Mechanisms of Action
A number of in vitrostudies suggested that alemtuzumab (ALEM) exerts its depleting effect on CD52-expressing immune cells by complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and induction of apoptosis.[57–60] While ALEM is known to cause a long-lasting depletion of CD4+ and CD8+ lymphocytes, an overshooting regeneration of CD19+ B cells lasting for at least 1 year (end of observation period or new treatment cycle) after ALEM administration was recently described. This overshooting B-cell response was first dominated by CD19+CD23−CD27− bone marrow emigrants (T1 phenotype), then by an increasing number of an intermediate phenotype (CD19+CD23+CD27−). It was paralleled by increased serum levels of B-cell-activating factor (BAFF), which was previously shown to promote the survival of peripheral immature B cells, but not of the B/plasma-cell-regulating factors a proliferation-inducing ligand (APRIL) and transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI). In contrast to B cells at an earlier developmental stage, memory B cells did not show an overshooting response after ALEM administration, and recovered slowly to only 25% of baseline levels 12 months after administration, which may contribute to the prolonged therapeutic effect of ALEM (see section entitled 'Further results of the CAMMS223 trial') in patients with MS. These effects were repeatedly observed with recurring ALEM cycles.
A recently published study sought to further elucidate the in vivomechanism of action of ALEM in a human CD52 transgenic mouse model, as ALEM is not cross-reactive with murine CD52. These mice exhibited a similar tissue and immune cell distribution of CD52 as observed in humans, and treatment with ALEM resulted in profound peripheral immune cell depletion. Interestingly, immune cell depletion was less profound in lymphoid organs, in particular in lymph nodes and thymus, providing a possible explanation for only modestly more frequent infections in ALEM-treated patients in comparison to those receiving placebo in RA and MS clinical trials.[64,65] High CD52 expression was found in lymphoid organs. The authors, therefore, hypothesized that ALEM might not have reached lymphoid organs at sufficient concentrations, or that ADCC was less effective in these organs, as CDC was found to play a minor role for lymphocyte depletion by ALEM in this animal model, while ADCC was crucial. Of note, a relative sparing of CD4+CD25+FoxP3+ Tregs, which are thought to play a protective role in MS pathogenesis, in comparison to the overall population of CD4+ cells was observed, which corresponded to a previous ex vivo study in MS patients receiving ALEM and might be a mechanism of action in MS patients.
Creation of a tolerogenic environment – that is, a condition of increased immune tolerance to autoantigens – by ALEM, as indicated by these studies, seems to contradict the occurrence of thyroid autoimmunity in 20–30% of MS patients receiving ALEM. Of note, increased thyroid autoimmunity was not reported in patients with other disease conditions receiving ALEM, and seems to reflect an organ-specific mechanism of autoimmunity specific to MS patients. Nevertheless, the development of thyroid autoimmunity has also been observed in other, ALEM-unrelated clinical contexts of immune reconstitution, such as HAART treatment of HIV infection or stem cell transplantation.[67–69] As most lymphopenic patients do not develop autoimmunity, it was suggested that additional factors might be active, in particular an overproduction of IL-21. Indeed, a recent study demonstrated that a genetically determined overproduction of IL-21, which is a T-cell-regulating cytokine promoting the generation of self-reactive T cells, drives thyroid autoimmunity in MS patients treated with ALEM. Importantly, IL-21 levels before ALEM treatment were more than twofold higher in patients developing thyroid autoimmunity after ALEM treatment than in those who did not. Although IL-21 levels overlapped between both cohorts and did not allow for sharp discrimination between patients developing and those not developing thyroid autoimmunity (positive-predictive value 70%, negative-predictive value 62%), the determination of IL-21 serum levels in conjunction with a genetic analysis of gene polymorphisms might serve to determine the individual ALEM-associated risk of thyroid autoimmunity to a clinically relevant extent.
