“thinking without thinking” about natalizumab and pml

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Thinking without thinkingabout natalizumab and PML Richard M. Ransohoff Neuroinflammation Research Center, Department of Neurosciences, The Lerner Research Institute, The Cleveland Clinic Foundation, United States Received 27 January 2006; accepted 13 April 2006 Available online 22 May 2007 Abstract The novel multiple sclerosis (MS) therapeutic natalizumab has taken neurologists and their MS patients on a roller-coaster ride: initial encouraging efficacy data led to expedited release in the United States, followed by suspension of dosing with the unexpected occurrence of progressive multifocal leukoencephalopathy (PML) in three clinical trial participants. The drug was re-released in 2006, in a restricted distribution format. Aside from PML, natalizumab treatment was not associated with opportunistic infections, suggesting the possibility that PML in these individuals was mechanism-based, and was not a consequence of generalized immunosuppression. This commentary proposes a hypothesis to account for PML in natalizumab-treated patients. © 2007 Elsevier B.V. All rights reserved. Keywords: Integrin alpha4beta1; Monoclonal antibodies; Multiple sclerosis; Progressive multifocal leukoencephalopathy; JC virus; Immunologic surveillance; Demyelinating diseases A strange emotional state, equally composed of elation and despair, has been induced by progress and complications in the development of drug treatments for multiple sclerosis (MS) and other inflammatory disorders such as Crohn's disease [1,2]. In his new book Blink [3], Malcolm Gladwell argues in favor of the value of initial impressions, arrived at using only that information garnered in the first few seconds of an en- counter. The author terms this cognitive mode thinking with- out thinking. While granting Gladwell that blinkthinking is an intriguing phenomenon, it is also valid to consider cir- cumstances in which these instantaneous impressions need to be revisited, to arrive at a correct apprehension of a complex situation. The relationship between natalizumab administra- tion and progressive multifocal leukoencephalopathy (PML) is one such case. The blinkview of this relationship is that natalizumab recipients lacked effective immunosurveillance of JC virus (JCV), the causative agent of PML, leading to unrestrained viral replication and spread of infection to central nervous system (CNS) glia, with the catastrophic consequence of PML. A recent editorial stated Therefore, it appears likely that natalizumab, by preventing normal trafficking of lym- phocytes, led to unbridled JC virus replication…”, and summarized the situation by declaring that Bad things may happen when rescuers are turned back at the gates[4]. This type of blinkthinking about natalizumab and PML is logical: prior PML cases invariably arose in the context of immunosuppression and natalizumab, which blocks α4 integrins (including α4β1/VLA-4 and α4β7), had a powerful anti-inflammatory effect in treating multiple sclerosis (MS) and Crohn's disease, so it seems plausible that natalizumab- mediated immunosuppression caused PML. However, several lines of evidence indicate that this conclusion is premature. Relevant considerations include effects of natalizumab on bone marrow physiology (quite apart from mechanisms for inhibiting inflammation) and the incompletely deciphered biology of JCV infection. As we proceed beyond the blinkresponse, it seems apparent that more information is required to understand how PML occurred in natalizumab recipients. Was PML in natalizumab recipients an off-target adverse effect, or a direct consequence of the mechanism of thera- peutic action? The answer to this question is important for defining how MS drug development will proceed. If PML was a unavoidable result of inhibiting leukocyte trafficking, then we must abandon this extremely promising avenue for treating the vast majority of our patients, especially those Journal of the Neurological Sciences 259 (2007) 50 52 www.elsevier.com/locate/jns 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2006.04.011

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Page 1: “Thinking without thinking” about natalizumab and PML

ences 259 (2007) 50–52www.elsevier.com/locate/jns

Journal of the Neurological Sci

“Thinking without thinking” about natalizumab and PML

Richard M. Ransohoff

Neuroinflammation Research Center, Department of Neurosciences, The Lerner Research Institute, The Cleveland Clinic Foundation, United States

