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Preclinical research suggests the anticancer agent ibrutinib can ameliorate chronic graft-vs-host disease (GVHD).
Ibrutinib reduced the symptoms and progression of chronic GVHD in mouse models, and it decreased the activation of T and B cells isolated from patients with chronic GVHD.
These results indicate that T and B cells drive chronic GVHD and ibrutinib should be explored as a treatment option for human GVHD, according to investigators.
Bruce Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues described this work in The Journal of Clinical Investigation.
The team noted that CD4+ T cells and B cells mediate chronic GVHD, so it follows that targeting these populations might inhibit chronic GVHD pathogenesis.
As ibrutinib targets Th2 cells and B cells, the investigators decided to test whether the drug could reverse established chronic GVHD in 2 mouse models—a model of T cell–driven sclerodermatous chronic GVHD and an alloantibody-driven, multiorgan-system chronic GVHD model that induces bronchiolar obliterans.
Sclerodermatous chronic GVHD
The researchers first found that ibrutinib can reduce the clinical signs of sclerodermatous chronic GVHD. Fourteen days after treatment began, vehicle-treated mice and those that received cyclosporine exhibited sclerodermatous lesions, hair loss, hunched posture, and scabbing. But ibrutinib-treated mice did not.
Animals treated with ibrutinib had a significantly lower overall intensity of chronic GVHD—as measured by body weight, posture, mobility, hair loss, skin lesions, and vitality—than vehicle-treated mice (P=0.0184).
Ibrutinib also extended the median time to chronic GVHD progression by 14 days when compared to control. Thirty-three percent of ibrutinib-treated mice remained progression-free, compared to 12% of vehicle-treated mice (P<0.02).
Overall survival was 100% among ibrutinib-treated mice, 82% for cyclosporine-treated mice, and 88% for vehicle-treated mice.
The investigators also discovered that prolonged administration of ibrutinib is needed to reap the maximum therapeutic benefit in sclerodermatous chronic GVHD. Withdrawing treatment at day 60 enabled clinical breakthrough of chronic GVHD in a single mouse.
Alloantibody-driven chronic GVHD
In this model, ibrutinib inhibited the development of bronchiolar obliterans, as measured by pulmonary resistance (P=0.0090), elastance (P=0.0019), and compliance (P=0.0071).
In addition, there was less peribroncheolar collagen fibrosis among ibrutinib-treated animals and a significant reduction in pulmonary fibrosis (P<0.0001) compared to vehicle-treated controls.
However, continued therapy was necessary to see a long-term benefit with ibrutinib. Prophylactic ibrutinib given from day -2 to day 28 was not effective against chronic GVHD or bronchiolar obliterans.
Lastly, the investigators found that ibrutinib reduced the overall size, cellularity, and number of germinal center reactions (P<0.001), and the drug eliminated pulmonary immunoglobulin deposition (P<0.001).
Verifying the results
Additional experiments showed that mice lacking Bruton tyrosine kinase and IL-2 inducible T-cell kinase (both of which are inhibited by ibrutinib) did not develop chronic GVHD, which suggests these molecules are necessary for the condition to occur.
The investigators also discovered that ibrutinib reduced the activation of T and B cells from patients with active chronic GVHD.
CD4+ T cells pretreated with ibrutinib had lower surface expression of CD69 after ex vivo T-cell receptor stimulation using anti-CD3 (P=0.033). And purified B cells pretreated with ibrutinib showed lower levels of pBTK-Y223, pPLCγ2-Y1217, and pERK1/2.
Dr Blazar and his colleagues said these results indicate that B cells and T cells drive chronic GVHD and suggest that ibrutinib should be considered for testing in clinical trials of chronic GVHD. 
Preclinical research suggests the anticancer agent ibrutinib can ameliorate chronic graft-vs-host disease (GVHD).
Ibrutinib reduced the symptoms and progression of chronic GVHD in mouse models, and it decreased the activation of T and B cells isolated from patients with chronic GVHD.
These results indicate that T and B cells drive chronic GVHD and ibrutinib should be explored as a treatment option for human GVHD, according to investigators.
Bruce Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues described this work in The Journal of Clinical Investigation.
The team noted that CD4+ T cells and B cells mediate chronic GVHD, so it follows that targeting these populations might inhibit chronic GVHD pathogenesis.
As ibrutinib targets Th2 cells and B cells, the investigators decided to test whether the drug could reverse established chronic GVHD in 2 mouse models—a model of T cell–driven sclerodermatous chronic GVHD and an alloantibody-driven, multiorgan-system chronic GVHD model that induces bronchiolar obliterans.
Sclerodermatous chronic GVHD
The researchers first found that ibrutinib can reduce the clinical signs of sclerodermatous chronic GVHD. Fourteen days after treatment began, vehicle-treated mice and those that received cyclosporine exhibited sclerodermatous lesions, hair loss, hunched posture, and scabbing. But ibrutinib-treated mice did not.
Animals treated with ibrutinib had a significantly lower overall intensity of chronic GVHD—as measured by body weight, posture, mobility, hair loss, skin lesions, and vitality—than vehicle-treated mice (P=0.0184).
Ibrutinib also extended the median time to chronic GVHD progression by 14 days when compared to control. Thirty-three percent of ibrutinib-treated mice remained progression-free, compared to 12% of vehicle-treated mice (P<0.02).
Overall survival was 100% among ibrutinib-treated mice, 82% for cyclosporine-treated mice, and 88% for vehicle-treated mice.
