A good summary of the Campath research to date, that includes statistics for the early trials of the drug between 1991 and 2002 (along with the widely published Phase II trial results). The pdf linked below is much easier to read!
Spotlight on Alemtuzumab
Alemtuzumab, formally known as Campath-1H, is a humanized monoclonal antibody directed against CD52, a protein on the surface of lymphocytes and monocytes with unknown function. A single dose of alemtuzumab leads to a rapid, profound and prolonged lymphopenia. A Phase II trial has shown that alemtuzumab reduces the risk of relapse and accumulation of disability by over 70% compared with interferon beta in patients with early relapsing-remitting multiple sclerosis (MS). Alemtuzumab has been used in Cambridge as an experimental treatment for MS since 1991. In this review we summarize our experience; describing how this prototypical, ‘bench-to-bedside’ therapy continues to inform basic science, revealing aspects of the pathogenesis of MS and lymphopeniaassociated autoimmunity.
Ehrlich’s ‘Magic Bullets’
As early as 1900, Paul Ehrlich theorized that it should be possible to create a therapeutic agent capable of targeting pathogens and diseased cells whilst leaving healthy cells unharmed. Three-quarters of a century later, Köhler and Milstein identified a method of producing antibodies of a given specificity by fusing an antibody-producing cell with a tumour cell.1 In doing so they launched the technology to perpetually produce Ehrlich’s ‘magic bullets’. In the early 1980s Waldmann and Hale utilized this technology to generate a rat monoclonal antibody that would lyse human lymphocytes, and so treat lymphocytic malignancies. They developed the Cambridge Pathology-1, or Campath-1, series of antibodies. These were amongst the first monoclonals to be ‘humanized’ by Greg Winter’s group,2, and hence, Campath-1H was born. Alemtuzumab Targets the Cell Surface Protein CD52 Campath-1H (now known as alemtuzumab) targets CD52, a glycoprotein present on all T- and B-lymphocytes, monocytes and eosinophils, but importantly, not haematological precursors.3 Despite being one of the most abundant proteins on the surface of these cells, the function of CD52 remains unclear. Treatment with alemtuzumab rapidly produces a profound lymphopenia. Lymphocytes regenerate, but the speed and degree of recovery varies between cell types: CD4+ T-cells are particularly slow to recover, taking 5 years to reach pre-treatment levels.4 At present, alemtuzumab is only licensed for the treatment of chronic lymphocytic leukaemia (CLL)5, but it has been used with success in a variety of autoimmune diseases,6–12 as well as in renal transplantation13 and non-myeloablative conditioning prior to stem cell therapy.14 This paper focuses on its use as an experimental treatment of multiple sclerosis (MS).
The Rationale for Using Alemtuzumab as a Treatment for MS
MS is an inflammatory disease of the central nervous system (CNS). At its onset, MS can be categorized clinically into relapsing-remitting MS (RRMS: 85–90% of patients) or primary progressive MS (PPMS),15 Relapses typically present sub-acutely over hours to days with neurological symptoms persisting for days to weeks before they gradually dissipate. At first, full recovery is the norm. Later, patients accumulate persistent deficits after each relapse and ultimately most undergo transition into secondary progressive MS (SPMS), a slowly progressive phase of the disease with or without superimposed relapses. Pathologically, MS is characterized by perivascular infiltration of lymphocytes (mainly CD4+ T-cells) and monocytes within the brain and spinal cord leading to disruption of the myelin-oligodendrocyte unit, and to breakdown of saltatory conduction. Although the immune response is primarily directed against myelin, axonal transection has been shown to occur acutely.16,17 Chronic MS plaques are characterized by the attrition of neurons and axons.17 Oligodendrocyte precursors are present in chronic MS lesions and remyelination is attempted;18 however, this fails, perhaps as a result of an unfavourable local environment. In addition to the well-recognized role of Th1 CD4+ T-cells in MS pathogenesis, there is good evidence that Th17 CD4+ T-cells, Th2 CD4+ T-cells, CD8+ T-cells and B-cells all play a role.19–25 The concept that MS is an exclusively Th1-driven disease, therefore, has to be revised and replaced by the concept of synergistic interactions between multiple cell types. The initial rational for using alemtuzumab in MS was simply to disable the aberrant immune response by removing lymphocytes; as we will describe in this article, we now believe this to be an oversimplified view of its mechanism of action.
