Downloaded from gut.bmj.com on August 18, 2014 - Published by group.bmj.com
Gut Online First, published on June 19, 2014 as 10.1136/gutjnl-2014-307397 Commentary
Targeting of gut specific leucocyte recruitment in IBD by vedolizumab Bertus Eksteen IBD is characterised by an inappropriate immune response to our own gut microbiota in the setting of a genetically susceptible individual. The consequence of this dysregulated process is activation of the innate immune system which in turn produces cytokines such as tumour necrosis factor α (TNFα) and activation of the adaptive immune system with subsequent recruitment of pro-inflammatory T and B cells to the colon or small bowel. This in turn leads to further amplification of pro-inflammatory cytokines release which bind to cognate receptors and activation of intercellular pathway such as JAK and STAT to mediate tissue inflammation. The mainstay of treatment for individuals with moderate to severe disease UC or Crohn’s disease has been therapeutic targeting of the pro-inflammatory cytokine, TNFα. Unfortunately, a significant proportion of individuals will be refractory to these medications or eventually lose efficacy. This has widened the search for other pathways that might be targeted to treat IBD. The most advanced of these treatments are the integrin inhibitors that target trafficking of lymphocytes to the gut.1 The maintenance of gut immunity is critically dependent on regional immune responses that are generated in the gut-associated lymphoid tissues. Dendritic cells (DCs) are positioned within the lamina propria in close relation to the enterocytes to continuously monitor the micro environment for potential antigens. Once an antigen is detected, gut DCs migrate to the mesenteric lymph nodes and the Peyer’s patches. Within these secondary lymphoid tissues, DCs imprint on naive T and B cells’ knowledge of the antigen to generate an appropriate immune response. DC– lymphocyte priming conveys recognition of the antigen and the shape of the immune response required such as a pro-inflammatory response to a potentially harmful pathogen or tolerance to an autoantigen. A third consequence of this
Correspondence to Dr Bertus Eksteen, Division of Gastroenterology and Hepatology, Snyder Institute for Chronic Diseases, Health Research and Innovation Centre (HRIC), University of Calgary, 4AC66—3280 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1; [email protected]
interaction is the induction of the gut specificity on these newly programmed lymphocytes. This is an important feature of regional immunity so that immune cells are generated and directed back to the site where they are most likely to encounter the antigen, in this case the gut.2 Gut specificity is driven by gut-derived DCs that express CD1033 and have the unique ability to convert retinol to alltrans retinoic acid which in turn induces the expression of the chemokine receptor, CCR9 and the integrin combination, α4β7 on B and T lymphocytes during priming.4 5 This provides a molecular postal code to selectively recruit these lymphocytes to the gut where restricted expression of the chemokine, CCL25 (ligand for CCR9) and the α4β7 integrin ligand, MAdCAM-1 acts in tandem as molecular Velcro to capture gut-homing lymphocytes2 (figure 1). Other integrin ligands are also expressed in the gut during inflammation and do not add to tissue specificity but are generic to inflammation such as VCAM-1 (ligand for α4β1). The first molecule to successfully target gut-specific adhesion and provide a paradigm for this strategy in treating IBD was natalizumab which targeted the α4 integrin.6 α4 Can associate with either β1 which binds to VCAM-1 or β7 which binds to MAdCAM-1. This drug proved efficacious in patients with moderate to severe Crohn’s disease. Unfortunately, some individuals treated with natalizumab developed progressive multifocal leucoencephalopathy which is a rare, fatal demyelinating disease of the brain caused by reactivation of JC virus. Reactivation of JC virus is thought to be related to the α4β1 inhibitory effects of natalizumab. Subsequently, much work has been done to selectively target α4β7 specifically without interfering of α4β1 to limit unwanted systemic immunosuppression. Several compounds have emerged as potential candidates. This includes etrolizumab (Genentech) which selectively targets β7 ( phase II development) and PF-00547659 (Pfizer) as a selective inhibitor of MAdCAM-1, the ligand for α4β7 ( phase I/II development). The most successful new drug in this class is vedolizumab which has been developed by Millennium Pharmaceuticals and Takeda.
