"Scientists hail autoimmune breakthrough" - the Guardian

T

Tia

Senior Member (Voting Rights)
I don't know if this has been posted elsewhere but I thought it was very interesting. I wonder if something like this might end up being helpful for a subset of pwME...

https://www.theguardian.com/science...disease-therapy-breakthrough-car-t-cell-lupus

"In the latest work, doctors took T-cells from the lupus patients and modified them so that, on re-infusion, they attacked the patients’ B cells. In lupus, B cells churn out autoantibodies, which instead of defending the body against invading pathogens, attack healthy tissues instead.

According to the study in Nature Medicine, the therapy in effect wiped out the patients’ aberrant B cells and dramatically improved their condition. The disease affected multiple organs in all five patients, but after the therapy severe symptoms including arthritis, fatigue, fibrosis of the heart valves, and lung inflammation all cleared up."
Blood tests on the patients showed that their B cells recovered about four months after the treatment, but they no longer produced aberrant antibodies and the patients remained disease-free. Writing in the journal, the authors speculate that the therapy led to a “rebooting of the immune system”.
 
Yes, it is exciting.

But remember that Leandro, Edwards et al., in around 2000, reported a similar series (actually a bigger one) of SLE patients treated with rituximab - with similar results. And in the recent series patients had to have two cytotoxic drugs in addition to the CAR T cells.

Nevertheless, if CAR T cells can kill more B cells than rituximab and really do produce sustained remission in lupus then our original hypothesis is finally confirmed and the long awaited upgrade in technology has arrived. It would mean that we do not need to chase plasma cells.

We need much more data on long term follow up though.

I hope to make use of these data for a presentation on B cell depletion treatments in ten days time.
 
The study the Guardian article is based on:
Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus Andreas Mackensen et al

Abstract
Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation.

Five patients with SLE (four women and one man) with a median (range) age of 22 (6) years, median (range) disease duration of 4 (8) years and active disease (median (range) SLE disease activity index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use chimeric antigen receptor (CAR) T cell program.

Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded and reinfused at a dose of 1 × 106 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. CAR T cells expanded in vivo, led to deep depletion of B cells, improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-double-stranded DNA antibodies.

Remission of SLE according to DORIS criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (2). Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration) and even after the reappearance of B cells, which was observed after a mean (±s.d.) of 110 ± 32 d after CAR T cell treatment. Reappearing B cells were naïve and showed non-class-switched B cell receptors. CAR T cell treatment was well tolerated with only mild cytokine-release syndrome. These data suggest that CD19 CAR T cell transfer is feasible, tolerable and highly effective in SLE
 
Barry said:
Is it known why lupus affects far more women than men?
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Almost all B cell based autoimmune diseases are more common in women. Differences in antibody production between males and females make sense because women make antibodies for their newborn babies. The antibody levels are not different but I gather that recent work has shown that women produce a more vigorous antibody response to antigens they have seen recently - maybe the B cell system is more immediately reactive than in men. That might explain more mistakes. Autoimmunity is basically when the system makes an antibody by chance that manages to slip through quality control far enough to take advantage of the normal chain reaction that is used for antibodies to microbes.

The intriguing thing about lupus is that whereas most autoimmune diseases are about three ties as common in women lupus is nine times as common. That might be because the check point that fails in lupus is specifically associated with complement. There is also an interesting recent report of a lupus case with a TLR gene defect that I think was on the X chromosome so there might be an additional sex linked factor there. What is a bit odd about that is that genes on X chromosomes tend to produce diseases in men because they can be x-linked recessive since men only have one x so cannot make up the defect with the other one.
 
