Cell therapy trials for multiple sclerosis – 2012 update

by Alexey Bersenev on January 2, 2013 · 1 comment

in Uncategorized

This post was edited Jan. 4, 2013 at 10:03 pm EST

Multiple sclerosis (MS) is one of the most frequent indications for cell therapy trials. Drug therapy could be ok for some patients to slow rate of relapses in initial course of disease (relapsing remitting form = RR and malignant form), but useless in progressive neurodegenerative phase (secondary progressing form = SP). Therapy has many side effects and could cost $30-50k per year. Most of RR patients will progress to SP. So, the key questions for cell therapy field:

  1. Can cell therapy halt SP MS (stop/ reverse progressive neurodegeneration)?
  2. Can cell therapy revert disease and prevent progression in RR patients?
  3. Can cell therapy guarantee cessation of drug therapy and provide good quality of life?
  4. Can cell therapy offer the best alternative when all drugs are failing in RR patients?
  5. Can positive effect from one cell therapy procedure last for long time or forever?

Historically, Richard Burt from Northwestern University attempted to use cell therapy of MS more than 15 years ago. Since that time, a lot of cell therapy trials were started around the world. Today, I’ll overview some recent trends and updates.

Hematopoietic stem cell (HSC) transplantation
In the last 15 years, autologous HSC transplant for MS moved from myeloablative (which basically killed some patients due to toxicity) to non-ablative settings. You can watch the latest updates for “Northwestern U trials” in the recent Burt’s talk:

First, he gave an update on non-controlled, non-blinded trial, which was published in Lancet Neurology in 2009. Now they have treated 113 patients and have data for 5-years follow-up. 75% of patients in the trial significantly improved (EDSS) at 5-year and didn’t get back to drug therapy. However, patients with neuroinflammation rather than profound neurodegeneration were selected for the trial. As Burt have mentioned many times – “no inflammation – no response“.

So, the improvement (no relapses, less frequent relapses) we can see mostly in RR form of MS. Unfortunately, for SP form (15 out of 113 patients), there was no such improvement, but was no progression either at 5-years –> no improvement – no progression (EDSS curve remained flat). This data should be published in 2013.

The current international trial (MIST) is randomized, open-labeled and partially-blinded (patients unblinded). Burt didn’t report updated data from MIST, but mentioned that the trial went half way through.

Two-year follow-up of HALT MS trial was recently reported at ASH 2012 conference. This is Phase 2 non-randomized non-controlled multicenter trial, sponsored by government (NIH). 25 patients with RR form of MS, who had failed drug therapy, were enrolled. Progression-free and relapse-free survival at 2 year were 95.8% and 91.7%, respectively. One patient died from disease progression. The enrollment in trial is closed. It is unclear to me, whether they will proceed for extended – randomized and controlled Phase 2 or report 5-year follow-up and proceed for Phase 3. Some funding problems were noticed:

Both – MIST and HALT-MS are trials “must-to-watch” in the next 2 years!
Long-term follow-up results from few more trials were reported this year. Novik reported progression-free survival at 5-years as 92% in the group after early HSC transplant and 73% in the group after salvage HSC. The stability of EDSS improvement, in the recently published Italian study, was 66% at 5 years and only 27% at 7 years or later. However, in the Chinese study, progression-free survival was 48% at 9 years.

Overall, more than 600 patients received autologous HSC transplants for MS around the world. The most dramatic improvement was observed in malignant MS. It could significantly improve EDSS and reverse disability in RR. Most patients will never go back to therapy (~75% according Burt’s study). There is no evidence for efficacy of HSC transplant in SP MS so far, but maybe it could slow down neurodegeneration at some degree. In the future, more likely, HSC transplant in MS should be done in RR and malignant form as early as possible in order to block its progression to SP. It seems to me, that in the future, HSC transplant have all chances to replace drug therapy in RR MS. Despite the pronounced efficacy of HSC transplant in RR, a lot of challenges need to be addressed in order to move to the wide clinical practice:

