Tag: OCBs

Goalposts

We need to keep pushing the envelope and moving the goalposts in terms of our treatment targets in MS. 

As MS advances innate immune activation with microglial and astrocyte activation occurs. However, the latter may be adaptive in response to damage and hence a good thing, which is why I am sceptical about treatments aimed at targeting these cells in advanced MS. 

In comparison, B-cells and plasma cells are a different story. These cells are part of the adaptive immune system and are likely producing pathogenic, or damaging, antibodies. B cells and plasma cells set-up shop in the brain and spinal cords of MSers and churn out these heat-seeking missiles that are likely to be responsible for smouldering MS; i.e. the cortical lesions and the slowly expanding lesions or (SELs), which cause disease worsening even in those MSers who are NEDA (no relapses or no new or enhancing MRI lesions). The problem we have is that our current DMTs don’t appear to target these cells with the possible exception of cladribine that is a small molecule and gets into the brain and spinal cords of MSers.  Konrad Rejdak and colleagues in Poland have shown that about 50% of cladribine treated MSers lose their oligoclonal IgG bands (OCBs) from their CSF and that the patients who lose their OCBs tend to be stable compared to those who don’t lose their OCBs. We need to replicate these findings and supports our hypothesis to target CNS-resident plasma cells in MS.

Please note spinal fluid OCBs and immunoglobulin free light chains are at the bottom of our treat-2-target pyramid. This is our new goalposts.

This is why we are starting two studies in parallel, and want to start more studies with additional agents, to see if we can get rid of OCBs in MSers.

Our first study will look at oral cladribine’s effect on B-cell and plasma cell activity within the brain and spinal cords of MSers. Does cladribine reduce OCBs and immunoglobulin production? This study is called the “Oral Cladribine B-cell study” or CLAD B.

The following are the inclusions criteria for CLAD B:

  1. Patients with RRMS who are being treated with oral cladribine at Barts Health NHS Trust
  2. Patients must be willing and able to undergo lumbar punctures
  3. Patients who are OCB positive in their CSF (from previous diagnostic lumbar puncture) 

In our second study, we are testing a myeloma drug called Ixazomib in MS. Ixazomib is a second-generation proteasome inhibitor that works against malignant plasma cells. This study is called “Safety of targeting plasma cells in Multiple Sclerosis: A phase 1b randomised, double-blind, placebo-controlled trial” or SIZOMUS.

The following are the SIZOMUS inclusion criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the SIZOMUS study:

  1. Male and female patients 18 to 65 years old at screening.
  2. Must have a diagnosis of MS, and:
    1. Patients with RRMS must be on DMT
    2. Patients with progressive MS must not be on DMT
  3. Participants with RRMS must be on stable DMT (i.e. must not have had a relapse within 1 month prior to the screening visit)
  4. OCB positive CSF either from a previous CSF analysis or from the screening CSF analysis
  5. Patients must be willing and able to undergo lumbar punctures
  6. Agree to use of effective contraception

For those interested in proteasome inhibitors there is an emerging evidence base of them working in autoimmune diseases in general, in particular with the 1st-generation drug called Bortezomib. 

Do you think we are crazy? We have been working on getting these trials off the ground for over 3 years and the ideas, and hypotheses, underpinning these trials goes back more than 15 years. I originally wanted to do a thalidomide trial, targeting plasma cells, way back in 1997. However, I was advised against it by Professor W. Ian McDonald who thought it would be too risky. 

If you live in London, or the home counties, and are interested in participating in these trials, and you think you are eligible, let your HCP know and they can contact us.

Baker et al. Plasma cell and B cell-targeted treatments for use in advanced multiple sclerosis. Mult Scler Relat Disord. 2019 Jun 26;35:19-25

There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.

CoI: multiple

Beyond the B-cell

Do we have the right cell target in MS? Yes and no; we need a multicellular approach.

Recently the attention in MS has been on the B-cell as if it was the holy grail of MS treatments. It is not.

In several posts, over the last few weeks, I have made the case that the B-cell is important, probably as an antigen presenting cell, but it is not the ‘be all and end all’ of MS treatments. It is clear that rebound post-natalizumab is driven my B-cells and the positive data on the first BTK inhibitor would indicate that the B-cells are working via the B-cell receptor on antigen presentation. If only we knew what these antigens were we would have a much better handle on the cause of MS.

I know this science stuff is hard, but it is important. At the end of the day, the nut and bolts of MS must be molecular; molecules mean treatment targets and potentially more focused and hopefully better and safer treatments in the future.

