ABSTRACT
Neuroinflammation plays a prominent role in promoting the disease progression of ALS, mediated in part by the interaction of injured motoneurons with surrounding glia and dysregulated central and peripheral immunomodulatory cells. Prominent among such immunomodulatory cells are the CD4+ CD25highFOXP3+ T-lymphocytes that mediate neuroprotection by suppressing proinflammatory responses. However, Treg suppressive functions are impaired in ALS, but are restored and even enhanced following expansion ex vivo. Autologous infusions of these expanded T regs together with subcutaneous IL- 2 injections formed the basis of two ALS clinical trials. In a Phase 1 pilot study of 3 ALS patients, infusions were safe and well-tolerated and slowed progression rates during early and later stages of the disease. Treg numbers and suppressive function increased after each infusion and correlated with slowing of disease progression. However, the duration of the clinical benefit was limited, possibly related to the serum biomarkers of oxidative stress, 4-hydroxynonenal, and oxidized LDL These lipid peroxide biomarkers were increased prior to Treg infusions, fell with Treg infusions and slowing of disease progression, rose again as disease progression accelerated in the absence of infused Tregs, then fell again when Tregs were reinfused. Thus, the levels of 4-HNE and ox- LDL were effectively responsive to Treg infusions and mirrored the stabilization or deterioration of the subject's clinical status. A Phase 2A study of autologous infusion of expanded Tregs in combination with subcutaneous IL-2 injections was undertaken at Houston Methodist and Massachusetts General Hospitals. The study was planned for 12 ALS pts enrolled in a 24-week randomized control trial (RCT) followed by a 24- week open label extension (OLE). In the RCT Treg/IL-2 treatments were safe and well-tolerated;with increased Treg suppressive function in the active group. Evaluation of relative progression rates in the RCT was precluded by the COVID pandemic which decreased the number of participants. However, 8 ALS patients did complete the 24-week OLE;Treg/IL-2 treatments were safe and well-tolerated, and Treg suppressive function and numbers were increased. Six patients showed slow to no progression in the OLE (mean change of -2.7 points on ALSFRS-R) Two patients progressed rapidly;they were unresponsive to Treg infusions and had elevated markers of peripheral inflammation (IL-17C and IL-17F) as well as elevated markers of oxidative stress (OLR1 and oxidized-LDL). The 6 participants in the slow progressing group had normal levels. Whether Treg/IL-2 treatments can slow disease progression in ALS requires a large double-blind randomized controlled study. Nevertheless, our open-label studies, albeit in a limited population, suggest that Treg therapy is safe and well tolerated, and a promising approach to slowing ALS progression;lipid peroxide biomarkers may not only reflect a heightened pro-inflammatory milieu but may also be useful in monitoring clinical responsiveness to therapy.
ABSTRACT
Introduction: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody that may target T-regulatory (T-reg) cell function. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 for a single cycle of treatment. We provided longterm treatment with IC14 to 17 individuals with ALS via an expanded access protocol (EAP) and documented target engagement, safety, and disease endpoints. Method(s): Participants received intravenous IC14 every two weeks. Consistent with FDA guidelines, participants were ineligible for clinical trials and the EAP was inclusive of a broad population. Participants unable to travel to MGH due to the COVID-19 pandemic or disease progression, were transitioned to infusions in-home or local clinics. Blood samples for hematology, chemistry, and coagulation were collected to monitor safety. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) was administered monthly to track disease progression. Respiratory function was measured through slow vital capacity tests -data for this is limited due to the COVID-19 pandemic. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), soluble CD14, and antidrug antibodies (ADA). Ex vivo T regulatory functional assays were performed with five participants. Result(s): Participants received IC14 for up to 103 weeks (average: 30.1 weeks, range: 1-103 weeks). Treatmentemergent adverse events were uncommon, mild, and self-limited. There were 18 serious adverse events (SAEs) which were related to disease progression and unrelated (17) or likely unrelated (1) to IC14. Three participants died due to disease progression. Most participants achieved >80% monocyte mCD14 RO on a 14-day dosing schedule, although one individual required more frequent dosing (every 10 days) to achieve >80% RO. ADA were detected in only one participant and were transient, low titer, and non-neutralizing. Tregs were isolated from the available longitudinal samples and assayed for suppression of CD4 T cell proliferation and cytokine production versus baseline T-reg activity. Conclusion(s): IC14 administration to ALS patients was safe and well tolerated in this EAP, with no significant changes in laboratory tests and no drug-related SAEs. Measuring RO guided dosing frequency. Preliminary data suggest IC14 enhanced T-reg activity. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.