This molecule selectively targets the combination of α4β7 as a heterodimer with minimal effects individually on α4 or β7. Its potential utility in IBD came from studies in Cotton-top tamarins where rapid and dramatic improvements were seen at 24 and 72 h after treatment. This resulted in significant improvements in gut histology and reduction in mucosal T cell infiltration.7 Vedolizumab has subsequently shown clinical efficacy in randomised, placebocontrolled studies as an induction and maintenance therapy in moderate to severe UC (Gemini 1 study),8 moderate to severe Crohn’s disease (Gemini 2)9 and moderate to severe Crohn’s disease patients who had previously failed other treatments (Gemini 3).10 It was given FDA approval in May 2014 and ongoing safety data are being collected in the Gemini LTS study which is a 7-year study that aims to report in 2016. The majority of adverse events have been headache, nasopharyngitis, nausea, arthralgia, upper respiratory infections and fatigue. Serious infections tended to occur more frequently in Crohn’s disease rather than UC. The study by Wyant et al11 published in this edition of Gut builds on the existing data of vedolizumab as a gut selective therapy by assessing the effects of vedolizumab on humoral responses following intestinal or systemic immunisation. The reasoning behind the study is to gain more evidence for its gut specificity and assess its impact on gut antibodyproducing B cells. In the study, the investigators performed a phase I randomised, double blind, placebo-controlled study where 127 individuals were randomly assigned in a 1 : 1 ratio to receive either a single dose of vedolizumab 750 mg or placebo. This dose of vedolizumab is higher than the 300 mg that has been used in the clinical trials but was picked to ensure that serum drug concentrations led to complete α4β7 saturation of peripheral blood leucocytes for the subsequent 74 days. In addition to either receiving vedolizumab or placebo, individuals were also assigned an intramuscular dose of HBV vaccine on days 4, 32 and 60 of the study and an oral dose of the oral cholera vaccine (OCV) on days 4 and 18. Vaccine responses were assessed at day 74 and safety up to day 127. Immunity to HBV was defined as an anti-Hepatitis B surface antigen (HBS) antibody serum concentration of greater than 10 IU/L and for OCV it was defined as >4-fold increase from the baseline in the combined antibody titre (immunoglobulin (Ig) G, IgM and IgA). HBV seroconversion
Eksteen B. Gut Month 2014 Vol 0 No 1 Copyright Article author (or0 their employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from gut.bmj.com on August 18, 2014 - Published by group.bmj.com
Commentary Figure 1 CD103 gut dendritic cells (DCs) imprint antigen specificity in naive T and B lymphocytes by presentation of antigen on major histocompatibility complex (MHC) to T cell (TCR) and B cell (BCR) receptors and co-stimulatory signals in mesenteric lymph nodes. Production of all-trans retinoic acid by CD103 DCs induces CCR9 and α4β7 expression which allows these newly generated effector T cells and IgA-producing B cells to be selectively recruited to the gut. Expression of the chemokine, CCL25, is restricted to the gut which upon binding to CCR9 activates α4β7 to bind MAdCAM-1 and subsequent recruitment to the lamina propria.
was similar between placebo treated (90.3%) and vedolizumab treated (88.7%) participants. However, the placebo treated group responded better to the OCV with 96.8% responses compared with 82.5% responses in the vedolizumab treated group. Anticholera immunoglobulin levels were higher in the placebo group than the vedolizumab group at day 74 (9210.08 vs 3007.8 units/mL). The data support a selective role for vedolizumab in regional gut immunity and raise questions whether vedolizumab will be associated in the longer term with an excess of gut infections. This has not been brought out in the clinical trials and although in this study there is a reduction in the antibody responses, the majority of the cases were still able to generate sufficient protection from the OCV. It suggests that even at a relatively high dose, vedolizumab is not able to completely abrogate gut humeral responses. This is likely due to redundancy with α4β1 and is an important observation as IBD patients are more prone to gut infections and require appropriate immune responses to control enteric viruses and bacteria. The authors conclude that vedolizumab is able to modulate immune responses in the gut without compromising the host defences. Further clinical data will be required to
2
confirm this observation and will hopefully be generated through the long-term Gemini LTS Safety Study.
3
4
Contributors BE compiled the data and wrote the manuscript. Funding Canadian Institutes for Health Research (CIHR).
