patients who meet the inclusion criteria will be enrolled, with an expected sample size of 10 participants.