Терапевтические достижения в множестве склерозов: новые методы лечения (иммунные ингибиторы на контрольно-пропускных пунктах, CAR-T, Anti-CD40L).

Immune checkpoint inhibitors and multiple sclerosis

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies approved to treat a growing number of cancers including melanoma, lung, bladder, renal and breast cancer [ 1 ]. ICIs work by inhibiting immune checkpoints (e.g. PD-1, PDL-1, CTLA-4) thereby allowing the host immune system to attack the cancer [ 1 ]. The use of ICIs is limited by immune related adverse events (irAEs) such as colitis, myocarditis, pneumonitis, endocrinopathies, hepatotoxicity and neurologic adverse events [ 2 ]. The incidence of neurologic irAEs ranges from 4% with CTLA-4 blockade and up to 12% with combined CTLA-4 and PD-1 inhibition [ 3 ]. The most common neurologic irAEs are acute inflammatory demyelinating polyneuropathy, myasthenia gravis and myositis [ 4 ]. Other central nervous system complications such as autoimmune encephalitis have also been reported [ 5 ]. The pathophysiology of irAEs is likely due to activation of T-cells and production of pro-inflammatory cytokines which lead to off-target autoimmunity [ 6 ].

Patients with pre-existing autoimmune disease are at increased risk for irAEs or flare of their disease with ICI use. One systematic review of patients with rheumatologic disease found that half of patients had an exacerbation of their preexisting autoimmune disease and one third had an irAE on ICI therapy [ 7 ]. Data on pre-existing neurologic autoimmune disease suggests similarly a higher risk of irAEs especially for patients with pre-existing myasthenia gravis, myositis and paraneoplastic encephalitis [ 8 ].

There initially was concern about use of ICI therapy in patients with MS and patients with MS were excluded from ICI clinical trials. A number of earlier case reports were published on the development of MS [ 9 , 10 ] after ICI use or severe MS relapses associated with ICI [ 11 ]. A review of 10 cases with MS or radiologically isolated syndrome who received ICI found that 60% of cases had MS relapses after ICI initiation, with the risk of relapse 75% in those not on disease modifying therapy (DMT) and 50% in those on DMT [ 8 ]. However, it is likely that these case reports were not generalizable and there may have been reporting bias.

Larger retrospective analyses have shown overall lower risks of ICI use in patients with MS. A single-center U.S. study on 16 older (average age of 67.4 years), inactive patients with MS found no increased clinical disease activity associated with ICI use [ 12 ]. A French multicenter study analyzed 18 patients with MS with a median age of 48 years. In this cohort, only 3 (17%) had either clinical or radiographic signs of MS activity on average 3–6 months after ICI initiation. All 3 of the patients who had disease activity were age 50 or younger, and 2 of the patients had stopped natalizumab prior to ICI use. The one patient who had a clinical relapse fully recovered after high dose corticosteroids [ 13 ]. Anti-trafficking DMTs, such as fingolimod and natalizumab, are associated with a risk of MS disease rebound when they are discontinued [ 14 , 15 ]. It is possible that discontinuation of anti-trafficking DMT prior to ICI use may have contributed to disease activity in these cases.

An additional single center cohort of 7 patients with MS (6 who received ICI for cancer, and 1 who received ICI for progressive multifocal leukoencephalopathy) found that no patients had an MS relapse, and only 2 had asymptomatic radiographic activity (1 patient had been on ocrelizumab which was discontinued, and 1 patient had been on fingolimod which was continued) [ 16 ]. A review of 24 patients with demyelinating disease who received ICI at Mayo Clinic found that 3 patients had disease activity (two had radiographic activity, and one had a clinical relapse). These 3 patients were among the youngest in the cohort. Interestingly these 3 patients all had radiographically isolated syndrome (RIS), which suggests that ICI may unmask subclinical autoimmunity [ 17 ]. In one of the largest cohorts to date of 66 patients with MS who received ICI identified through the Medical Partnership 4 MS ​+ ​listserv only 2 patients (3%) had either relapse or MRI activity (one patient was on glatiramer, and one on interferon beta-1a which were both discontinued prior to ICI start) [ 18 ].

A recent meta-analysis on ICI use and patients with MS also found a low relapse rate (pooled relapse rate 5.45 per 100 patient-years) following ICI treatment with a higher risk of isolated radiographic activity (24.9 new MRI lesions per 100 patient-years). DMT was discontinued in 80% of the cases with radiographic activity [ 19 ].

When considering ICI use in patients with MS, it is important to balance the risk of MS worsening with cancer outcomes. In prior cohorts of MS patients receiving ICI, mortality rates were high. In the French Cohort, the mortality rate was 44%, and all fatalities were attributed to cancer (median follow up time from ICI initiation of 11.5 months) [ 13 ]. In a U.S. cohort there was a 75% mortality rate related to cancer (median follow up time from ICI initiation was 22.2 months). In both of these cohorts fatalities were from malignancy or complications of cancer related therapy and not MS disease activity or neurologic irAEs. Moreover, in the French cohort, in the one patient who had an MS relapse associated with ICI therapy, that patient remained on anti-PD1 treatment for 12 months without additional MS activity.

