Ibrutinib preserves immune memory while fighting cGVHD

 

SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.

The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.

Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).

In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.

The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.

“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.

 

The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.

Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.

The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.

Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127^dim Treg cells saw depletion.

 

Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.

“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.

In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.

“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.

 

Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.

“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.

Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.

Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.

koakes@mdedge.com

SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.

 

SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.

The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.

Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).

In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.

The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.

“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.

 

The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.

Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.

The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.

Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127^dim Treg cells saw depletion.

 

Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.

“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.

In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.

“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.

 

Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.

“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.

Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.

Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.

koakes@mdedge.com

SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.

 

SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.

The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.

Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).

In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.

The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.

“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.

 

The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.

Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.

The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.

Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127^dim Treg cells saw depletion.

 

Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.

“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.

In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.

“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.

 

Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.

“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.

Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.

Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.

koakes@mdedge.com

SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.