“The B cell is now firmly in the MS spotlight and will be even more so after we get to hear the ocrelizumab results at ECTRIMS. When proposing a cause of MS we have to be able to explain the effect of all the DMTs on the causal pathway. When I did this exercise using cell types the B cell was the only common cell to all the highly effective DMTs with exception of daclizumab (anti-CD25). It appears that B cell function in MSers treated with daclizumab is relatively normal although B cell numbers in the spinal fluid do drop. The lack of a direct impact of daclizumab on B cell function is one of the reasons why I find the drug so interesting.”
“Back to the B cell; why is it so important? I would like to think it has to do with EBV, but until we have a treatment that targets the EB virus and leaves B cells intact we won’t be able to address this issue. This is why we launched the Charcot Project and why we still want to do the ARTEMIS study. However, is it simply good enough to deplete B cells, or block their trafficking into the central nervous system? There is evidence that B-cell follicle like structures in the brain of MSers is responsible for progressive MS. The problem with simply targeting B cells with anti-CD20 therapies is that you leave the plasma cells intact. Plasma cells are long-lived specialised factory cells that produce antibodies in large quantities. This is why we need to test treatments that cull the plasma cell pool within the brains of MSers.”
“We know already that the OCBs (oligoclonal IgG bands) in the spinal fluid don’t disappear with rituximab treatment and are unlikely to disappear with ocrelizumab treatment as well. Nor do they disappear with alemtuzumab treatment and HSCT or BMT. However, there is an emerging literature that in MSers on long-term natalizumab treatment OCBs may disappear. Unfortunately, most of the studies looking at this have been relatively small and one study was negative. Therefore a larger more systematic study is needed. The question is how does natalizumab get rid of OCBs? I nearly fell off my chair at the EAN meeting earlier this year when I heard that the plasma cells need VCAM-1-VLA interactions to remain in their niche. As natalizumab blocks the VCAM-1-VLA interaction it may be responsible for displacing plasma cells and results in the death of long-lived plasma cells within the CNS. If this is true it may change the treatment paradigm of MS. What is clear is that plasma cell biology within the CNS in MSers needs much more careful study; particularly in MSers on highly effective DMTs.”
“Since learning about the plasma cell niche I am much more upbeat about natalizumab’s chances in progressive MS. We won’t have to wait too long; Biogen are due to announce the results of the ASCEND trial (natalizumab in SPMS) in the next few weeks. Let’s hope it is good news. I am still concerned that the ASCEND trial may have be too short (24 months) to give a positive read-out. However, Biogen enriched the study for rapid progressors and it is one of the most effective DMTs we have so it has more than a fighting chance of clearing the efficacy hurdle.”
“When you look at B-cell and plasma cell biology it is clear that that there are therapeutic targets other than CD20 and VLA-4. Anti-CD19 is expressed on plasmablasts and plasma cells so it has the potential to be more effect that anti-CD20 treatments. Similarly, the recent trial of anti-CD38 in myeloma (a malignancy of plasma cells) was very encouraging. Maybe we can target anti-CD38 to the CNS as a potential MS treatment? Similarly, thalidomide and thalidomide-derivatives are drugs that are used to treat myeloma; could they be used to treat MS? I suspect the side effect profile makes them too risky. The good news is there is still much to learn about MS and many therapeutic strategies to test.”
|The peripheral plasma cell niche is likely to be similar to the CNS niche in MS!|
Mancuso et al. Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: a longitudinal study. Mult Scler. 2014 Dec;20(14):1900-3.
Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. In this study, we prospectively analyzed both serum and CSF samples from 24 MS patients, before and after 2 years ofnatalizumab-based therapy. Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy. Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. Our data showed thatnatalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported.
Intrathecal immunoglobulin synthesis in an oligoclonal pattern is the most common immunologic abnormality detected in MS patients. Various treatments, such as immunomodulators and immunosuppressors, have not been found to modify it. Natalizumab hinders migration of encephalitogenic T-cells into the central nervous system (CNS), reducing inflammatory response. Its impact on CSF oligoclonal bands (OCBs) has not been demonstrated. This report describes its effect in four out of six patients with multiple sclerosis after a mean of 10 infusions: the CSF was negative for OCBs at the second lumbar puncture. In conclusion, natalizumab treatment can reduce CSF OCBs to undetectable levels, although the clinical significance of this observation is not yet known.
BACKGROUND: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML).
OBJECTIVE: We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37).
METHODS: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid.
RESULTS: In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid.
CONCLUSIONS: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.
METHODS: In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics.
RESULTS: No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥ 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months.
CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).