Received 27 January 2006; accepted 13 April 2006Available online 22 May 2007

Abstract

The novel multiple sclerosis (MS) therapeutic natalizumab has taken neurologists and their MS patients on a roller-coaster ride: initialencouraging efficacy data led to expedited release in the United States, followed by suspension of dosing with the unexpected occurrence ofprogressive multifocal leukoencephalopathy (PML) in three clinical trial participants. The drug was re-released in 2006, in a restricteddistribution format. Aside from PML, natalizumab treatment was not associated with opportunistic infections, suggesting the possibility thatPML in these individuals was mechanism-based, and was not a consequence of generalized immunosuppression. This commentary proposesa hypothesis to account for PML in natalizumab-treated patients.© 2007 Elsevier B.V. All rights reserved.

Keywords: Integrin alpha4beta1; Monoclonal antibodies; Multiple sclerosis; Progressive multifocal leukoencephalopathy; JC virus; Immunologic surveillance;Demyelinating diseases

A strange emotional state, equally composed of elationand despair, has been induced by progress and complicationsin the development of drug treatments for multiple sclerosis(MS) and other inflammatory disorders such as Crohn'sdisease [1,2].

In his new book Blink [3], Malcolm Gladwell argues infavor of the value of initial impressions, arrived at using onlythat information garnered in the first few seconds of an en-counter. The author terms this cognitive mode ‘thinking with-out thinking’. While granting Gladwell that ‘blink’ thinking isan intriguing phenomenon, it is also valid to consider cir-cumstances in which these instantaneous impressions need tobe revisited, to arrive at a correct apprehension of a complexsituation. The relationship between natalizumab administra-tion and progressivemultifocal leukoencephalopathy (PML) isone such case. The ‘blink’ view of this relationship is thatnatalizumab recipients lacked effective immunosurveillanceof JC virus (JCV), the causative agent of PML, leading tounrestrained viral replication and spread of infection to centralnervous system (CNS) glia, with the catastrophic consequenceof PML. A recent editorial stated “Therefore, it appears likelythat natalizumab, by preventing normal trafficking of lym-phocytes, led to unbridled JC virus replication…”, and

0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jns.2006.04.011

summarized the situation by declaring that “Bad things mayhappen when rescuers are turned back at the gates” [4].

This type of ‘blink’ thinking about natalizumab and PMLis logical: prior PML cases invariably arose in the contextof immunosuppression and natalizumab, which blocks α4integrins (including α4β1/VLA-4 and α4β7), had a powerfulanti-inflammatory effect in treating multiple sclerosis (MS)and Crohn's disease, so it seems plausible that natalizumab-mediated immunosuppression caused PML. However, severallines of evidence indicate that this conclusion is premature.Relevant considerations include effects of natalizumab onbone marrow physiology (quite apart from mechanisms forinhibiting inflammation) and the incompletely decipheredbiology of JCV infection. As we proceed beyond the ‘blink’response, it seems apparent that more information is requiredto understand how PML occurred in natalizumab recipients.

Was PML in natalizumab recipients an off-target adverseeffect, or a direct consequence of the mechanism of thera-peutic action? The answer to this question is important fordefining how MS drug development will proceed. If PMLwas a unavoidable result of inhibiting leukocyte trafficking,then we must abandon this extremely promising avenue fortreating the vast majority of our patients, especially those

Page 2: “Thinking without thinking” about natalizumab and PML

51R.M. Ransohoff / Journal of the Neurological Sciences 259 (2007) 50–52

with early, mild disease and uncertain prognosis for disability[5]. If PML was an off-target adverse effect, then leukocytetrafficking remains a valid therapeutic target.

