Alice Laroni

Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases

The rationale for use of adult stem cells as a treatment for neurological diseases such as multiple sclerosis arose from the hope that they had the capacity to foster repair of the CNS through tissue integration and differentiation into neural cells. Evidence from preclinical studies suggested that mesenchymal stem cells (MSCs), a subset of adult progenitor cells, are an effective therapy in preclinical animal models of neurological diseases such as experimental autoimmune encephalomyelitis, a model for multiple sclerosis, and stroke. In experimental autoimmune encephalomyelitis, intravenous injection of MSCs ameliorates clinical course and decreases demyelination, immune infiltrates, and axonal loss. Surprisingly, these effects do not require full CNS engraftment by MSCs, but rely on the capacity of MSCs to inhibit pathogenic immune responses and release neuroprotective and pro-oligodendrogenic molecules favouring tissue repair. These results led to the conclusion that therapeutic use of MSCs should initially focus on individuals with multiple sclerosis and persistent inflammation. Small clinical studies in different neurological diseases have suggested that MSCs are safe, paving the road for larger phase 2 studies addressing the effect of MSCs on clinical outcomes and markers of disease activity.

T‐cell trafficking in the central nervous system

Summary:  To perform their distinct effector functions, pathogen‐specific T cells have to migrate to target tissue where they recognize antigens and produce cytokines that elicit appropriate types of protective responses. Similarly, migration of pathogenic self‐reactive T cells to target organs is an essential step required for tissue‐specific autoimmunity. In this article, we review data from our laboratory as well as other laboratories that have established that effector function and migratory capacity are coordinately regulated in different T‐cell subsets. We then describe how pathogenic T cells can enter into intact or inflamed central nervous system (CNS) to cause experimental autoimmune encephalomyelitis or multiple sclerosis. In particular, we elaborate on the role of CCR6/CCL20 axis in migration through the choroid plexus and the involvement of this pathway in immune surveillance of and autoimmunity in the CNS.

Mesenchymal stem cells as treatment for MS – progress to date:

The unmet need for therapies capable of repairing the central nervous system (CNS) damage occurring in many diseases including multiple sclerosis (MS) has sparked the interest of the neurological community for stem cell-based therapies. An exhaustive amount of preclinical data has shown that the intravenous administration of mesenchymal stem cells (MSC), a subset of progenitor cells isolated from many mesodermal tissues, effectively ameliorates experimental autoimmune encephalomyelitis (EAE), a model of MS, through the release of anti-inflammatory and neuroprotective molecules. Based on these results, several small pilot clinical trials in subjects with advanced MS have demonstrated that MSC administration is safe and provided an early signal of clinical effectiveness. The current aim of clinicians and scientists interested in the development of MSC-based strategies for the treatment of MS is to have the ultimate demonstration in large clinical trials that MSC can inhibit CNS inflammation and foster tissue repair as realized clinically, with functional recovery, or visualized by magnetic resonance imaging (MRI).

Early switch to fingolimod may decrease the risk of disease recurrence after natalizumab interruption