5
6
Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
7
To cite Eksteen B. Gut Published Online First: [ please include Day Month Year] doi:10.1136/gutjnl-2014307397
8
Received 28 May 2014 Revised 30 May 2014 Accepted 2 June 2014
▸ http://dx.doi.org/10.1136/gutjnl-2014-307127
9
10
Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-307397 11
REFERENCES 1
2
Lobaton T, Vermeire S, Van Assche G, et al. Review article: anti-adhesion therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2014;39:579–94. Agace WW. Tissue-tropic effector T cells: generation and targeting opportunities. NatRevImmunol 2006;6:682–92.
Jaensson E, Uronen-Hansson H, Pabst O, et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. JExpMed 2008;205:2139–49. Mora JR, Iwata M, Eksteen B, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006;314:1157–60. Iwata M, Hirakiyama A, Eshima Y, et al. Retinoic Acid imprints gut-homing specificity on T cells. Immunity 2004;21:527–38. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24–32. Podolsky DK, Lobb R, King N, et al. Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonal antibody. JClinInvest 1993;92:372–80. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699–710. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369:711–21. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of Vedolizumab Induction Therapy for Patients With Crohn’s Disease in Whom Tumor Necrosis Factor Antagonist Treatment Had Failed. Gastroenterology 2014. doi:10.1053/j.gastro.2014.05.008 Wyant T, Leach T, Sankoh S, et al. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut Published online first: 24 Apr 2014. doi:10.1136/gutjnl-2014-307127
Eksteen B. Gut Month 2014 Vol 0 No 0
Downloaded from gut.bmj.com on August 18, 2014 - Published by group.bmj.com
Targeting of gut specific leucocyte recruitment in IBD by vedolizumab Bertus Eksteen Gut published online June 19, 2014
doi: 10.1136/gutjnl-2014-307397
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/06/19/gutjnl-2014-307397.full.html
These include:
References
This article cites 9 articles, 2 of which can be accessed free at: http://gut.bmj.com/content/early/2014/06/19/gutjnl-2014-307397.full.html#ref-list-1
P
Gut Online First, published on June 19, 2014 as 10.1136/gutjnl-2014-307397 Commentary
Targeting of gut specific leucocyte recruitment in IBD by vedolizumab Bertus Eksteen IBD is characterised by an inappropriate immune response to our own gut microbiota in the setting of a genetically susceptible individual. The consequence of this dysregulated process is activation of the innate immune system which in turn produces cytokines such as tumour necrosis factor α (TNFα) and activation of the adaptive immune system with subsequent recruitment of pro-inflammatory T and B cells to the colon or small bowel. This in turn leads to further amplification of pro-inflammatory cytokines release which bind to cognate receptors and activation of intercellular pathway such as JAK and STAT to mediate tissue inflammation. The mainstay of treatment for individuals with moderate to severe disease UC or Crohn’s disease has been therapeutic targeting of the pro-inflammatory cytokine, TNFα. Unfortunately, a significant proportion of individuals will be refractory to these medications or eventually lose efficacy. This has widened the search for other pathways that might be targeted to treat IBD. The most advanced of these treatments are the integrin inhibitors that target trafficking of lymphocytes to the gut.1 The maintenance of gut immunity is critically dependent on regional immune responses that are generated in the gut-associated lymphoid tissues. Dendritic cells (DCs) are positioned within the lamina propria in close relation to the enterocytes to continuously monitor the micro environment for potential antigens. Once an antigen is detected, gut DCs migrate to the mesenteric lymph nodes and the Peyer’s patches. Within these secondary lymphoid tissues, DCs imprint on naive T and B cells’ knowledge of the antigen to generate an appropriate immune response. DC– lymphocyte priming conveys recognition of the antigen and the shape of the immune response required such as a pro-inflammatory response to a potentially harmful pathogen or tolerance to an autoantigen. A third consequence of this
Correspondence to Dr Bertus Eksteen, Division of Gastroenterology and Hepatology, Snyder Institute for Chronic Diseases, Health Research and Innovation Centre (HRIC), University of Calgary, 4AC66—3280 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1; [email protected]
