Leukocyte depletion for leukaemia and multiple sclerosis
1
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-metHuG- CSF), 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 508 N e w s MOLECULAR MEDICINE TODAY, DECEMBER 1998 1357-4310/98/$ - see front matter © 1998 Elsevier Science. All rights reserved. Restoring interleukin 2 production in AIDS patients 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 10 5 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 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 CD4 1 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 Leukocyte depletion for leukaemia and multiple sclerosis
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Transcript of Leukocyte depletion for leukaemia and multiple sclerosis
A drug usually given to patients undergoingmyelosuppressive chemotherapy, radiotherapy, orbone marrow transplantation might also helpboost immune function in patients infected withHIV. Filgrastim, or recombinant humangranulocyte colony-stimulating factor (r-metHuG-CSF), reverses neutropenia and reduces the risk ofinfection in patients with HIV, but a recent studysuggests that the drug might also restoreinterleukin 2 (IL-2) levels, thus boosting immunefunction even further [Hartung, T. et al. (1998) J. Infect. Dis. 178, 686–692].
Diminishing IL-2 production plays a centralrole in the progression of HIV infection to AIDS.As a major growth factor of lymphocytes, IL-2stimulates proliferation of both CD4+ and CD8+ Tcells; it is thought to influence CD8+ T-cell controlof viral replication; and a switch from IL-2 to IL-4
and IL-10 production is key to the change fromasymptomatic HIV infection to AIDS.
Dr Thomas Hartung (University of Konstanz,Germany) and colleagues at Amgen Inc.(Thousand Oaks, CA, USA) exposed blood from31 patients infected with HIV and 13 healthyvolunteers to staphylococcal enterotoxin B (SEB)with and without G-CSF and then measuredcytokine levels. As expected, release of both IL-2and IL-4 was impaired in blood from patientswith HIV but IL-2 release was restored by G-CSF.
The mechanism of action of G-CSF is unclearalthough Dr Hartung says: ‘We do know fromstudies in healthy volunteers that lymphocytestaken 24 hours after injection of G-CSF producemore IL-2 and show a stronger proliferativeresponse to mitogenic stimuli. Furthermore, weobserve that lymphocytosis peaks after one week
in these volunteers. Since lymphocytes do notcarry G-CSF receptors, we assume that themechanism involves indirect effects viamonocytes or neutrophils.’
IL-2 levels can be supplemented directly bygiving patients low-dose IL-2, but this therapy hasconsiderable side effects. G-CSF has been inclinical use for about ten years in patients withneutropenia and as this study hints at benefitsbeyond the reversal of neutropenia and improveddefence against infection, it might be a moreacceptable alternative. In addition, Hartung says,‘Our data from volunteer treatment studies indicatethat the effects of G-CSF might be reinforced bynew treatment regimens, such as high-dose intervaltherapy. In addition, G-CSF might also be useful asan adjunct to triple or quadruple therapy.’ He alsospeculates: ‘The fact that IL-2 production wasrestored by the direct effects of G-CSF on bloodleukocytes suggests that the lack of IL-2 formationis not due to reduced formation capacity but to asuppressive mechanism, which might also be thetarget of future therapies.’
Sharon Dorrell
508
N e w s MOLECULAR MEDICINE TODAY, DECEMBER 1998
1357-4310/98/$ - see front matter © 1998 Elsevier Science. All rights reserved.
Restoring interleukin 2 production in AIDS patients
LeukoSite, Inc. (Cambridge, MA, USA), and ILEXOncology, Inc. (San Antonio, TX, USA), havecompleted the enrolment for their joint, investigationalclinical trial of a humanized monoclonal antibody,CAMPATH-1H, in the treatment of B-cell chronicleukaemia (BCLL).
CAMPATH-1H (a humanized rat IgGI antibody)selectively targets the CD52 (CAMPATH-1) antigen, asmall glycosylphosphatidylinositol (GPI)-anchoredglycoprotein antigen of unknown function that isabundantly expressed on lymphocytes, but is absentfrom haemopoietic stem cells. ‘Unlike existingcytotoxic drugs and radiation therapy, which destroymany types of cell, CAMPATH-1H selectivelydepletes all lymphocytes but spares the haemopoieticstem cells that are needed to repopulate the immunesystem’, says Herman Waldmann, professor ofpathology at Oxford University (UK) and a memberof LeukoSite’s scientific advisory board. ‘TheCAMPATH-1 antigen appears to be an unusuallygood target for cell lysis’, explains Waldmann. Thesusceptibility of the CAMPATH-1 antigen as a targetcannot simply be explained by its abundance –~5 3 105 molecules per lymphocyte – because evensmall amounts of antibody are lytic. Waldmannspeculates that the proximity of the antigen to theplasma membrane might make it very susceptible tothe cytotoxic mechanisms of natural killer cells.
The 96 patients taking part in the trial of intravenousCAMPATH-1H, which will take place in several centresthroughout the USA and Europe, have BCLL that has
failed to respond to standard second-line cytotoxictherapy (fludarabine, an antipurine). In two preliminarytrials in which 54 BCLL patients received intravenousCAMPATH-1H, major responses were seen in 40% ofpatients. ‘The response rates were very, veryencouraging, and survival improved significantly – toone or two years or more’, says Chris Mirabelli,chairman and chief executive officer of LeukoSite.
The preliminary trials of CAMPATH-1H inpatients with BCLL were carried out by the formercompany Burroughs Wellcome, but it discontinued thedevelopment programme for commercial reasons,concentrating instead on developing the antibody forthe treatment of patients with rheumatoid arthritis.‘Although the antibody worked, this programme toowas abandoned because of its adverse effects – mainlyinfection’, says Mirabelli.
Nevertheless, Mirabelli is confident that themarriage between LeukoSite’s expertise in leukocytebiology and therapeutic antibodies and ILEX’sexperience with the clinical development of cancerdrugs will lead to the successful development ofCAMPATH-1H for the treatment of BCLL. Heexpects an application for regulatory approval andmarketing will be made to the US Food and DrugAdministration in mid-1999.
Several other diseases might benefit fromlymphocyte depletion with the CAMPATH-1 familyof antibodies. Waldmann and Alastair Compston(University of Cambridge, UK) are about to publishthe results of a preliminary trial of CAMPATH-1H
in multiple sclerosis (MS). MS is thought to be anautoimmune disease that is mediated by CD41 Tcells that cross the blood2brain barrier and causeneuronal inflammation and demyelination, leadingto axonal degeneration. In this trial, in which 37patients with progressive MS were treated,CAMPATH-1H successfully stopped nerveinflammation (by magnetic resonance imaginganalysis). However, half of the patients worsenedclinically, indicating that axonal degenerationcontinued during treatment with CAMPATH-1H.Compston plans to try the drug in patients with veryearly MS in the near future.
CAMPATH-1 antibodies have already beenused extensively to prevent graft-versus-hostdisease in bone-marrow transplant recipients, andLeukoSite is considering using CAMPATH-1Hnot only as front-line therapy for BCLL, but alsofor non-Hodgkin’s lymphoma.
The effects of CAMPATH-1H on the immunesystem might vary from disease to disease and willdepend on the degree of lymphocyte depletion; at therelatively small doses used in the MS study, increasedsusceptibility to infection is a rare side effect. ‘Inlymphoma, where high doses are used and patientshave already had drugs such as fludarabine, immuneimpairment is likely to last some weeks’, cautionsWaldmann. ‘BCLL is itself an immunosuppressivedisease; the decision is really one of risk versus benefit.’
Dorothy Bonn
Leukocyte depletion for leukaemia andmultiple sclerosis
