Autoimmunity and Alemtuzumab (CAM-Thy)

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Secondary Autoimmunity after alemtuzumab, is one of the problems associated with this drug. It was suggested that autoimmunity occurred in people who repopulated their T cells from memory cells compared to getting new ones from the thymus. So the suggestion was that if you make more cells from the thymus you get a more diverse T cell repertoire you get less autoimmunity. The Cambridge group thought that a skin cell growth factor would do this based on animal data.

However, we suggested because alemtuzumab was depeting T regulatory cells rather than enhancing then at a time when immature B cells, which can be potentially autoreactive, are being generated. Making new T cells could help those new autoimmune B cells and may make MS worse.

What happened?

The trial was terminated early.

Keratinocyte growth factor impairs human thymic recovery from lymphopenia. Coles AJ, Azzopardi L, Kousin-Ezewu O, Mullay HK, Thompson SA, Jarvis L, Davies J, Howlett S, Rainbow D, Babar J, Sadler TJ, Brown JWL, Needham E, May K, Georgieva ZG, Handel AE, Maio S, Deadman M, Rota I, Holländer G, Dawson S, Jayne D, Seggewiss-Bernhardt R, Douek DC, Isaacs JD, Jones JL. JCI Insight. 2019;5. pii: 125377. doi: 10.1172/jci.insight.125377

BACKGROUND: The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates.

METHODS: Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30.

FINDINGS:At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229×107/L vs. 7.733×107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groupsConclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.

Althought the skin growth factor had promoted thymic development in mice and non-human primates, to the surprise of the investigators it actually reduced the production of thymic emigrants and reduced the diversity of the immune response and did not enhance them. There was no change in the occurance of autoimmunity, which may have been predicted as diversity was being even more restricted (although many people got hair loss/thinning…alopecia?), but no new T cells would mean no change to autoimminity according to our view, which was seen.

However, where next in the idea of stopping autoimmunity after alemtuzumab?

Is it too little, too late as more alternatives arrive.

So moral of the story do not trust those pesky animal experiments!

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