Background

Low-dose interleukin 2 is being tested as an immunomodulatory approach in neurodegenerative diseases. It increases the number and activity of regulatory T cells (Tregs) that suppress inflammation. At high doses, IL-2 stimulates the immune response to tumors, and is approved for treating cancer.

Treg-mediated immune control appears to be compromised in people with AD (Faridar et al., 2020). In preclinical studies, Tregs that were transferred into AD mice entered the brain and stopped Aβ plaque growth (Faridar et al., 2022). Multiple labs have reported that low-dose IL-2 induces expansion of Treg cells, decreases hippocampal Aβ plaque load, and lessens memory deficits in APP/PS1 mice (Dansokho et al., 2016; Alves et al., 2017; Yuan et al., 2023).

Tregs also play a role in ALS and in Parkinson’s disease. In people with ALS, an observed decline in Tregs correlated with faster disease progression. In the SOD1 mouse model of ALS, giving IL-2 or Tregs resulted in motor neuron preservation, less spinal cord inflammation, and longer survival (Sheean et al., 2018; Banerjee et al., 2008). A Phase 1 study in ALS patients demonstrated reduction in markers of oxidative stress and inflammation after Treg infusion (Beers et al., 2022).

In PD patients, reductions in Treg number and function correlated with proinflammatory T cell activation, and increases in Tregs were associated with improved clinical measures (Thome et al., 2021; Arce-Sillas et al., 2024). Administration of low-dose IL-2 led to Treg expansion in a mouse model of PD (Markovic et al., 2022). In other preclinical studies, transplantation or expansion of Tregs was neuroprotective in rodent models of PD (Reynolds et al., 2010; Badr et al., 2022; Park et al., 2023).

Findings

In June 2019, academic investigators in Houston, Texas, began an open-label feasibility study of low-dose commercially available recombinant human IL-2 in people with AD dementia. Eight participants injected 1 million units of Aldesleukin daily for five days per month, for four months. Results are published (Faridar et al., 2023). The treatment was safe and well-tolerated. Most common adverse events were injection site reactions and mild leukopenia, each affecting one-third of patients. After each cycle, participants had increased Treg numbers and function, which returned to baseline between treatments. IL-2 treatment downregulated inflammatory cytokine expression in circulating monocytes, and some plasma pro-inflammatory markers decreased compared to baseline. The investigators claimed an improvement on the MMSE that reverted to baseline after treatment had ended. ADAS-Cog and CDR-SB scores did not change.

In 2020, COYA Therapeutics was founded by the Houston researchers to develop low-dose IL-2 under the name COYA-301. The company presented more results of the open-label AD study in May 2023, indicating a significant lowering of monocyte inflammatory mediators TNFα, IL-6, and IL-1β after treatment. In one patient, TSPO-PET scans suggested a reduction in brain inflammation two weeks after the last dose (slides).

In January 2022, Phase 2 began with support from the Gates Foundation and the Alzheimer’s Association. The Houston investigators enrolled 38 AD patients with mild to moderate dementia, for six months of Aldesleukin, given as a five-day course by subcutaneous injection once or twice per month. The primary endpoint was safety and tolerability. Change in Tregs as a percentage of total CD4 T cells served as a secondary endpoint. In May 2024, COYA announced completion of the study, with results to follow later in the year (press release).

In September 2022, an independent Phase 2 trial began enrolling 45 AD patients with mild dementia at the Centre Hospitalier St. Anne in Paris. Treatment consists of 1 million units of IL-2 or placebo, on a schedule of daily injections for five days, followed weekly injections for four months. The primary endpoint is change in Clinical Dementia Rating 18 months after the first injection. Other endpoints include the MMSE, ADAS-Cog, ADCS-ADL, CDR-SB, change in Tregs and other immune cells, PET scans for neuroinflammation, hippocampal atrophy, and safety. The trial will run until September 2025.

In March 2023, a biomarker study began to assess the effects of low-dose IL-2 on CSF and blood markers of inflammation, and on brain inflammation using the ER176 PET tracer that binds TSPO. This placebo-controlled study will enroll 40 patients in Houston, to receive IL-2 every two or four weeks for six months. The study will run until December 2025.

Testing of low-dose IL-2 for ALS began in 2015, with a Phase 2 trial by researchers in Nimes, France. Thirty-six patients received 1 or 2 million units of IL-2, or placebo, by subcutaneous injection for five days each month for three months, in addition to riluzole. IL-2 was tolerated, with mild adverse events that included injection site reactions and flu-like symptoms. The study achieved its primary outcome of increasing Tregs in the treatment groups. The plasma inflammation marker CCL2 decreased dose-dependently, but there was no change in the surrogate efficacy marker of plasma neurofilament light (Camu et al., 2020). Analysis of leucocyte gene expression showed a dose-dependent increase in Treg markers at the end of treatment (Giovanelli et al., 2021). Inhibition of inflammatory gene expression was apparent after the first cycle of treatment, and was less pronounced after three cycles. Higher baseline inflammatory gene expression predicted poorer response to treatment.

From 2017-2021, researchers followed up with a larger Phase 2 trial in France and the U.K. The MIROCALS study enrolled 220 patients newly diagnosed with ALS, for five-day courses of 2 million units Il-2 per day, or placebo, monthly for 18 months. The primary outcome was survival. Results were announced in December 2022 (press release). Treatment was safe, tolerated, and resulted in elevated Treg numbers. Treatment was associated with a non-significant 19 percent reduction in the risk of death. In a prespecified subgroup analysis, participants with low CSF phosphorylated neurofilament heavy chain and less aggressive disease had a significant 40 percent increase in survival. This subgroup included most of the participants in the trial.

From 2019-2022, investigators in Houston and Boston tested the combination of monthly injections of patient-derived Tregs with low dose IL-2 in 12 ALS patients. The treatment was safe and resulted in elevations of Treg suppressive function (Thonhoff et al., 2022).

In 2020, another open-label trial began recruiting 13 ALS patients in China; its status is unknown.

In October 2021, COYA started an open label study in people with ALS of low-dose IL-2 in combination with CTLA4-IgG. Called Abatacept, this drug suppresses the activation of monocytes and microglia; it is used to treat autoimmune diseases. The company is testing this dual immunomodulator under the name COYA-302. The study, at the Houston Methodist Research Institute, planned to treat 10 patients every two weeks for one year, and assess safety and tolerability. Secondary and exploratory outcomes include Treg function, serum biomarkers of oxidative stress, inflammation, and neurodegeneration, and clinical functioning on the ALSFRS-R scale. Results are published (Thonhoff et al., 2024). Four patients enrolled; all completed it without serious adverse events. Increases in Treg in number and function occurred over the entire treatment period, and returned to baseline levels after treatment stopped. Biomarkers showed trends to reduction in the first 16 weeks, but were not uniformly changed. ALSFRS-R scores remained stable over 48 weeks.

In May 2024, the Houston researchers began a small trial testing COYA-302, dosed every two or four weeks, in 10 frontotemporal dementia patients. The open-label treatment will run for six months with a primary outcome of safety, and a secondary outcome of blood Treg numbers. Completion is expected in April 2026.

For details on low dose IL-2 trials, see clinicaltrials.gov.