Leukocyte depletion for leukaemia and multiple sclerosis

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MOLECULAR MEDICINE TODAY, DECEMBER 1998

Restoring interleukin 2 production in AIDS patients A drug usually given to patients undergoing myelosuppressive chemotherapy, radiotherapy, or bone marrow transplantation might also help boost immune function in patients infected with HIV. Filgrastim, or recombinant human granulocyte colony-stimulating factor (r-metHuGCSF), reverses neutropenia and reduces the risk of infection in patients with HIV, but a recent study suggests that the drug might also restore interleukin 2 (IL-2) levels, thus boosting immune function even further [Hartung, T. et al. (1998) J. Infect. Dis. 178, 686–692]. Diminishing IL-2 production plays a central role in the progression of HIV infection to AIDS. As a major growth factor of lymphocytes, IL-2 stimulates proliferation of both CD4+ and CD8+ T cells; it is thought to influence CD8+ T-cell control of viral replication; and a switch from IL-2 to IL-4

and IL-10 production is key to the change from asymptomatic HIV infection to AIDS. Dr Thomas Hartung (University of Konstanz, Germany) and colleagues at Amgen Inc. (Thousand Oaks, CA, USA) exposed blood from 31 patients infected with HIV and 13 healthy volunteers to staphylococcal enterotoxin B (SEB) with and without G-CSF and then measured cytokine levels. As expected, release of both IL-2 and IL-4 was impaired in blood from patients with HIV but IL-2 release was restored by G-CSF. The mechanism of action of G-CSF is unclear although Dr Hartung says: ‘We do know from studies in healthy volunteers that lymphocytes taken 24 hours after injection of G-CSF produce more IL-2 and show a stronger proliferative response to mitogenic stimuli. Furthermore, we observe that lymphocytosis peaks after one week

in these volunteers. Since lymphocytes do not carry G-CSF receptors, we assume that the mechanism involves indirect effects via monocytes or neutrophils.’ IL-2 levels can be supplemented directly by giving patients low-dose IL-2, but this therapy has considerable side effects. G-CSF has been in clinical use for about ten years in patients with neutropenia and as this study hints at benefits beyond the reversal of neutropenia and improved defence against infection, it might be a more acceptable alternative. In addition, Hartung says, ‘Our data from volunteer treatment studies indicate that the effects of G-CSF might be reinforced by new treatment regimens, such as high-dose interval therapy. In addition, G-CSF might also be useful as an adjunct to triple or quadruple therapy.’ He also speculates: ‘The fact that IL-2 production was restored by the direct effects of G-CSF on blood leukocytes suggests that the lack of IL-2 formation is not due to reduced formation capacity but to a suppressive mechanism, which might also be the target of future therapies.’ Sharon Dorrell

Leukocyte depletion for leukaemia and multiple sclerosis LeukoSite, Inc. (Cambridge, MA, USA), and ILEX Oncology, Inc. (San Antonio, TX, USA), have completed the enrolment for their joint, investigational clinical trial of a humanized monoclonal antibody, CAMPATH-1H, in the treatment of B-cell chronic leukaemia (BCLL). CAMPATH-1H (a humanized rat IgGI antibody) selectively targets the CD52 (CAMPATH-1) antigen, a small glycosylphosphatidylinositol (GPI)-anchored glycoprotein antigen of unknown function that is abundantly expressed on lymphocytes, but is absent from haemopoietic stem cells. ‘Unlike existing cytotoxic drugs and radiation therapy, which destroy many types of cell, CAMPATH-1H selectively depletes all lymphocytes but spares the haemopoietic stem cells that are needed to repopulate the immune system’, says Herman Waldmann, professor of pathology at Oxford University (UK) and a member of LeukoSite’s scientific advisory board. ‘The CAMPATH-1 antigen appears to be an unusually good target for cell lysis’, explains Waldmann. The susceptibility of the CAMPATH-1 antigen as a target cannot simply be explained by its abundance – ~5 3 105 molecules per lymphocyte – because even small amounts of antibody are lytic. Waldmann speculates that the proximity of the antigen to the plasma membrane might make it very susceptible to the cytotoxic mechanisms of natural killer cells. The 96 patients taking part in the trial of intravenous CAMPATH-1H, which will take place in several centres throughout the USA and Europe, have BCLL that has 508

failed to respond to standard second-line cytotoxic therapy (fludarabine, an antipurine). In two preliminary trials in which 54 BCLL patients received intravenous CAMPATH-1H, major responses were seen in 40% of patients. ‘The response rates were very, very encouraging, and survival improved significantly – to one or two years or more’, says Chris Mirabelli, chairman and chief executive officer of LeukoSite. The preliminary trials of CAMPATH-1H in patients with BCLL were carried out by the former company Burroughs Wellcome, but it discontinued the development programme for commercial reasons, concentrating instead on developing the antibody for the treatment of patients with rheumatoid arthritis. ‘Although the antibody worked, this programme too was abandoned because of its adverse effects – mainly infection’, says Mirabelli. Nevertheless, Mirabelli is confident that the marriage between LeukoSite’s expertise in leukocyte biology and therapeutic antibodies and ILEX’s experience with the clinical development of cancer drugs will lead to the successful development of CAMPATH-1H for the treatment of BCLL. He expects an application for regulatory approval and marketing will be made to the US Food and Drug Administration in mid-1999. Several other diseases might benefit from lymphocyte depletion with the CAMPATH-1 family of antibodies. Waldmann and Alastair Compston (University of Cambridge, UK) are about to publish the results of a preliminary trial of CAMPATH-1H

in multiple sclerosis (MS). MS is thought to be an autoimmune disease that is mediated by CD41 T cells that cross the blood2brain barrier and cause neuronal inflammation and demyelination, leading to axonal degeneration. In this trial, in which 37 patients with progressive MS were treated, CAMPATH-1H successfully stopped nerve inflammation (by magnetic resonance imaging analysis). However, half of the patients worsened clinically, indicating that axonal degeneration continued during treatment with CAMPATH-1H. Compston plans to try the drug in patients with very early MS in the near future. CAMPATH-1 antibodies have already been used extensively to prevent graft-versus-host disease in bone-marrow transplant recipients, and LeukoSite is considering using CAMPATH-1H not only as front-line therapy for BCLL, but also for non-Hodgkin’s lymphoma. The effects of CAMPATH-1H on the immune system might vary from disease to disease and will depend on the degree of lymphocyte depletion; at the relatively small doses used in the MS study, increased susceptibility to infection is a rare side effect. ‘In lymphoma, where high doses are used and patients have already had drugs such as fludarabine, immune impairment is likely to last some weeks’, cautions Waldmann. ‘BCLL is itself an immunosuppressive disease; the decision is really one of risk versus benefit.’ Dorothy Bonn

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