The Cambridge Experience
Between 1991 and 2002, 58 patients with MS were treated with alemtuzumab in Cambridge.4,26,27 Clinically, two cohorts were treated: those with SPMS (36 patients: 22 female) and those with RRMS (22 patients: 17 female). At the time of treatment, disease duration in the progressive group was 11.2 years (standard deviation [SD] +/– 6.1 years). In the year prior to treatment, this group had experienced an annualized relapse rate (ARR) of 0.7 (relapses/ person/year) and had continued to accrue disability, increasing their Expanded Disability Status Scale (EDSS) score28 by at least one point. For the relapsing cohort, the duration of disease was 2.7 years (+/– 2.9 years). These patients were selected because they had aggressive, active MS, with an ARR of 2.2 in the year prior to treatment, during which time they accrued disability; between 0.0 and 7.5 points on the EDSS.
Treatment with alemtuzumab effectively suppressed acute attacks in both the relapsing-remitting and secondary progressive groups. Relapse rate in the SPMS group fell from 0.7 to 0.02, representing a 97% reduction. Relapse suppression was comparable in the relapsing group, with relapse rates falling from 2.2 to 0.14; a 94% reduction. New magnetic resonance imaging (MRI) lesion formation, the radiological correlate of a clinical relapse, was assessed in a subgroup of secondary progressive patients. It mirrored the clinical findings, showing a 90% reduction. However, despite these findings, the two cohorts fared very differently. In spite of successfully suppressing inflammation, the progressive group continued to accumulate disability, with a mean rate of increase of +0.2 EDSS points per patient per year, and with evidence of progressive cerebral atrophy radiologically. Patients with the greatest inflammatory load at the time of treatment accumulated disability most rapidly. The disability/EDSS findings in the relapsing group were in stark contrast: unexpectedly, nine of 15 patients observed 1 year later showed a sustained improvement in EDSS, giving a mean change in disability of –1.2 EDSS points at 2 years when compared with baseline.
These findings suggest that neurodegeneration occurs through non-inflammatory mechanisms, but that these mechanisms are set up by, and depend upon, prior inflammation. It was this key observation that led to a change in strategy towards the early treatment of patients with MS, before the consequences of inflammation are irretrievably established. If our hypothesis about the nature of SPMS is correct, then the dividends from early suppression of inflammation will be considerable.
The CAMMS-223 Phase II Trial
CAMMS-223 was a commercially sponsored, multicentre, randomized, single-blind Phase II trial designed to compare the efficacy of alemtuzumab with interferon beta-1a (Rebif®) in early, active MS. Two primary end-points were examined: relapse rate and time to accumulation of clinically significant disability as measured by EDSS. Three hundred and thirty-four patients with active RRMS, at 49 medical centres across Europe and the USA, were randomized to receive either Rebif®, administered subcutaneously three times per week, or alemtuzumab at one of two doses: 24 mg or 12 mg daily – given intravenously on five consecutive days Consistent with the Cambridge experience, alemtuzumab was shown to reduce the risk of relapse and the risk of sustained accumulation of disability by more than 70% when compared with treatment with Rebif®. In addition, the EDSS of those treated with alemtuzumab improved by –0.39 points, whereas those receiving Rebif® continued to acquire disability by +0.38 points (P<0.0001), both from a mean baseline score of 2.0. These clinical observations were paralleled by changes in brain volume as measured by MRI: increased MRI-T1 brain volume was seen between 12 and 36 months post-alemtuzumab suggesting a restoration of brain structure, whereas brain atrophy progressed in those treated with Rebif®. This positive effect on disability is unprecedented in treatment trials of MS.
In common with other cell-depleting monoclonal antibodies, alemtuzumab infusion causes an acute cytokine-release syndrome consisting of pyrexia, headache, malaise and an urticarial rash. This is typically accompanied by a transient exacerbation of neurological symptoms.27 These symptoms are all substantially ameliorated by pre-treatment with corticosteroids.29
Critical to the continued use has been the unexpected lack of infections following treatment with alemtuzumab. The Cambridge cohort has, to date, received a total of 87 courses of alemtuzumab and has been followed prospectively for 316 patientyears. There have been only eight infections which might be attributable to immunosuppression by alemtuzumab: three cases of herpes zoster and one case each of spirochaetal gingivitis, varicella zoster virus, measles, aphthous mouth ulceration and pyogenic granuloma. All patients recovered fully. In the CAMMS-223 trial, infections were more common amongst patients in the alemtuzumab group than those receiving Rebif® (65.7% versus 46.7%); however, this was largely due to an increase in mildto- moderate respiratory tract infections. One patient, newly treated with alemtuzumab, developed listeria meningitis after eating unpasteurized cheese; she recovered without sequelae. There were no cases of progressive multifocal leucoencephalopathy, cytomegalovirus or pneumocystis pneumonia.
