Alemtuzumab is one of the most effective disease modifying treatments, but the major problem associated with it’s use is the development of secondary autoimmunities. What is the problem?
- One suggestion was that it depends on how T cells repopulate from the thymus.
- However, we suggested that it could be due to uncontrolled B cell hyper-proliferation in the relative absence of T cell regulation.
Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K.JAMA Neurol. 2017 Aug 1;74(8):961-969.
- We put this hypothesis in a paper submitted in Jan 2017 that was reviewed by Prof Steinman. How do we know that?. This was because he did an editorial on the paper. Steinman L “Induction of New Autoimmune Diseases After Alemtuzumab Therapy for Multiple Sclerosis: Learning from Adversity.” in JAMA Neurol, doi: 10.1001/jamaneurol.2017.0325. ” Baker et al explain how alemtuzumab might trigger new autoimmune disease as the immune system reconstitutes itself after administration”
This idea had been suggested before by a Mexican Lab, but it was ignored and refuted based on the idea that T regulatory cells increase after treatment. However, as we showed that science was flawed and regulatory cells are in fact depleted in absolute numbers. Therefore, there are less T regs to control the rapidly expanding immature B cells.
You may be surprised to know that ProfG and I travelled to Boston about 6-7 years ago to pitch the idea of doing a trial with anti-CD20 to deplete the B cells after alemtzumab.
However, we were before our time and the powers that be were not sufficiently interested in doing the study. Alemtuzumab had no competition at the time as ocrelizumab had not been approved. Remember, rule number 1 of Pharma club is “Do not bring attention to a problem” and rule #2 of Pharma club is “Do not bring attention to a problem”
Importantly it was suggested that we were seeing the hyper-populating B cell response in 1-3 months from treatment, but autoimmunity occurred 12-36 months after infusion. Therefore, how could that be a problem? However, we suggested the autoimmunity was caused early as B cell hyper-populate but do not develop autoimmunity until T cell help appeared and this would take on average over 2 years.
This would say to get rid of autoimmunity, treat shortly after alemtuzumab infusion, if I and ProfG were correct or wait a few years to treat for years as an alternative view if the others were correct.
We are therefore happy that Prof Steinman got off his bum and tested this idea and waited for the B cells to recover and then the team would bash them with rituximab to induce a transient depletion to keep the numbers low such that B cells recover in an environment when T cells are regulated. In this study, there was no autoimmunity during the observation period.
Did our ideas spawn the study, as they were submitted over 4 years ago…. we certainly weren’t credited with this view in the paper, maybe they started before they saw our work..Yes I am sure that’s it……..Yes let’s give them the benefit of the doubt and the credit. Ideas are ten a penny, but it is doing the work that is important.
You stand of the shoulders of what came before…that’s called learning and progress 🙂
Mitigating alemtuzumab-associated autoimmunity in MS A “whack-a-mole” B-cell depletion strategy Ethan Meltzer, Sarah Campbell, Benjamin Ehrenfeld, Roberto A. Cruz, Lawrence Steinman, Matthew S. Parsons, Scott S. Zamvil, Elliot M. Frohman, Teresa C. August 07, 2020 Neurology Neuroinflammation, Neuroimmunology.
Objective To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%–50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity.
Methods In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50–150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy.
Results Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed.
Conclusions An anti-CD20 “whack-a-mole” B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation.
Whack a mole means smash a mole over the head with a hammer to squash it when it reaches the surface to keep the moles under ground.
Will this give alemtuzumab a new lease of life, maybe but I fear it has collected too much baggage. Will other neuros follow suite and do the rituximab depletion?
Time will tell