Nevertheless, the mechanism by which ALEM increases the risk of Graves' disease in MS patients, but not in patients with other autoimmune disorders, is still unknown. Identifying the cause underlying thyroid autoimmunity in ALEM-treated MS patients might finally help to develop a method for the prevention of this frequent adverse effect, and might provide new insight into the immunological basis for organ-specific autoimmunity.
Further Results of the CAMMS223 Trial
The Campath-1H in MS (CAMMS223) trial compared the safety and efficacy of two different dosages of ALEM with IFN-β1a 44 µg three-times per week subcutaneously in 334 patients with early RRMS who were treatment-naive. The design of the trial and 1- and 2-year results, which were finally published in the meantime, were summarized in the March 2008 review.[1,74] Over 3 years, ALEM, in comparison to IFN-β1a, reduced the risk for relapse by 74% (p < 0.001) and the risk for sustained accumulation of disability by 71% (p < 0.001). Although most ALEM patients only received infusions at month 0 (n = 216) and 12 (n = 207), and only 46 patients were treated with a third cycle at month 24, the treatment effect on both measures was found to be sustained through year 4 to a similar level. However, while most patients completed 36 months of follow-up, only 48% of the study participants were available for this 4-year analysis. Of note, late-arising immune events were observed in ALEM-treated patients, most often thyroid autoimmunity. Thyroid autoimmunity, usually only at a laboratory level, was also the most frequent adverse event observed in a recently published multicenter series of 39 patients with highly active MS who received ALEM in an off-label setting, and one case of autoimmune skin disease was reported here. No further cases of immune thrombocytopenic purpura in the CAMMS223 trial have been reported so far, and the outcome of the five surviving patients (the first diagnosed case ended fatal) remained favorable.[76,74] Over 3 years, anti-ALEM Abs, which developed in a significant proportion of patients and peaked at approximately 1 month after each ALEM cycle, were not associated with a diminished clinical effect or increased adverse reactions in the CAMMS223 trial.
Regarding further autoimmune phenomena, one patient in the Cambridge cohort and one patient in the Phase III program were reported to have developed Goodpasture's syndrome, which is a potentially life-threatening disease of the kidneys and the lung where an autoantibody and T-cell-mediated immune reaction against collagen components of the basement membrane takes place.[66,78] Furthermore, single cases of autoimmune neutropenia and of autoimmune hemolytic anemia in ALEM-treated MS patients were reported.
In the CAMMS223 trial, three malignancies have been diagnosed so far in 216 ALEM-treated patients – non-Epstein–Barr-virus-associated Burkitt's lymphoma, breast cancer and cervical carcinoma in situ – with onset ranging from 22 to 64 months after the first annual cycle, while in 107 IFN-β1a-treated patients, one case of colon cancer was diagnosed after 36 months.[66,74] It was speculated that the case of Burkitt's lymphoma was specifically related to ALEM treatment. Furthermore, a case of superficial spreading melanoma in a MS patient, which rapidly developed out of a longstanding melanocytic nevus 6 months after a first ALEM cycle (120 mg divided over five consecutive days), was recently reported. However, despite these cases, there is currently no clear evidence for a carcinogenic effect of ALEM in MS patients, and Phase III data have to be awaited.
According to CAMMS223, ALEM appears to show a sustained effect on the immune system, translating into a sustained and impressive effect on MS disease activity over at least 2–3 years after the last infusion, and into partially late-occurring autoimmune phenomena in the phase of immune reconstitution, which are most often treatable.
Phase III Program in RRMS
Information on protocols and end points of Comparison of Alemtuzumab and Rebif Efficacy (CARE)-MS1 and CARE-MS2 was provided in the previous review. Both trials are ongoing. CARE-MS1 compares ALEM with IFN-β1a and enrolled 581 treatment-naive patients with RRMS. It started in September 2007 and the estimated study completion date as of December 2009 was March 2011. CARE-MS2 enrolled 840 RRMS patients with breakthrough disease under therapy with IFN-β or glatiramer acetate. It started in October 2007, and the estimated study completion date was April 2012.
Expert Rev Neurother. 2010;10(5):791-809. © 2010 Expert Reviews Ltd.
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