Thus, we believe that MS should not be a strict contraindication to ICI use. The decision to use ICI in a patient with MS should depend on an individualized risk benefit discussion. No study to date has been adequately powered to determine statistically significant risk factors for MS disease activity while on ICI but based on our review of the data we have identified possible risk factors for worsening MS activity and possible protective factors ( Table 1 ). Continuing MS DMT concurrently with ICI maybe helpful if compatible with oncologic treatment plan but further data is needed regarding oncologic and MS outcomes in these patients.

Table 1 Factors that may impact MS disease activity in patients with MS who receive ICI. Table 1 Factors that may increase risk of disease activity (clinical relapse or radiographic activity) Younger age (<50 years old) High relapse rate, or high rate of radiographic disease activity prior to ICI initiation Discontinuation of anti-trafficking agents (natalizumab, sphingosine-1-phosphate modulators) Factors that may decrease risk of disease activity (clinical relapse or radiographic activity) ∖ Older age (>50 years old) Low relapse rate, or low rate of radiographic disease activity prior to ICI initiation Concurrent use of cytotoxic chemotherapy Concurrent use of MS DMT

Factors that may impact MS disease activity in patients with MS who receive ICI.

Immune checkpoint inhibitor use in progressive multifocal leukoencephalopathy

One emerging use for ICIs has been in the treatment of progressive multifocal leukoencephalopathy (PML). PML is caused by the polyomavirus JC (JCV). PML is a devastating neurologic illness which presents as progressive neurologic symptoms such as cognitive dysfunction, hemianopsia, aphasia, and ataxia. Many healthy individuals have JCV in their kidneys, which remains latent due to cellular immune responses. Patients with MS, specifically on DMTs that reduce T lymphocyte or immune surveillance, are potentially at risk for the development of PML. Mortality rates depend on underlying condition. One cohort of 584 French patients with PML had a 38% mortality rate [ 20 ]. Historic treatments such as mirtazapine and mefloquine have demonstrated minimal benefit on treating JCV infection and use are limited to case reports [ 21 , 22 ]. The goal of ICI use in PML is to activate JCV specific CD8 + cytotoxic T-cells to try to eradicate the virus. Nivolumab was first used in a pivotal clinical trial in 8 cases of PML in which 5 patients had clinical improvement or stabilization [ 23 ]. A larger multicenter retrospective study of ICI use in patients with PML showed a one-year survival rate of 51.9% [ 24 ]. More data is needed to understand which types of patients will respond best to ICI for PML treatment.

Background: Limitations of current therapy CAR-T, Anti-IL40L

B lymphocytes (B cells) are central to the development and progression of MS [ 25 ]. In addition to initiating a cascade of inflammatory events peripherally, B cells also form lymphoid-like structures within the brain's cerebral meninges. This compartmentalized inflammation, occurring both in early relapsing and progressive stages of MS, is proposed as an important driver of disease progression in many patients [ 26 ].

While peripherally acting B cell-depleting antibodies like ocrelizumab have become a mainstay in MS treatment, these therapies are limited in their ability to penetrate the central nervous system (CNS). As a result, peripherally acting therapies are less effective in addressing compartmentalized inflammation from B-cell follicles and reducing their impact on disease progression. This limitation has spurred interest in therapies capable of crossing the blood-brain barrier and targeting inflammation within this privileged region. There are a number of new therapies that may hold potential to address both relapsing and progressive disease.

CAR-T therapy for MS

One promising approach to addressing compartmentalized inflammation involves Chimeric Antigen Receptors (CARs). CARs are synthetic receptors inserted into immune cells, typically via viral vectors, to activate specific immune responses. Once the CAR-T binds to the site on the target cell, it causes intracellular signaling, which then triggers the T-cell to proliferate and release cytokines to attack the target cell ( Fig. 1 ). CAR-engineered T cells have demonstrated dramatic success in targeting B-cell malignancies [ 27 ]. More recently, CAR-T therapy has shown potential in refractory autoimmune diseases [ 28 ]. The theoretical benefit of CAR-T therapy in these cases is that B cell depletion is more effective and would better eliminate autoreactive B cells. In eliminating autoreactive B cells, CAR-T therapy could induce remission and potentially be curative [ 29 ]. In cases of MS, CAR-T cells could offer the added advantage of crossing the blood-brain barrier directly, potentially impacting a critical aspect of disease progression and effectively controlling relapses.

This figure shows a schematic of how CAR-T cells are engineered and administered. Abbreviation: CAR= Chimeric Antigen Receptors.