The paper offers an explanation for why rituximab doesn’t work for SLE

Despite substantial advances in the treatment of SLE, some patients do not respond to the current state-of-the art therapies and are at high risk for organ failure and even death7. Furthermore, there is currently no solid strategy for achieving drug-free remission or even cure of SLE, which would require a deep reset of the immune system. Therefore, patients with SLE usually require lifelong treatment. Because the B cell response against DNA and nuclear antigens precedes the onset of clinical symptoms, tackling SLE by B cell blockade is an attractive therapeutic strategy8. Monoclonal antibodies that interfere with B cell activation targeting BAFF/BLySS or deplete B cells targeting CD20 have been successfully used in the treatment of SLE9,10. Nonetheless, such treatment approaches, although effective, only work for some patients and certain severe forms of SLE appear to be resilient. Biopsy studies have shown that the CD20-targeting monoclonal antibody rituximab does not thoroughly deplete B cells in the tissues11,12. Thus, a considerable number, if not the majority of B cells escape depletion, hindering an effective reset of the (auto)immune response observed in SLE11,12.
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Despite their young age, all patients had previously been exposed to several immunosuppressive drugs, such as pulsed glucocorticoids (5/5), hydroxychloroquine (5/5), mycophenolate mofetil (MMF; 5/5), belimumab (5/5), cyclophosphamide (3/5) and azathioprine (2/5). B cell counts at baseline were 19 (patient 1; previous rituximab exposure; 3.2% of lymphocytes), 85 (patient 2; 8.0%), 84 (patient 3; 6%), 280 (patient 4; 27.8%) and 234 (patient 5; 7.3%) cells per microliter.
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Sid said:
The paper offers an explanation for why rituximab doesn’t work for SLE
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Yes, we knew about that before we started with RA in 1998. Rituximab does not clear follicular B cells. But I am not clear that we have evidence for CAR T cells doing that in these patients? As far as I know no biopsies have been done - they are very hard to justify. If CAR T cells do clear follicular B cells that may be a major development. But if plasma cells are the real problem then it won't make any long term difference. We got up to five years remission in RA but eventually the plasma cells (or residual B cells??) won.

The key thing is what happens to these patients in this CAR T cell trial over a period of five years. Do they relapse like after rituximab or not? Rituximab actually works pretty well. The reason it was never licensed for lupus is that the the trials were extremely badly designed by the drug companies. A more recent trial with a rituximab successor has shown good results.
 
Clinical efficacy. Disease activity of SLE was continuously assessed after administration of CD19 CAR T cells using the SLEDAI-2K scale. All five patients had active SLE with multiorgan involvement at baseline with SLEDAI-2K scores between 8 and 16 (Fig. 3a). Signs and symptoms of SLE continuously improved in all five patients to SLEDAI-2K scores equal to zero in four of five patients and a SLEDAI-2K score of 2 in patient 2 at 3 months after CAR T cell administration. Patient no. 2 had residual low-level proteinuria after 3 months, most likely due to previously accrued damage in glomerular filter function. No active sediment (protein casts, cellular casts and dimorphic erythrocytes) was found in urine analysis. Furthermore, residual proteinuria (0.3 g/g creatinine) successively improved with dose adaptation of angiotensin-converting enzyme (ACE) inhibitors after 3 months. Nephritis ceased in all five patients upon CAR T cell treatment (Fig. 3b). Also, complement factor levels normalized in all five patients (Fig. 3c) and anti-dsDNA antibody levels, as measured by radioimmunoassay dropped below the cutoff (Fig. 3d). In addition, other severe manifestations of SLE such as arthritis (patient 4), fatigue (all patients; baseline numeric rating scale-based intensity, 8.2 ± 1.4; 3-months numeric rating scale-based intensity, 2.4 ± 1.6; P = 0.007; Fig. 3e), fibrosis of cardiac valves (patient 1) and lung involvement (restriction and diffusion impairment, patients 1 and 3) disappeared after the administration of CAR T cells.
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None of the traditional immunosuppressives mentioned have the sort of effect B cell depletion gives (i.e. as quoted in the above post). Belimumab depletes B cells but not very powerfully. I am surprised that only one case seems to have tried rituximab but that probably reflects licensing. Belimumab got licensed because the people involved were more intelligent about trial design.
 
Immune phenotyping of B cells before CAR T cell treatment and of recurring B cells after CAR T cell therapy showed that reconstituted B cells are mostly CD21+CD27− naive cells, with CD21+CD27+, memory B cells and CD38+CD20− plasmablasts being low to absent (Fig. 4c). In addition, CD11c+CD21lo activated memory B cells, which are expanded in SLE30,31, were absent among recurring B cells. Furthermore, comparative data from B cell receptor (BCR) sequencing of B cells before as compared to after CAR T cell therapy showed a shift from class-switched IgG and IgA heavy chains at baseline to non-class-switched IgM and IgD heavy chains in the newly emerging B cells (Fig. 4d). In the two patients with the longest follow-up, seroconversion of antinuclear antibodies was observed, indicating that abrogation of autoimmune B cell clones may lead to a more widespread correction of autoimmunity.
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In the two patients with the longest follow-up, seroconversion of antinuclear antibodies was observed, indicating that abrogation of autoimmune B cell clones may lead to a more widespread correction of autoimmunity.

