Tecfidera with immune tolerizing cell therapy shows promise for MS
Therapy uses patient’s own modified dendritic cells to induce immune tolerance
Combining the approved medication Tecfidera (dimethyl fumarate) with targeted therapy using a patient’s own immune cells may eventually be a promising way of treating multiple sclerosis (MS), according to recent research.
The targeted therapy uses tolerogenic dendritic cells (tolDCs), which are being tested in clinical trials, to make alterations to a person’s own immune cells that will stop the immune system from wrongfully attacking healthy tissues. However, this approach is limited by the fact that MS immune cells have an overly inflammatory profile and may be resistant to the therapeutic modifications.
In lab studies and a mouse model of MS, findings suggested that adding in Tecfidera, which is also sold as generics in the U.S., could help the immune cells take on a more favorable profile for tolDC therapy.
‘Potentially revolutionizing how multiple sclerosis is treated’
“This study represents a significant step forward in the use of personalized cell therapies for autoimmune diseases, potentially revolutionizing how multiple sclerosis is treated,” the Josep Carreras Leukaemia Research Institute stated in a news story announcing the publication.
The study, “Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis,” was published in the Journal of Clinical Investigation.
The immune system is carefully designed to attack foreign invaders, like bacteria and viruses, while leaving alone the body’s own tissues through a process known as immune tolerance.
In autoimmune diseases, however, self-tolerance mechanisms fail, causing the immune system to wrongfully attack healthy parts of the body. MS is characterized by autoimmune attacks that target myelin, the protective substance surrounding nerve cells.
Dendritic cells (DCs) are a class of immune cells that are heavily involved in regulating immune tolerance. Treating these cells with vitamin D causes them to take on a tolerogenic profile, or one that promotes immune tolerance, which may help to treat autoimmune conditions such as MS.
TolDC therapy essentially involves treating DCs with vitamin D to make them more tolerogenic, and then loading them up with molecules that are wrongfully attacked in an autoimmune state. When returned to the body, the tolDCs are thought to help re-educate the rest of the immune system to tolerate those molecules.
The researchers previously developed one therapy for MS wherein monocytes, which are a type of immune cell that gives rise to DCs, are collected from the blood, differentiated into DCs in the presence of vitamin D, and loaded with a pool of myelin-specific proteins. The idea is that these tolDCs will teach the immune system to leave myelin unharmed after being injected in or near the lymph nodes of the neck.
TolDC therapy found safe, feasible in 2 Phase 1 clinical trials
In two Phase 1 clinical trials (NCT02903537; NCT02618902) involving relapsing-remitting MS (RRMS) patients, the tolDC therapy was found safe and feasible, according to the team.
However, because immune cells, including monocytes, tend to be dysregulated in autoimmune diseases, these patient-derived cells may resist the tolerizing protocol and have diminished therapeutic effects.
In the recent study, the scientists characterized the properties of monocytes taken from people with active, untreated RRMS and healthy people, finding that the immune cells from MS patients indeed had a more activated, inflammatory state.
That inflammatory signature was maintained when the monocytes were differentiated into mature DCs, and tolerization with vitamin D was not able to revert it, supporting the idea that MS monocytes might be resistant to tolerization.
Across experiments, the scientists found that cells from MS patients exhibited dysregulation of pathways related to aryl hydrocarbon receptors (AhRs), which are involved in immune function.
When tolDCs from MS patients were incubated in the lab with a molecule to activate AhRs, the cells were better able to take on a tolerogenic profile, whereas a molecule to block AhRs had the opposite effect.
Tecfidera shown to have better safety profile than other AhR activators
Notably, Tecfidera, which has been shown to boost AhR signaling pathways but has a better safety profile than other AhR activators, had similar benefits in terms of increasing tolerogenic function.
When monocytes were isolated from MS patients who’d been treated with Tecfidera, the cells had a less inflammatory profile and a greater tolerogenic capacity than cells from untreated patients, looking more similar to cells from healthy people.
In a mouse model of MS, treatment with both Tecfidera and tolDC therapy led to greater reductions in disease severity and disease-related immune cell populations than either treatment alone.
The scientists indicated they recommend a combined approach for treating MS patients, as Tecfidera could help reduce monocytes’ inflammatory profile and boost their ability to become tolerogenic.
Ultimately, this will “fully aid the generation of fully potent tolDCs with maximal tolerance induction capability … in MS and other autoimmune diseases,” the team concluded.
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