interaction is the induction of the gut specificity on these newly programmed lymphocytes. This is an important feature of regional immunity so that immune cells are generated and directed back to the site where they are most likely to encounter the antigen, in this case the gut.2 Gut specificity is driven by gut-derived DCs that express CD1033 and have the unique ability to convert retinol to alltrans retinoic acid which in turn induces the expression of the chemokine receptor, CCR9 and the integrin combination, α4β7 on B and T lymphocytes during priming.4 5 This provides a molecular postal code to selectively recruit these lymphocytes to the gut where restricted expression of the chemokine, CCL25 (ligand for CCR9) and the α4β7 integrin ligand, MAdCAM-1 acts in tandem as molecular Velcro to capture gut-homing lymphocytes2 (figure 1). Other integrin ligands are also expressed in the gut during inflammation and do not add to tissue specificity but are generic to inflammation such as VCAM-1 (ligand for α4β1). The first molecule to successfully target gut-specific adhesion and provide a paradigm for this strategy in treating IBD was natalizumab which targeted the α4 integrin.6 α4 Can associate with either β1 which binds to VCAM-1 or β7 which binds to MAdCAM-1. This drug proved efficacious in patients with moderate to severe Crohn’s disease. Unfortunately, some individuals treated with natalizumab developed progressive multifocal leucoencephalopathy which is a rare, fatal demyelinating disease of the brain caused by reactivation of JC virus. Reactivation of JC virus is thought to be related to the α4β1 inhibitory effects of natalizumab. Subsequently, much work has been done to selectively target α4β7 specifically without interfering of α4β1 to limit unwanted systemic immunosuppression. Several compounds have emerged as potential candidates. This includes etrolizumab (Genentech) which selectively targets β7 ( phase II development) and PF-00547659 (Pfizer) as a selective inhibitor of MAdCAM-1, the ligand for α4β7 ( phase I/II development). The most successful new drug in this class is vedolizumab which has been developed by Millennium Pharmaceuticals and Takeda.
This molecule selectively targets the combination of α4β7 as a heterodimer with minimal effects individually on α4 or β7. Its potential utility in IBD came from studies in Cotton-top tamarins where rapid and dramatic improvements were seen at 24 and 72 h after treatment. This resulted in significant improvements in gut histology and reduction in mucosal T cell infiltration.7 Vedolizumab has subsequently shown clinical efficacy in randomised, placebocontrolled studies as an induction and maintenance therapy in moderate to severe UC (Gemini 1 study),8 moderate to severe Crohn’s disease (Gemini 2)9 and moderate to severe Crohn’s disease patients who had previously failed other treatments (Gemini 3).10 It was given FDA approval in May 2014 and ongoing safety data are being collected in the Gemini LTS study which is a 7-year study that aims to report in 2016. The majority of adverse events have been headache, nasopharyngitis, nausea, arthralgia, upper respiratory infections and fatigue. Serious infections tended to occur more frequently in Crohn’s disease rather than UC. The study by Wyant et al11 published in this edition of Gut builds on the existing data of vedolizumab as a gut selective therapy by assessing the effects of vedolizumab on humoral responses following intestinal or systemic immunisation. The reasoning behind the study is to gain more evidence for its gut specificity and assess its impact on gut antibodyproducing B cells. In the study, the investigators performed a phase I randomised, double blind, placebo-controlled study where 127 individuals were randomly assigned in a 1 : 1 ratio to receive either a single dose of vedolizumab 750 mg or placebo. This dose of vedolizumab is higher than the 300 mg that has been used in the clinical trials but was picked to ensure that serum drug concentrations led to complete α4β7 saturation of peripheral blood leucocytes for the subsequent 74 days. In addition to either receiving vedolizumab or placebo, individuals were also assigned an intramuscular dose of HBV vaccine on days 4, 32 and 60 of the study and an oral dose of the oral cholera vaccine (OCV) on days 4 and 18. Vaccine responses were assessed at day 74 and safety up to day 127. Immunity to HBV was defined as an anti-Hepatitis B surface antigen (HBS) antibody serum concentration of greater than 10 IU/L and for OCV it was defined as >4-fold increase from the baseline in the combined antibody titre (immunoglobulin (Ig) G, IgM and IgA). HBV seroconversion
Eksteen B. Gut Month 2014 Vol 0 No 1 Copyright Article author (or0 their employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from gut.bmj.com on August 18, 2014 - Published by group.bmj.com
Commentary Figure 1 CD103 gut dendritic cells (DCs) imprint antigen specificity in naive T and B lymphocytes by presentation of antigen on major histocompatibility complex (MHC) to T cell (TCR) and B cell (BCR) receptors and co-stimulatory signals in mesenteric lymph nodes. Production of all-trans retinoic acid by CD103 DCs induces CCR9 and α4β7 expression which allows these newly generated effector T cells and IgA-producing B cells to be selectively recruited to the gut. Expression of the chemokine, CCL25, is restricted to the gut which upon binding to CCR9 activates α4β7 to bind MAdCAM-1 and subsequent recruitment to the lamina propria.