Seroconversion is fairly easy for anti-DNA but more difficult for other ANA. Their figures look fairly similar to what we are used to. But yes, this is what we predicted in our 1998 paper before we actually started using B cell depletion - that abrogating autoimmune clones would get rid of the problem. In fact if one didn't think that the treatment would look fairly poor risk/benefit.

What is slightly odd is the idea of 'more widespread correction of autoimmunity'. What more is there to correct if the autoimmune clones are gone? I suspect they cannot quite get themselves to abandon the old myth that there is some T cell drive behind it all. If that were the case the chances of any of this working would I think be low.
 
Furthermore, generalizability of the CD19-targeted CAR T cell approach to other autoimmune diseases is unclear. This approach requires that the disease is driven by B cell activation and plasmablast generation rather than on long-lived plasma cells, which are usually CD19 negative35. Hence, patients in whom autoimmunity is driven by autoantibody production by long-lived plasma cells, for example, those with antibodies against RNA-binding proteins, may respond less well to the approach presented here36.
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Jonathan Edwards said:
What is slightly odd is the idea of 'more widespread correction of autoimmunity'. What more is there to correct if the autoimmune clones are gone? I suspect they cannot quite get themselves to abandon the old myth that there is some T cell drive behind it all. If that were the case the chances of any of this working would I think be low.
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Elsewhere they talk about how the patients also lost other autoantibodies. I think that’s what they’re referring to, not T cells.

A second finding is the rapid and sustained breakdown of the B cell-mediated autoimmune response in SLE after CD19 CAR T cell treatment. While autoantibodies against dsDNA usually also decrease by conventional therapy, seroconversion is infrequent33. All patients in our study seroconverted, lost dsDNA antibodies and showed decreases of levels of other SLE-associated antibodies. Considering that SLE in these patients was highly resistant to several previous immunosuppressive treatments, these findings indicate that CD19 CAR T cells could abrogate the underlying autoimmune processes of SLE. Deep depletion of memory B cells and plasmablasts upon CD19 CAR T cell treatment could be one explanation: CAR T cells bring effector function directly to the B cell niches in the tissues, such as the lymph nodes and the bone marrow. This feature is considered to be an important advantage of CAR T cells during the antitumor immune response, as they migrate and stay in the tissues, including immunologic niches, where they can kill their target cells2. In contrast, antibody-mediated B cell depletion, which is also used in autoimmune disorders, seems to achieve a much more incomplete B cell depletion. Despite their elimination from circulation, tissue B cells are still present after CD20-targeted B cell-depleting antibody treatment23,24. Hence, deep depletion of B cells in the tissues paired with the approach of targeting CD19, which, in contrast to CD20, is also expressed by plasmablasts, may be a key advantage of this CAR-based approach to treat autoimmune diseases. This concept may also explain why CD19 CAR T cell therapy can also work on patients with SLE that previously failed on anti-CD20 therapy, as was observed in one of the five patients with SLE.
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Furthermore, generalizability of the CD19-targeted CAR T cell approach to other autoimmune diseases is unclear.

Again, yes, as we have said since Maria Leandro's original findings on long lived autoantibodies, but I think they miss a trick here.

If autoimmune plasma cells are long lived the disease may still gradually fade away if you break the cycle of regeneration of auto reactive clones fed by autoantibody. I don't think these people have cottoned on to the dynamics of B cells really. The long lived plasma cells do two things. They go on making antibody, which may produce symptoms, but those antibodies may also educate new B cell clones recognising the same antigen to survive and proliferate.

The 64 thousand dollar question is whether relapse after rituximab was due to old B cell clones (hidden in follicles) getting going again or new clones being educated. If CAR T cells do better by killing follicular B cells then leaving plasma cells behind may not matter long term. If killing all follicular B cells isn't the problem then CAR T cells aren't going to be much of an advance.
 
Sid said:
Elsewhere they talk about how the patients also lost other autoantibodies. I think that’s what they’re referring to, not T cells.
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No, the autoantibodies are made by the B cell clones they think they have killed, or at least their plasma cell offspring. So that would not be 'more widespread'. If they mean anything it must be something else. I have a suspicion that they know perfectly well that we have provided an explanation for all this but the politics don't allow them to quote it !!
 
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