Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma
Background In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with a...
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2023-01-01
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| author | Li Zhang Matthew Crocker Lawrence Fong Lisa M Coussens Charles D Lopez Shamilene Sivagnanam Meenal Sinha Brandon Chen Jaqueline Marquez Alexander Cheung Whitney Tamaki Jacob Stultz Kendra Todd Courtney Betts Madeline J Griffith Isabelle Solman Eric Liu Denise Pener Anne Fahlman Erin Taber Kimberly Lerner Brindha Rajagopalan Clarisha Ware Mark Bridge Johnson Vo Hannah Dragomanovich Julie Sudduth-Klinger Gina Vaccaro Margaret Tempero |
| author_facet | Li Zhang Matthew Crocker Lawrence Fong Lisa M Coussens Charles D Lopez Shamilene Sivagnanam Meenal Sinha Brandon Chen Jaqueline Marquez Alexander Cheung Whitney Tamaki Jacob Stultz Kendra Todd Courtney Betts Madeline J Griffith Isabelle Solman Eric Liu Denise Pener Anne Fahlman Erin Taber Kimberly Lerner Brindha Rajagopalan Clarisha Ware Mark Bridge Johnson Vo Hannah Dragomanovich Julie Sudduth-Klinger Gina Vaccaro Margaret Tempero |
| author_sort | Li Zhang |
| collection | DOAJ |
| description | Background In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.Methods Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality.Results In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1–) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation.Conclusion Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors.Trial registration number NCT02562898. |
| format | Article |
| id | doaj-art-f2e879165f87473d90582730476b150c |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-f2e879165f87473d90582730476b150c2025-01-29T10:10:12ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005425Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinomaLi Zhang0Matthew Crocker1Lawrence Fong2Lisa M Coussens3Charles D Lopez4Shamilene Sivagnanam5Meenal Sinha6Brandon Chen7Jaqueline Marquez8Alexander Cheung9Whitney Tamaki10Jacob Stultz11Kendra Todd12Courtney Betts13Madeline J Griffith14Isabelle Solman15Eric Liu16Denise Pener17Anne Fahlman18Erin Taber19Kimberly Lerner20Brindha Rajagopalan21Clarisha Ware22Mark Bridge23Johnson Vo24Hannah Dragomanovich25Julie Sudduth-Klinger26Gina Vaccaro27Margaret Tempero28Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, ChinaDepartment of Medicine, Oregon Health & Science University, Portland, Oregon, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USAAff1 grid.5288.70000000097585690Oregon Health & Science University Portland OR USA8 Department of Oncology, School of Medicine, Oregon Health and Science University Foundation, Portland, Oregon, USAOregon Health and Science University, Portland, OR, USADivision of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California, USA1University of California San Francisco, San Francisco, CA, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USADivision of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California, USADivision of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California, USASchool of Health and Exercise Sciences, The University of British Columbia, Kelowna, British Columbia, CanadaDepartment of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USAAbbVie, Irvine, California, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USADepartment of Medicine, Oregon Health & Science University, Portland, Oregon, USADepartment of Medicine, Oregon Health & Science University, Portland, Oregon, USADepartment of Medicine, Oregon Health & Science University, Portland, Oregon, USADepartment of Medicine, Oregon Health & Science University, Portland, Oregon, USADepartment of Medicine, Oregon Health & Science University, Portland, Oregon, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USADepartment of Medicine, Oregon Health & Science University, Portland, Oregon, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USAMedical Oncology, Providence Portland Medical Center, Portland, Oregon, USADivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USABackground In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.Methods Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality.Results In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1–) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation.Conclusion Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors.Trial registration number NCT02562898.https://jitc.bmj.com/content/11/1/e005425.full |
| spellingShingle | Li Zhang Matthew Crocker Lawrence Fong Lisa M Coussens Charles D Lopez Shamilene Sivagnanam Meenal Sinha Brandon Chen Jaqueline Marquez Alexander Cheung Whitney Tamaki Jacob Stultz Kendra Todd Courtney Betts Madeline J Griffith Isabelle Solman Eric Liu Denise Pener Anne Fahlman Erin Taber Kimberly Lerner Brindha Rajagopalan Clarisha Ware Mark Bridge Johnson Vo Hannah Dragomanovich Julie Sudduth-Klinger Gina Vaccaro Margaret Tempero Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma Journal for ImmunoTherapy of Cancer |
| title | Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma |
| title_full | Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma |
| title_fullStr | Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma |
| title_full_unstemmed | Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma |
| title_short | Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma |
| title_sort | modulation of myeloid and t cells in vivo by bruton s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma |
| url | https://jitc.bmj.com/content/11/1/e005425.full |
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