I have stressed that simply targeting B-cells in both the periphery and central nervous system will not be enough to effectively treat MS in the long-term. When we look at end-organ damage markers in pwMS who are on B-cell therapies they have ongoing brain volume loss, albeit at a lower rate, and enlarging lesions (T1 black holes), which are both indicative of ongoing smouldering MS. So what do we need to do? I have provided circumstantial evidence that NIRTs (non-selective immune reconstitution therapies) have a slight edge on the B-cell therapies and this may be because they are also targeting T-cells. The latter, however, comes at a price of greater adverse events in relation to immunosuppression. The proportion of MSers on NIRTs who experience disability improvement seems higher when compared to the anti-B cell agents, which indicates that NIRTs are doing something else over and above their effect on the B-cell compartment. However, based on their overall safety profile it is unlikely that the NIRTs (alemtuzumab & HSCT) will be a therapeutic strategy that the wider MS community will adopt with vigour. Although from comments on this blog there is an informed group of MSers who feel hard done by because their HCPs won’t offer them the option of using NIRTs first-line, i.e. very early in the course of their disease when they have the most to gain from these therapies.

Is there anything else we can do to improve on the profile of B-cell therapies to make them better? Yes, I think there is. Targeting the plasma cell,in addition to the B-cell. Data on plasma cells goes back decades and surprisingly the plasma cell has never been a major therapeutic target in MS. John Prineas, one of my MS heroes, has always stressed the importance of the plasma cell in MS. His paper below from 1978 documents just how enriched the brains of MSers are with this population of cells. What is often not stressed is that the biology of plasma cells is so so different to the B-cell, which opens up new therapeutic targets that are quite different to those in the T and B cell compartments. More on this topic another time.

You are aware of the recent publication showing that about 55% of Polish MSers treated with intravenous cladribine lost their oligoclonal bands 10 or more years after treatment and if they did lose their OCBs they tended to have lower EDSS scores. We have known for years that MSers, with either relapse-onset or primary progressive diseases, who don’t have OCBs do better. There is also evidence from biomarker and pathology studies that the OCBs may be driving several of the disease processes that have been linked to advanced or progressive MS, i.e. microglial activation and grey matter pathology. Based on these observations, we hypothesise that OCBs are very likely to be pathogenic in MS, which is why we are embarking a research programme to try and target the plasma cells within the CNS of MSers. Do you think we are crazy?

To get a handle on the plasma cell we are going to have to study what happens in the spinal fluid. There are simply too many plasma cells in the periphery which will drown out any signal from the CNS. To participate in the studies we are planning we will have to perform serial, annual, lumbar punctures or spinal taps to see if our add-on therapy is killing and/or reducing the number of plasma cells in your brain and spinal cords. The good news is that we have de-risked the lumbar puncture with the use of atraumatic needles and screening. I never thought I would be saying this but most of our patients don’t mind having LPs, particularly when they understand the reason behind the LP.  CSF neurofilament levels are now part of our prognostic profile of MSers at baseline and we are increasingly using them to assess response, or lack of response, to treatment. So if you want to be treated and treated-2-target beyond NEDA, and beyond the B-cell, then having an LP is important.

We hope our proposed plasma cells studies will lead to a mindset that goes beyond the B-cell to target some of the mechanisms that are responsible for smouldering MS.

Prineas & Wright. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest. 1978 Apr;38(4):409-21.

Perivascular cells in CNS tissue from six multiple sclerosis (MS) patients and a patient with motor neuron disease were examined by light and electron microscopy. Lymph node tissue from one MS patient was also examined. CNS perivascular macrophages in both MA and motor neuron disease were found to closely resemble free macrophages elsewhere in the body except that they often contained unusually large primary lysosomes. Cytoplasmic inclusions consisting of membrane-bound stacks of curved linear profiles, presumed to be a product of myelin degradation, were constantly observed in microglia in MS plaques but were rarely observed in perivascular macrophages in the same area. Unidentified cylindrical bodies were observed within cysternae of rough endoplasmic reticulum in some lymph node cells. Quantitative studies of the perivascular cell population in one MS case revealed, in histologically normal white matter 260 lymphocytes and 178 plasma cells per cubic millimeter of fresh tissue. Typical chronic plaque tissue without obvious inflammatory cell cuffing contained 1772 plasma cells per cubic millimeter of fresh tissue. No plasma cells were observed in the CNS in motor neuron disease. The results of this study suggest that perivascular macrophages in the CNS represent a specialized population of monocyte-derived free macrophages, that these cells differ functionally from microglial cells, and that the digestion of myelin breakdown products in MS requires the participation of both cell types. The results also suggest that in some chronic MS cases there is a large, permanent population of CNS plasma cells that persists, like the elevated cerebrospinal fluid IgG level in this disease, for the life of the patient, that these cells, rather than inflammatory cells in fresh lesions, are the major source of this raised IgG, and that the existence of such a population of cells may indicate the continuing expression of antigens in chronic MS lesions in the absence of fresh lesion formation.

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