was similar between placebo treated (90.3%) and vedolizumab treated (88.7%) participants. However, the placebo treated group responded better to the OCV with 96.8% responses compared with 82.5% responses in the vedolizumab treated group. Anticholera immunoglobulin levels were higher in the placebo group than the vedolizumab group at day 74 (9210.08 vs 3007.8 units/mL). The data support a selective role for vedolizumab in regional gut immunity and raise questions whether vedolizumab will be associated in the longer term with an excess of gut infections. This has not been brought out in the clinical trials and although in this study there is a reduction in the antibody responses, the majority of the cases were still able to generate sufficient protection from the OCV. It suggests that even at a relatively high dose, vedolizumab is not able to completely abrogate gut humeral responses. This is likely due to redundancy with α4β1 and is an important observation as IBD patients are more prone to gut infections and require appropriate immune responses to control enteric viruses and bacteria. The authors conclude that vedolizumab is able to modulate immune responses in the gut without compromising the host defences. Further clinical data will be required to
2
confirm this observation and will hopefully be generated through the long-term Gemini LTS Safety Study.
3
4
Contributors BE compiled the data and wrote the manuscript. Funding Canadian Institutes for Health Research (CIHR).
5
6
Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.
7
To cite Eksteen B. Gut Published Online First: [ please include Day Month Year] doi:10.1136/gutjnl-2014307397
8
Received 28 May 2014 Revised 30 May 2014 Accepted 2 June 2014
▸ http://dx.doi.org/10.1136/gutjnl-2014-307127
9
10
Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-307397 11
REFERENCES 1
2
Lobaton T, Vermeire S, Van Assche G, et al. Review article: anti-adhesion therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2014;39:579–94. Agace WW. Tissue-tropic effector T cells: generation and targeting opportunities. NatRevImmunol 2006;6:682–92.
Jaensson E, Uronen-Hansson H, Pabst O, et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. JExpMed 2008;205:2139–49. Mora JR, Iwata M, Eksteen B, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006;314:1157–60. Iwata M, Hirakiyama A, Eshima Y, et al. Retinoic Acid imprints gut-homing specificity on T cells. Immunity 2004;21:527–38. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Engl J Med 2003;348:24–32. Podolsky DK, Lobb R, King N, et al. Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonal antibody. JClinInvest 1993;92:372–80. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699–710. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369:711–21. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of Vedolizumab Induction Therapy for Patients With Crohn’s Disease in Whom Tumor Necrosis Factor Antagonist Treatment Had Failed. Gastroenterology 2014. doi:10.1053/j.gastro.2014.05.008 Wyant T, Leach T, Sankoh S, et al. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut Published online first: 24 Apr 2014. doi:10.1136/gutjnl-2014-307127
Eksteen B. Gut Month 2014 Vol 0 No 0
Downloaded from gut.bmj.com on August 18, 2014 - Published by group.bmj.com
Targeting of gut specific leucocyte recruitment in IBD by vedolizumab Bertus Eksteen Gut published online June 19, 2014
doi: 10.1136/gutjnl-2014-307397
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/06/19/gutjnl-2014-307397.full.html
These include:
References
This article cites 9 articles, 2 of which can be accessed free at: http://gut.bmj.com/content/early/2014/06/19/gutjnl-2014-307397.full.html#ref-list-1
P