  • HSC transplant procedure is still considered as toxic. Intensity of immunosuppresive regimens directly correlates with toxicity of transtplant. Importantly, transplant-related mortality due to conditioning toxicity have dropped to 1-2% in the last few years. However,  wiped out T-cell immunity is still a severe challenge for the patients.
  • Progression-free survival is much lower in long-term follow-up.
  • Reconstituted immune system retains a “memory of autoimmunity”. There is a problem of secondary autoimmune disorders.
  • The cost-effectiveness of HSC transplant in MS should be calculated and considered in economic evaluation.
  • A big problem in Phase 3 trials is a funding. Because it’s “highly personalized” therapy, only government or charity can support such trials. Generally, Pharma or Biotech industry have no interest in investing in such therapy. Also, Pharma, “may even consider the treatment as market competition“.

The proposed place of HSC transplantation in therapy of MS could be illustrated by this scheme:
(Mult Scler 2012; 18; 6: 825-834)

Mesenchymal stromal cell transplantation
Autologous mesenchymal stromal cells (MSC), derived from bone marrow or adipose tissue were proposed as an alternative to HSC transplant and drug therapy in MS. The potential mechanism of action is immunomodulation (supression of auto-reactive T-cells). In case of MSC therapy there is no need for severe immunosuppressive conditioning. Because immune system is not going to be destroyed, the therapy suppose to be not toxic at all. There were a number of experimental studies, validating scientific background of MSC therapy in MS.

6 clinical trials, assessing MSC in MS have been registered in databases in 2011-2012. I would estimate at least 10-15 trials are currently ongoing. Results of 5 studies have been published (as per November 2012) and reviewed here. Unfortunately, none of published studies assessed and concluded the efficacy of MSC therapy:

However, the uncontrolled nature of the trials and the limited number of patients enrolled make these encouraging results yet anecdotal.

Interim results of open label Phase 2 trial (MSCIMS), published this year in Lancet Neurology, demonstrated improvement of visual activity among 10 patients with SP MS. These results could suggest some degree of neuroprotection by MSC.

The results of Iranian trial, including 25 patients with SP MS were recently reported:

Clinical course of the disease (measured by EDSS) improved in 4, deteriorated in 6 and had no change in 12 patients. In MRI evaluation, 15 patients showed no change, whereas 6 patients showed new T2 or gadolinium enhanced lesions (1 lost to follow-up).

These results look inconclusive. The necessity of larger controlled studies is highly advised. It seem to me, that published MSC trials and cases focused mostly on SP MS, rather then RR. It could be very interesting to dissect effect of MSC on SP MS versus RR, since HSC transplant doesn’t reverse neurodegeneration. Antonio Uccelli concluded in the recent review:

While available data do not support, at this stage, the possibility of regenerating the complex neural circuitry deranged by inflammatory events during the course of MS…

Finally, International MSC transplantation (IMSCT) study group, proposed a randomized double-blind multicenter and international Phase 2 trial for assessment MSC efficacy in MS. The description of trial (MESEMS) you can read here. Patients with both RR and SP forms of MS will be enrolled. This trial is “must watch” in the next few years!

Opexa Therapeutics is developing autologous “T-cell vaccines” for MS. Tcelna (Tovaxin) – “in vitro expanded myelin-reactive T-cells“. This type of T-cell therapy failed in Phase 2 trial, included 150 patients. This year, Opexa launched a new Phase 2 trial (Abili-T), designed specifically for SP MS. This trial will enroll 180 patients in 30 centers.

Personally, I don’t see reasons to be optimistic about T-cell therapy so far.

{ 1 comment… read it below or add one }

SammyJo Wilkinson December 22, 2013 at 6:12 pm

This MSC trial was just started end of 2013.
Tisch MS Research Center of New York

Cleveland Clinic has an ongoing MSC trial for MS


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