One must first considerα4β1/VCAM-1 interactions in theadult hematopoietic system, beyond those which supportinflammation. α4β1 is required for generating T cells and Bcells from bone marrow progenitors in adult mice, and forsome inflammatory lymphocyte trafficking but not for entryinto spleen, lymph nodes or intestinal epithelium [6]. In adultmice with conditional, interferon-induced deletion of α4-integrin from hematopoietic cells, circulating cells showedlarge numbers of myeloid progenitors (for nearly one year),along with doubling in blood lymphocyte counts [7].Tellingly, there were 20% fewer B cell progenitors in marrow[7]. Patients that received natalizumab exhibited elevatedbasophil, eosinophil and lymphocyte counts, with approxi-mately 5% showing circulating nucleated erythrocytes(Tysabri™ package insert). Natalizumab, unlike many otherleukocyte trafficking modulators, potently affects bonemarrow physiology by blocking α4β1/VCAM-1 interactions[6,8–10].

This finding may be pertinent for the biology of JCV innatalizumab recipients. Eighty percent of the population areJCV seropositive, with an unknown number harboringreplication-competent virus in renal tubular epithelial cellsand bonemarrow, and a smaller number harboring potentiallypathogenic virus. When PML occurs, JCV sequences in bonemarrow and blood, but not kidney or urine, strongly resemblethose in CNS, and carry tandem repeats in the transcriptionalcontrol region (TCR) that are required for replication in glialcells in vitro. Reactivated, pathogenic JCV is believed totransit to CNS through B lymphocytes or as cell-free virus[11–13]. Therefore, effects of natalizumab on bone marrowphysiology, and B-cells in particular, may be pertinent forPML pathogenesis. It is conceivable that α4-integrin block-ade mobilizes JCV-infected cells from bone marrow storesand that poor control of viral replication occurs in infectedpre-B cells in the circulation, deprived of contact with bonemarrow stromal cells [1].

Natalizumab strongly suppresses inflammatory leukocytetrafficking intoCNS across parenchymalmicrovessels and alsoaffects immunosurveillance of the CNS. In particular, we andothers proposed that this function is carried out by cerebro-spinal fluid (CSF) memory T lymphocytes, whose entry intoCSF across the choroid plexus requires α4β1 [14–17], so thatCNS immunosurveillancewas clearly affected by natalizumab.During the time frame of clinical trials for MS and otherinflammatory disorders, natalizumab caused no other effectssuggesting immunosuppression: there were no increases incommon infections, nor other opportunistic infections, in morethan 4000 patient-years of clinical trial experience [18]. Takentogether, the effects of natalizumab on bone marrow physi-ology, inflammatory CNS trafficking and CNS immune sur-veillance suggest that natalizumab-associated PML wasspecific to the α4-integrin target, perhaps augmented by theprolonged and remarkable efficacy with which it was blocked

by natalizumab. Referring again to popular literature, thisconcurrence of effects may have represented a ‘perfect storm’[19] with regard to pathogenesis of PML.

We suggest consideration of the following hypothesis:Natalizumab treatment led to PML beginning with its actiontowards infected bone marrow cells, by promoting theirpremature exit from the marrow, which both reduced theirability to control JCV replication due to non-physiologicaldeprivation of contact with bone marrow stroma and alsogave these infected cells access to all body compartments.These effects of natalizumab treatment, in combination withreduced surveillance and inflammatory trafficking to theinfected CNS, promoted PML pathogenesis. A natalizumab-induced spike of JC viremia in a Crohn's-disease patient [20]may have represented proliferation of virus associated withcells that had been flushed from their physiological niche inthe bone marrow rather than uncontrolled JCV proliferationdue to immunosuppression. If this hypothesis is correct,agents that don't affect bone marrow will lack this com-plication, while those affecting bone marrow and lymphoidorgans (anti-CXCR4; anti-α4 integrin; for example) mightrequire caution and surveillance. In conclusion, PML may beregarded as an off-target adverse effect, and it remainspossible to consider treating MS patients with agents thataddress leukocyte trafficking to the CNS.