Malignancy In the CAMMS-223 trial, three cancers (non-Epstein- Barr-virus [EBV]-associated Burkitt’s lymphoma, breast cancer and cervical carcinoma in situ) were reported in patients in the alemtuzumab group, with onset ranging from 22 to 64 months after the first annual cycle; one patient treated with Rebif® developed colon cancer at 36 months.30 Whilst cancers were not statistically more frequent after alemtuzumab (1.4% of patients versus 0.9%), we speculate that the case of non-EBV-associated Burkitt’s lymphoma may have been caused by treatment with alemtuzumab.
The principal adverse effect of alemtuzumab is novel autoimmunity, arising months to years after treatment. Typically, this is directed against the thyroid gland: 20–30% of patients develop someform of thyroid autoimmunity, mainly Graves’ disease. This predilection is not fully explained, except by noting that two studies show an increase in the prevalence of Graves’ disease, amongst family members of patients with MS,31,32 perhaps suggesting that families may inherit common autoimmune susceptibility genes with the specific autoimmune phenotype determined by additional genetic and/or environmental factors. Thyroid autoimmunity is not confined to treatment with alemtuzumab. A number of authors,33–35 but not all,36 report a significant increase in anti-thyroid microsomal antibodies after starting interferon beta. There is also one case report of Graves’ disease following treatment of MS with glatiramer acetate.37 Autoimmunity following alemtuzumab is not restricted to the thyroid gland. In the CAMMS-223 trial, six patients (2.8%) receiving alemtuzumab, and one patient (0.9%) receiving Rebif®, developed idiopathic thrombocytopenia purpura (ITP), an immune-mediated condition directed against blood platelets. The index patient suffered a fatal brain haemorrhage before diagnosis. In retrospect, cutaneous signs of ITP had been present for a number of weeks, but went unreported.30 All subsequent cases were identified by the riskmanagement programme. Of those treated with alemtuzumab, remission of ITP occurred without treatment in one patient, after corticosteroid therapy in two patients, and after rituximab therapy in two patients.30 All are currently off treatment and have platelet counts within the normal range. In addition to ITP and thyroid autoimmunity, we have also observed two cases of Goodpasture’s disease (one in the Cambridge cohort, and one on the Phase III programme) and single cases of autoimmune neutropenia4 and autoimmune haemolytic anaemia (unpublished observation).
Mechanism of Action of Alemtuzumab
One explanation for alemtuzumab’s efficacy as a treatment of MS is its ability to cause a long-lasting lymphopenia. However, lack of infections and the appearance of novel autoimmunity after treatment suggest that immune responses are very much intact post-alemtuzumab. For this and other reasons, we prefer the explanation that the therapeutic effect of alemtuzumab is not due to lymphocyte depletion per se, but rather the homeostatic response it induces. For example, we have shown that the composition of the circulating lymphocyte pool is radically altered after alemtuzumab. In particular, memory T-cell numbers are reduced and, for the first 6 months after treatment, there is a predominance of cells with a regulatory phenotype (CD4+ CD25hi FoxP3+), with very reduced constitutive cytokine expression.38 We speculate that this provides a ‘tolerogenic environment’ for newly generated lymphocytes. Currently, we are unable to explain why autoimmunity develops as a late consequence of alemtuzumab, and why this does not include a return of MS disease activity.
Results from the uncontrolled Cambridge cohort and from the CAMMS-223 trial demonstrate that alemtuzumab may well be significantly more efficacious as a treatment of RRMS than other licensed disease-modifying therapies. We anticipate that similar levels of efficacy will be replicated in the current Phase III trial, CAREMS-1, and that any reservations around its use will be focused on its toxicity; in particular, the emergence of autoimmunity after treatment. Most of our current research efforts are, therefore, focused around understanding and preventing this complication of an otherwise exciting new immunotherapy.