We read with interest the case report by Daelman et al., regarding a severe reactivation of multiple sclerosis (MS) in a woman who switched from natalizumab (NTZ) to fingolimod (FTY).1 Here we report the follow-up of 19 subjects who withdrew NTZ at the MS Clinic, University of Genoa, Italy from January 2011 to January 2012 and subsequently began, in a non-randomized fashion, FTY (n=11) (7/11 started FTY in the framework of the open-label study with FTY, Protocol CFTY720DIT03), another immunomodulatory (IM) agent (either interferon-beta or glatiramer acetate (GA), n=4) or remained untreated (n=4). The FTY group included one subject initially treated with GA for 12 weeks who switched to FTY due to cutaneous side effects. NTZ was stopped after a mean of 30.42 months (standard deviation (SD) 12.94), due to drug-associated risk2 or patient’s decision. The treatment groups were homogenous as per demographic and disease characteristics (Table 1). Four out of 11 subjects in the FTY group and all the others received intravenous high dose methylprednisolone (MP) pulses as an arbitrary attempt to prevent disease exacerbation. Fewer subjects in the FTY group received MP pulses in order to accelerate the enrollment into the open-label study with FTY that required washout of steroids before inclusion. In detail, patients were scheduled to receive three to four courses of 1 gram MP intravenously once a day starting at 90, 135 and 180 days after stopping NTZ. The schedule was changed in the case of a relapse or due to intolerance to MP. Mean dose of MP administered (including the treatment of relapses) was 1.9 g (±2.7) for patients who switched to FTY, 7.4 g (±4.9) for patients who started another IM, and 10.0 g (±6.8) for those who remained untreated. Time to new treatment was 18.84±5.45 weeks for those who started FTY and 14.29±2.94 weeks for those who started another IM drug (p= not significant (ns)). The number of relapses occurring between 13 weeks (mean time required by serum NTZ concentration to decrease to nontherapeutic values3) and 34 weeks post NTZ interruptions were compared among groups. We observed an unbalanced distribution of relapses depending on the chosen treatment. In detail, one relapse occurred in 1/11 subjects who started FTY and in 5/8 subjects who remained untreated or started another IM drug (respectively 3/4 and 2/4) (Exact Chi-square test, p=0.03 FTY vs other IM agents vs untreated; p=0.04 FTY vs others) (Figure 1). Relapses required hospitalization in four cases (none in the FTY group). Of note, the only subject having a relapse in the FTY group was the one who had been treated with GA for 12 weeks after NTZ and started FTY later (31 weeks post NTZ stop). The administration of MP did not prevent the occurrence of a relapse. FTY treatment was well tolerated without serious adverse events. In summary, despite the limited number of cases and the observational nature of this report, we observed a better control of relapses in subjects with similar disease characteristics who switched from NTZ to FTY compared to those who remained untreated or started another IM drug. We may speculate on a possibly synergic effect of NTZ and 468498 MSJ19910.1177/1352458512468498Multiple Sclerosis JournalLaroni et al. 2012

Safety of the first dose of fingolimod for multiple sclerosis: results of an open-label clinical trial

BackgroundIn patients with relapsing-remitting MS (RRMS) fingolimod prevents disease relapses and delays disability progression. First dose administration of fingolimod is associated with a transient, dose-dependent decrease in heart rate (HR) in the 6 hours after drug intake.The aim of the study is to to assess safety and tolerability of the first dose of fingolimod in a cohort of Italian patients with RRMS without alternative therapeutic options.MethodsOpen-label, single arm, multicentre study. After the first dose of fingolimod, patients were observed for 6 hours and had their vital signs monitored hourly. Extended on-site monitoring was provided when required.ResultsOf the 906 patients enrolled in the study, most (95.2%) did not experience any adverse event (AE) following fingolimod administration. Cardiovascular AEs occurred in 18 patients and included bradycardia (1.3%), first-and second-degree atrioventricular block (0.1% and 0.2%), palpitations (0.1%), sinus arrhythmia (0.1%) and ventricular premature beats (0.1%). All events were self-limiting and did not require any intervention. Extended monitoring was required in 34 patients.ConclusionsThese results, in a population who better resembled real-world clinical practice in terms of concomitant diseases and medications, are consistent with previous clinical trials and confirmed that the first dose administration of fingolimod is generally safe and well tolerated.Trial registrationEudraCT 2011-000770-60

Autologous hematopoietic stem cell transplantation in multiple sclerosis A meta-analysis

