PT - JOURNAL ARTICLE AU - Meenal Sinha AU - Courtney Betts AU - Li Zhang AU - Madeline J Griffith AU - Isabelle Solman AU - Brandon Chen AU - Eric Liu AU - Whitney Tamaki AU - Jacob Stultz AU - Jaqueline Marquez AU - Shamilene Sivagnanam AU - Alexander Cheung AU - Denise Pener AU - Anne Fahlman AU - Erin Taber AU - Kimberly Lerner AU - Matthew Crocker AU - Kendra Todd AU - Brindha Rajagopalan AU - Clarisha Ware AU - Mark Bridge AU - Johnson Vo AU - Hannah Dragomanovich AU - Julie Sudduth-Klinger AU - Gina Vaccaro AU - Charles D Lopez AU - Margaret Tempero AU - Lisa M Coussens AU - Lawrence Fong TI - Modulation of myeloid and T cells in vivo by Bruton’s tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma AID - 10.1136/jitc-2022-005425 DP - 2023 Jan 01 TA - Journal for ImmunoTherapy of Cancer PG - e005425 VI - 11 IP - 1 4099 - http://jitc.bmj.com/content/11/1/e005425.short 4100 - http://jitc.bmj.com/content/11/1/e005425.full SO - J Immunother Cancer2023 Jan 01; 11 AB - 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.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Mass cytometry data will be shared publicly on Flow Repository while R-based analysis codes will be made publicly available on GitHub upon request. No novel materials were generated as part of this study.