However, there are some concerns about using CAR-T therapy in this population. CAR-T therapy has unique toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Both of these syndromes are thought to be due to immune system overactivation [ 30 ]. CRS is caused by the release of cytokines that clinically results in a flu-like state with myalgias and fevers [ 31 ]. In the case of patients with MS, these systemic symptoms could bring on recrudescence. The exact mechanism of ICANS is still under investigation, but the clinical symptoms include encephalopathy, language dysfunction, seizures, and, in extreme cases, cerebral edema and coma [ 30 ]. Given patients with MS already have a dysregulated immune state, there have been concerns that activating T cells in this disease could result in hyperactivation and a higher risk of known toxicities or novel neurotoxicity [ 29 ]. Additionally, others have noted the importance of identifying the most appropriate population of patients with MS to use these therapies. The cost of CAR-T therapy in complex cases has been estimated to be up to $500,000 [ 32 ]. Thus access and cost of CAR-T therapy is an important concern. Finally, it remains unclear how durable these therapies will be in patients with MS.

The first case reports of patients receiving CD19 CAR-T cells for MS have been published. In both patients CAR-T cell expansion in the central nervous system was demonstrated. One of those patients had CRS grade 1, according to consensus criteria, requiring treatment with tocilizumab and steroids. That patient did notably have a new spinal cord lesion on MRI in follow-up. There was no ICANS observed in either patient [ 33 ].

Reports from phase 1 studies are pending at this time though no significant safety signal has been reported to date. Approval from the FDA to pursue a phase 2 study was obtained in early 2024 (Kyverna) [ 34 ] and there are now several ongoing clinical trials for the use of CAR-T therapy in both progressive and relapsing MS.

Anti CD40L therapy for MS

Another therapy that can potentially address both peripheral and central inflammation in MS, is anti-CD40L therapy. CD40 is a protein found on the surface of several immune cells including B cells and dendritic cells. Interactions between CD40 and CD40L function as an immune checkpoint that controls responses to a number of inflammatory signaling cascades [ 35 , 36 ] ( Fig. 2 ). CD40L cells are not found in the CNS of healthy individuals but have been found in patients with MS, suggesting a pathologic role of CD40 in patients with MS [ 37 ]. Additionally, patients with MS have increased levels of T cells expressing CD40L in their blood [ 38 ]. CD40 is also expressed in resident and CNS infiltrated cells found in MS lesions [ 35 ] and has been reported to contribute to blood brain barrier breakdown [ 39 ]. Interestingly, EBV infection of cells induces CD40L expression in previously normal B cells [ 40 ]. Given the understanding that EBV is an important trigger in the development of MS [ 41 ] this combination of observations make targeting the CD40/CD40L dyed intriguing in the treatment of MS. Further, similarly to the discussion of CAR-T above, the ability to target compartmentalized inflammation in addition to peripheral inflammation make this an attractive target for therapy.

This figure highlights the role of the CD40 ligand (CD40L)-CD40 dyad and downstream inflammatory responses. The red “X” shows where frexalimab, a monoclonal antibody against CD40L binds thus blocking the CD40L/CD40 co-stimulatory pathway. Abbreviations CNS ​= ​central nervous system, PNS ​= ​peripheral nervous system.

In an experimental allergic encephalomyelitis (EAE) model of MS, administration of anti-CD40L antibody therapy prevented the development of disease amongst mice inoculated with proteolipid-peptide immunization to induce MS-like illness [ 37 ]. The first small study of CD40L therapy (Toralizumab) in MS patients showed good tolerability and safety. Exploratory data from that study showed stable EDSS scores and lack of relapses during the first 18 weeks of the study. The drug Toralizumab was ultimately withdrawn from further development due to reports of thromboembolic events in clinical trials of other patient populations [ 42 ].

Second generation CD40L agents have been developed that overcome the thrombotic risk through Fc-engineering. These therapies are being explored in different autoimmune conditions, including MS. Frexalimab is a monoclonal antibody against CD40L which blocks the pathway to activate T cells, B cells, dendritic cells, macrophages and microglia undergoing investigation for the use in MS. Reports from the phase 2, double-blind, randomized, placebo-controlled trial showed promise for at least relapsing remitting MS disease. After 12 weeks, 85% of the participants receiving 1200 ​mg IV of frexalimab every 4 weeks had no new gadolinium lesions, compared to 50% of the participants on placebo. The drug was overall well-tolerated. In the open-label period, headache, COVID and nasopharyngitis were the most common adverse events reported [ 43 ].

There are currently two phase 3 trials investigating the use of frexalimab in MS. The FREXALT Trial is a double-blind trial comparing outcomes on frexalimab and teriflunomide amongst patients with relapsing forms of MS. A second phase 3 trial ( NCT04879628 ) will determine if frexalimab can delay confirmed disability progression as compared to placebo amongst patients with non-relapsing secondary progressive MS.

Author contributions

Sarah Conway and Kristin Galetta both prepared and edited the manuscript with equal contributions.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Sarah Conway reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Sarah Conway reports a relationship with EMD Serono Inc that includes: consulting or advisory. Sarah Conway reports a relationship with Horizon Therapeutics USA Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

This article is part of a special issue entitled: Multiple Sclerosis published in Neurotherapeutics.

References