Check-point charlie

Barts-MS rose-tinted-odometer ★★★★★ 

The argument about whether or not MS is primarily a T-cell or B-cell disease is academic. Almost all the data suggests that both cell types are involved. Clinical trial data also suggests MS outcomes when it comes to end-organ damage (brain volume loss) is superior for therapies that target both  T and B cells, i.e. alemtuzumab and HSCT over say mainly B-cell therapies (rituximab, ocrelizumab, ofatumumab and cladribine). I have posted on the latter topic in the past, i.e. see ‘Beyond NEDA’. 

Another big clue is worsening MS and new-onset MS after the treatment of cancer with the relatively new class of treatments called immune checkpoint inhibitors (ICI). These drugs target cell surface receptors that inhibit T-cell activation. Remove the inhibition and you lower the threshold for T-cell activation. About 50% of patients treated with ICI develop immune-mediated complications including new-onset MS. 

The study below identifies 14 cases of MS after ICI, which I suspect is just the tip of the iceberg. The type of MS induced by ICI appears to be much more aggressive in onset and disease course. Why? I suspect because the activated T-cells are not being regulated as a result of ICI  treatment. 

I am aware that some people argue that these cases don’t represent true MS, but a different disease. I don’t agree. Why? There is an increasing number of people with established MS who develop malignancies requiring treatment with ICI.  In many of these cases, ICI triggers major relapses and rebound disease activity. The sceptics can’t really argue that these patients don’t have MS. 

The use of ICI in patients with established MS is creating a treatment dilemma. They clearly need the ICI to treat their cancer, but how do you manage their MS during the high-risk period when they are on ICI? 

I recently recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The potential downside of this strategy is that if she had occult secondaries in her CNS and gut, areas of the body that natalizumab reduced lymphocyte trafficking, natalizumab will prevent her activated T-cells finding and clearing cancer cells in these organs. As bowel cancer rarely metastasizes to the CNS we thought this was a risk worth taking. 

The last update I had about this patient was that she was doing well from the MS perspective (natalizumab is a very effective DMT), but she was not doing that well in relation to her bowel cancer. She, unfortunately, had liver metastases that had not responded as hoped to the ICI. 

I am also sure that natalizumab will prevent the CNS complications associated with CAR-T cell therapies. Could this be a repurposing opportunity for natalizumab? I have informed Biogen about this possibility. 

So in conclusion, don’t let anyone try and convince you that MS is only a B-cell disease. It is a T-cell and B-cell disease and we are really lulling ourselves into a false sense of security by thinking anti-B-cell monotherapy is sufficient to treat MS. The anti-B-cell therapies may appear very effective and safer in the short term, but as a class, their impact on brain volume loss (end-organ damage) is just not good enough for me (see NEDADI post). This is why we need to think about using anti-B-cell therapies differently, i.e. as part of an induction-maintenance strategy or in combination with other therapies that target other disease processes. 

Garcia et al. Multiple Sclerosis Outcomes After Cancer Immunotherapy. Clin Transl Oncol, 21 (10), 1336-1342 Oct 2019. 

Introduction: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes.

Methods: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution.

Results: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors.

Conclusions: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.

CoI: multiple

13 thoughts on “Check-point charlie”

  1. Thanks for this Prof G. MS can be an all consuming disease to those with it (like me) and it’s easy to forget that we are are also at risk (as is everyone) of getting other diseases such as cancer.

    “This is why we need to think about using anti-B-cell therapies differently, i.e. as part of an induction-maintenance strategy or in combination with other therapies that target other disease processes.” What progress is being made in relation to therapies that target other disease processes?

    What will be the trial implications for combination therapies ie would you have to do a trial of (made up example) of Lemtrada + statin + remyelination therapy, or it the latter two have shown effectiveness and are licensed , could the neuro decide on the combination. My father in law has a serious heart condition and bladder cancer and when he went into intensive care, they cut out his 14 tablets and did a different combination of 6. I can’t believe the 6 had been formally trialled, but the individual drugs were licensed and the combination was the decision of the treating doctor.

  2. Apologies for me being thick, but were the 14 patients on DMTs? Did they really need immunotherapy? Did they have a resection? I’m asking in relation to RCC and non small cell carcinoma lung cancer. Another question, is there any evidence that untreated MS protects against metastasis?

  3. Mavenclad reset the b-cells, was it not possible to add and element into the drug to target the t-cells as well?

    1. But it already does that. It depletes ~50% of T-cells as well. The question is, is this enough or not. The jury is still out on this, but some results, eg. its long term effect on OCBs indicate that, at least in some individuals, its enough. So maybe you don’t need to deplete T-cells completely.

  4. So in conclusion, don’t let anyone try and convince you that MS is only a B-cell disease. It is a T-cell and B-cell disease

    Well so much so for the ~”response to theraphy” mantra regarding anti cd 20 efficacy

    Your trial for killing plasma cd in the cns using proteasome inhibitors ,how that relate to your statement?


    1. Don’t worry Luis, it’s Prof G hedging his bets as always 😉

      The plasma cell question more accurately relates to the specific problem of intra-CNS immunoglobulin possibly facilitating neurodegeneration and not to overall disease modification per se.

  5. Maybe it tells us that natalizumab blocks trafficiking into more than just the brain or gut, why would biology need to invent such distinct trafficking mechanisms.

  6. “Don’t let anyone convince you”….OK Boss I’ll shut up…..:-), but of course T cells will be important to B cell biology just as B cells are important to T biology however is the emphasis equal?

    1. No there has been too much emphasis on the T-cell, but as the pendulum swings the other way we need to guard against a B-cell centric world view blinding us 😉

      1. The real question is how much T depletion is just enough to get the job done? Maybe Cladribine’s long term effect on OCBs show that you don’t need to deplete T cells as completely as Alem/HSCT do.

      2. “B-cell centric world view blinding us”
        The blind leading the RRMS to Secondary Progressive.
        “Would the course have been different had rituximab been initiated at clinical onset or used in a more intensive fashion ?”
        No..earlier rituximab treatment would have made no difference…
        “used in a more intensive fashion ?” Yes..hsct likely would have helped this patient avoid thoracic spinal cord lesion count .

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