Objective: To summarize the evidence on immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) to manage severe and treatment-refractory multiple sclerosis (MS). Methods: We collected all the published studies of aHSCT in any form of MS from 1995 to 2016, carefully excluding reports that were updated in subsequent studies. Endpoints were transplant-related mortality (TRM), rate of disease progression, and no evidence of disease activity (NEDA) status. A weighted metaregression based on a Poisson model was run, assessing whether there were study-specific characteristics with an effect on TRM and progression. Results: Fifteen studies including 764 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 2.1% (95% confidence interval [CI] 1.3%–3.4%). TRM was higher in older studies (p = 0.014) and in studies with a lower proportion of patients with relapsing-remitting MS (RRMS) (p = 0.028). A higher baseline Expanded Disability Status Scale (p = 0.013) was also significantly associated with a higher TRM. Pooled rate of progression was 17.1% at 2 years (95% CI 9.7%–24.5%) and 23.3% (95% CI 16.3%–31.8%) at 5 years. Lower 2-year progression rate was significantly associated with higher proportions of patients with RRMS (p = 0.004). The pooled proportion of NEDA patients at 2 years was 83% (range 70%–92%) and at 5 years was 67% (range 59%–70%). Conclusions: The emerging evidence on this therapeutic approach in MS indicates that the largest benefit/risk profile form this therapeutic approach can be obtained in patients with aggressive MS with a relapsing-remitting course and who have not yet accumulated a high level of disability.

Association of melanoma and natalizumab therapy in the Italian MS population: a second case report

There is debate about a possible association between natalizumab treatment and higher risk of melanoma. Here we report a case of melanoma in a patient who developed melanoma after 77 infusions of natalizumab, without known risk factors. Pharmacovigilance programs of new drugs can help to monitor adverse events in patients at risk.

Mesenchymal stem cells for the treatment of neurological diseases: Immunoregulation beyond neuroprotection.

An inflammatory response is often observed in neurological diseases, being characterized sometimes by activation of adaptive cells (T and B lymphocytes) and, almost inexorably, of cells of the innate immunity (microglial cells, macrophages). Mesenchymal stromal/stem cells represent a promising therapeutic approach for the treatment of intractable neurological diseases given the possibility that they affect neurodegeneration both directly and indirectly, through their potent immunomodulatory effect. Here we will review the evidence, mostly deriving from preclinical studies, that MSC, beyond their ability to foster neurorepair, can ameliorate neurodegenerative diseases through their effect on associated immune responses.

Assessing association of comorbidities with treatment choice and persistence in MS: A real-life multicenter study

Objective: To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort. Methods: We included newly diagnosed patients (2010–2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch. Results: The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04–1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07–1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon β, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04). Conclusions: Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.

Clinical baseline factors predict response to natalizumab: their usefulness in patient selection

BackgroundOptimal patient selection would improve the risk-benefit ratio of natalizumab treatment for relapsing-remitting multiple sclerosis (RR MS). Clinical features of subjects responding to natalizumab have not been univocally recognized.MethodsLongitudinal data on RR MS patients treated with natalizumab in Liguria, Italy are reported. Predictors of relapse occurrence and disability improvement were analyzed with a logistic regression method in subjects treated for one year (N = 62). A new score, called “Better EDSS Trend (BET)”, was devised to describe the impact of the treatment on disability. Changes in annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) after one and two years and proportion of disease-free patients were evaluated.ResultsPrevious EDSS worsening plus ARR ≥ 2 increased the risk of relapse during the treatment [Odds Ratio (OR) 4.12, P = 0.04], but this was not associated with an increase in disability at one year. EDSS 3.0-3.5 or high disease activity were associated with neurological improvement in the first year of treatment (respectively OR 5.78, P = 0.05 and OR 4.80, P = 0.05). Positive BET score, i.e. improvement in the disability trend, was observed in 40.3% of patients, and correlated with high ARR in the year before treatment (OR 1.69, P = 0.03).ConclusionSubjects with EDSS 3.0-3.5 and those with very active disease in the year before treatment are most likely to improve in neurological function under natalizumab. A relapse in the first year of treatment is associated to high pre-treatment disease activity; however, since the occurrence of a relapse did not have a negative impact on clinical improvement at one year, we suggest that it should not lead to treatment discontinuation. We propose BET as an additional endpoint of treatment response in MS.