The investigators also discovered that prolonged administration of ibrutinib is needed to reap the maximum therapeutic benefit in sclerodermatous chronic GVHD. Withdrawing treatment at day 60 enabled clinical breakthrough of chronic GVHD in a single mouse.
Alloantibody-driven chronic GVHD
In this model, ibrutinib inhibited the development of bronchiolar obliterans, as measured by pulmonary resistance (P=0.0090), elastance (P=0.0019), and compliance (P=0.0071).
In addition, there was less peribroncheolar collagen fibrosis among ibrutinib-treated animals and a significant reduction in pulmonary fibrosis (P<0.0001) compared to vehicle-treated controls.
However, continued therapy was necessary to see a long-term benefit with ibrutinib. Prophylactic ibrutinib given from day -2 to day 28 was not effective against chronic GVHD or bronchiolar obliterans.
Lastly, the investigators found that ibrutinib reduced the overall size, cellularity, and number of germinal center reactions (P<0.001), and the drug eliminated pulmonary immunoglobulin deposition (P<0.001).
Verifying the results
Additional experiments showed that mice lacking Bruton tyrosine kinase and IL-2 inducible T-cell kinase (both of which are inhibited by ibrutinib) did not develop chronic GVHD, which suggests these molecules are necessary for the condition to occur.
The investigators also discovered that ibrutinib reduced the activation of T and B cells from patients with active chronic GVHD.
CD4+ T cells pretreated with ibrutinib had lower surface expression of CD69 after ex vivo T-cell receptor stimulation using anti-CD3 (P=0.033). And purified B cells pretreated with ibrutinib showed lower levels of pBTK-Y223, pPLCγ2-Y1217, and pERK1/2.
Dr Blazar and his colleagues said these results indicate that B cells and T cells drive chronic GVHD and suggest that ibrutinib should be considered for testing in clinical trials of chronic GVHD.
Preclinical research suggests the anticancer agent ibrutinib can ameliorate chronic graft-vs-host disease (GVHD).
Ibrutinib reduced the symptoms and progression of chronic GVHD in mouse models, and it decreased the activation of T and B cells isolated from patients with chronic GVHD.
These results indicate that T and B cells drive chronic GVHD and ibrutinib should be explored as a treatment option for human GVHD, according to investigators.
Bruce Blazar, MD, of the University of Minnesota in Minneapolis, and his colleagues described this work in The Journal of Clinical Investigation.
The team noted that CD4+ T cells and B cells mediate chronic GVHD, so it follows that targeting these populations might inhibit chronic GVHD pathogenesis.
As ibrutinib targets Th2 cells and B cells, the investigators decided to test whether the drug could reverse established chronic GVHD in 2 mouse models—a model of T cell–driven sclerodermatous chronic GVHD and an alloantibody-driven, multiorgan-system chronic GVHD model that induces bronchiolar obliterans.
Sclerodermatous chronic GVHD
The researchers first found that ibrutinib can reduce the clinical signs of sclerodermatous chronic GVHD. Fourteen days after treatment began, vehicle-treated mice and those that received cyclosporine exhibited sclerodermatous lesions, hair loss, hunched posture, and scabbing. But ibrutinib-treated mice did not.
Animals treated with ibrutinib had a significantly lower overall intensity of chronic GVHD—as measured by body weight, posture, mobility, hair loss, skin lesions, and vitality—than vehicle-treated mice (P=0.0184).
Ibrutinib also extended the median time to chronic GVHD progression by 14 days when compared to control. Thirty-three percent of ibrutinib-treated mice remained progression-free, compared to 12% of vehicle-treated mice (P<0.02).
Overall survival was 100% among ibrutinib-treated mice, 82% for cyclosporine-treated mice, and 88% for vehicle-treated mice.
The investigators also discovered that prolonged administration of ibrutinib is needed to reap the maximum therapeutic benefit in sclerodermatous chronic GVHD. Withdrawing treatment at day 60 enabled clinical breakthrough of chronic GVHD in a single mouse.
Alloantibody-driven chronic GVHD
In this model, ibrutinib inhibited the development of bronchiolar obliterans, as measured by pulmonary resistance (P=0.0090), elastance (P=0.0019), and compliance (P=0.0071).
In addition, there was less peribroncheolar collagen fibrosis among ibrutinib-treated animals and a significant reduction in pulmonary fibrosis (P<0.0001) compared to vehicle-treated controls.
However, continued therapy was necessary to see a long-term benefit with ibrutinib. Prophylactic ibrutinib given from day -2 to day 28 was not effective against chronic GVHD or bronchiolar obliterans.
Lastly, the investigators found that ibrutinib reduced the overall size, cellularity, and number of germinal center reactions (P<0.001), and the drug eliminated pulmonary immunoglobulin deposition (P<0.001).
Verifying the results
Additional experiments showed that mice lacking Bruton tyrosine kinase and IL-2 inducible T-cell kinase (both of which are inhibited by ibrutinib) did not develop chronic GVHD, which suggests these molecules are necessary for the condition to occur.
The investigators also discovered that ibrutinib reduced the activation of T and B cells from patients with active chronic GVHD.
CD4+ T cells pretreated with ibrutinib had lower surface expression of CD69 after ex vivo T-cell receptor stimulation using anti-CD3 (P=0.033). And purified B cells pretreated with ibrutinib showed lower levels of pBTK-Y223, pPLCγ2-Y1217, and pERK1/2.
Dr Blazar and his colleagues said these results indicate that B cells and T cells drive chronic GVHD and suggest that ibrutinib should be considered for testing in clinical trials of chronic GVHD.