Given the risk of PML and the potential benefits of thisclass of agents, we need to learn much more about JCVinfection without delay. It is not known how many healthyindividuals harbor pathogenic, reactivation-competent JCV, orwhether we can reliably detect such persons. It is imperative toclarify whether there is a reservoir of JCV in the CNS, as somehave suggested. The mechanism that generates tandem repeatsof JCV TCR elements is unknown. Relatively little is securelyknown about CNS immunosurveillance. It is important to staymindful of the benefits that natalizumab showed, and resolveto recapitulate the efficacy of this agent without its adverseeffects. Little, however, can be done, until we stop ‘blink’-ingand open our eyes.

References

[1] Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005;8(10):1275.

[2] Multiple sclerosis woes. Nat Neurosci 2005;8(7):837.[3] Gladwell M. Blink. Boston: Little Brown and Company; 2005.[4] Berger JR, Koralnik IJ. Progressive multifocal leukoencephalo-

pathy and natalizumab—unforeseen consequences. N Engl J Med2005.

[5] Steinman L. Blocking adhesion molecules as therapy for multiplesclerosis: natalizumab. Nat Rev Drug Discov 2005;4(6):510–8.

[6] Arroyo AG, Yang JT, Rayburn H, Hynes RO. Differential requirementsfor alpha4 integrins during fetal and adult hematopoiesis. Cell 1996;85(7):997–1008.

[7] Scott LM, Priestley GV, Papayannopoulou T. Deletion of alpha4integrins from adult hematopoietic cells reveals roles in homeostasis,regeneration, and homing. Mol Cell Biol 2003;23(24):9349–60.

[8] Bonig H, Priestley GV, Papayannopoulou T. Hierarchy of molecularpathway usage in bone marrow homing and its shift by cytokines. Blood2005.

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52 R.M. Ransohoff / Journal of the Neurological Sciences 259 (2007) 50–52

[9] Hidalgo A, Sanz-Rodriguez F, Rodriguez-Fernandez JL, Albella B,Blaya C, Wright N, et al. Chemokine stromal cell-derived factor-1alpha modulates VLA-4 integrin-dependent adhesion to fibronectinand VCAM-1 on bone marrow hematopoietic progenitor cells. ExpHematol 2001;29(3):345–55.

[10] Koni PA, Joshi SK, Temann UA, Olson D, Burkly L, Flavell RA.Conditional vascular cell adhesion molecule 1 deletion in mice: im-paired lymphocyte migration to bone marrow. J Exp Med 2001;193(6):741–54.

[11] Houff SA, Major EO, Katz DA, Kufta CV, Sever JL, Pittaluga S, et al.Involvement of JC virus-infected mononuclear cells from the bonemarrow and spleen in the pathogenesis of progressive multifocalleukoencephalopathy. N Engl J Med 1988;318(5):301–5.

[12] Jensen PN, Major EO. Viral variant nucleotide sequences help exposeleukocytic positioning in the JC virus pathway to the CNS. J LeukocBiol 1999;65(4):428–38.

[13] Sabath BF, Major EO. Traffic of JC virus from sites of initial infectionto the brain: the path to progressive multifocal leukoencephalopathy.J Infect Dis 2002;186(Suppl 2):S180–6.

[14] Ransohoff RM, Kivisakk P, Kidd G. Three or more routes for leukocytemigration into the central nervous system. Nat Rev Immunol 2003;3(7):569–81.

[15] Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocytetrafficking to the CNS: anatomical sites and molecular mechanisms.Trends Immunol 2005;26(9):485–95.

[16] Stuve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, et al.Immune surveillance in multiple sclerosis patients treated withnatalizumab. Ann Neurol 2006;59:743–7.

[17] Stuve O, Marra CM, Bar-Or A, Nuno M, Cravens PD, Cepok S, et al.Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizu-mab-treated patients with multiple sclerosis. Arch Neurol 2006;63:1383–7.

[18] Ursell MR, O'Connor PW. Natalizumab and other monoclonal anti-bodies. Neurol Clin 2005;23(1):233–46 [viii].

[19] Junger S. The Perfect Storm. New York: HarperCollins; 1997.[20] Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman

M, et al. Progressive multifocal leukoencephalopathy after natalizu-mab therapy for Crohn's disease. N Engl J Med 2005.